Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes
Identifieur interne : 000527 ( Pmc/Corpus ); précédent : 000526; suivant : 000528Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes
Auteurs : Alexander Teumer ; Adrienne Tin ; Rossella Sorice ; Mathias Gorski ; Nan Cher Yeo ; Audrey Y. Chu ; Man Li ; Yong Li ; Vladan Mijatovic ; Yi-An Ko ; Daniel Taliun ; Alessandro Luciani ; Ming-Huei Chen ; Qiong Yang ; Meredith C. Foster ; Matthias Olden ; Linda T. Hiraki ; Bamidele O. Tayo ; Christian Fuchsberger ; Aida Karina Dieffenbach ; Alan R. Shuldiner ; Albert V. Smith ; Allison M. Zappa ; Antonio Lupo ; Barbara Kollerits ; Belen Ponte ; Bénédicte Stengel ; Bernhard K. Kr Mer ; Bernhard Paulweber ; Braxton D. Mitchell ; Caroline Hayward ; Catherine Helmer ; Christa Meisinger ; Christian Gieger ; Christian M. Shaffer ; Christian Müller ; Claudia Langenberg ; Daniel Ackermann ; David Siscovick ; Eric Boerwinkle ; Florian Kronenberg ; Georg B. Ehret ; Georg Homuth ; Gerard Waeber ; Gerjan Navis ; Giovanni Gambaro ; Giovanni Malerba ; Gudny Eiriksdottir ; Guo Li ; H. Erich Wichmann ; Harald Grallert ; Henri Wallaschofski ; Henry Völzke ; Herrmann Brenner ; Holly Kramer ; I. Mateo Leach ; Igor Rudan ; Hans L. Hillege ; Jacques S. Beckmann ; Jean Charles Lambert ; Jian'An Luan ; Jing Hua Zhao ; John Chalmers ; Josef Coresh ; Joshua C. Denny ; Katja Butterbach ; Lenore J. Launer ; Luigi Ferrucci ; Lyudmyla Kedenko ; Margot Haun ; Marie Metzger ; Mark Woodward ; Matthew J. Hoffman ; Matthias Nauck ; Melanie Waldenberger ; Menno Pruijm ; Murielle Bochud ; Myriam Rheinberger ; Niek Verweij ; Nicholas J. Wareham ; Nicole Endlich ; Nicole Soranzo ; Ozren Polasek ; Pim Van Der Harst ; Peter Paul Pramstaller ; Peter Vollenweider ; Philipp S. Wild ; Ron T. Gansevoort ; Rainer Rettig ; Reiner Biffar ; Robert J. Carroll ; Ronit Katz ; Ruth J. F. Loos ; Shih-Jen Hwang ; Stefan Coassin ; Sven Bergmann ; Sylvia E. Rosas ; Sylvia Stracke ; Tamara B. Harris ; Tanguy Corre ; Tanja Zeller ; Thomas Illig ; Thor Aspelund ; Toshiko Tanaka ; Uwe Lendeckel ; Uwe Völker ; Vilmundur Gudnason ; Vincent Chouraki ; Wolfgang Koenig ; Zoltan Kutalik ; Jeffrey R. O'Connell ; Afshin Parsa ; Iris M. Heid ; Andrew D. Paterson ; Ian H. De Boer ; Olivier Devuyst ; Jozef Lazar ; Karlhans Endlich ; Katalin Susztak ; Johanne Tremblay ; Pavel Hamet ; Howard J. Jacob ; Carsten A. Böger ; Caroline S. Fox ; Cristian Pattaro ; Anna KöttgenSource :
- Diabetes [ 0012-1797 ] ; 2015.
Abstract
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in
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DOI: 10.2337/db15-1313
PubMed: 26631737
PubMed Central: 4764151
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes</title><author><name sortKey="Teumer, Alexander" sort="Teumer, Alexander" uniqKey="Teumer A" first="Alexander" last="Teumer">Alexander Teumer</name><affiliation><nlm:aff id="aff1">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Tin, Adrienne" sort="Tin, Adrienne" uniqKey="Tin A" first="Adrienne" last="Tin">Adrienne Tin</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Sorice, Rossella" sort="Sorice, Rossella" uniqKey="Sorice R" first="Rossella" last="Sorice">Rossella Sorice</name><affiliation><nlm:aff id="aff4">Institute of Genetics and Biophysics, “Adriano-Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples, Italy</nlm:aff></affiliation></author><author><name sortKey="Gorski, Mathias" sort="Gorski, Mathias" uniqKey="Gorski M" first="Mathias" last="Gorski">Mathias Gorski</name><affiliation><nlm:aff id="aff5">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Department of Nephrology, University Hospital Regensburg, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Yeo, Nan Cher" sort="Yeo, Nan Cher" uniqKey="Yeo N" first="Nan Cher" last="Yeo">Nan Cher Yeo</name><affiliation><nlm:aff id="aff7">Department of Physiology, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Chu, Audrey Y" sort="Chu, Audrey Y" uniqKey="Chu A" first="Audrey Y." last="Chu">Audrey Y. Chu</name><affiliation><nlm:aff id="aff8">Preventive Medicine, Brigham and Women's Hospital, Boston, MA</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA</nlm:aff></affiliation></author><author><name sortKey="Li, Man" sort="Li, Man" uniqKey="Li M" first="Man" last="Li">Man Li</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Li, Yong" sort="Li, Yong" uniqKey="Li Y" first="Yong" last="Li">Yong Li</name><affiliation><nlm:aff id="aff10">Renal Division, Medical Center, University of Freiburg, Freiburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Mijatovic, Vladan" sort="Mijatovic, Vladan" uniqKey="Mijatovic V" first="Vladan" last="Mijatovic">Vladan Mijatovic</name><affiliation><nlm:aff id="aff11">Department of Life and Reproduction Sciences, University of Verona, Verona, Italy</nlm:aff></affiliation></author><author><name sortKey="Ko, Yi An" sort="Ko, Yi An" uniqKey="Ko Y" first="Yi-An" last="Ko">Yi-An Ko</name><affiliation><nlm:aff id="aff12">Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Taliun, Daniel" sort="Taliun, Daniel" uniqKey="Taliun D" first="Daniel" last="Taliun">Daniel Taliun</name><affiliation><nlm:aff id="aff13">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Luciani, Alessandro" sort="Luciani, Alessandro" uniqKey="Luciani A" first="Alessandro" last="Luciani">Alessandro Luciani</name><affiliation><nlm:aff id="aff14">Institute of Physiology, Mechanisms of Inherited Kidney Disorders Group, University of Zürich, Zürich, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Chen, Ming Huei" sort="Chen, Ming Huei" uniqKey="Chen M" first="Ming-Huei" last="Chen">Ming-Huei Chen</name><affiliation><nlm:aff id="aff15">Department of Neurology, Boston University School of Medicine, Boston, MA</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Department of Biostatistics, Boston University School of Public Health, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Yang, Qiong" sort="Yang, Qiong" uniqKey="Yang Q" first="Qiong" last="Yang">Qiong Yang</name><affiliation><nlm:aff id="aff16">Department of Biostatistics, Boston University School of Public Health, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Foster, Meredith C" sort="Foster, Meredith C" uniqKey="Foster M" first="Meredith C." last="Foster">Meredith C. Foster</name><affiliation><nlm:aff id="aff17">Tufts Medical Center, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Olden, Matthias" sort="Olden, Matthias" uniqKey="Olden M" first="Matthias" last="Olden">Matthias Olden</name><affiliation><nlm:aff id="aff5">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff18">Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Hiraki, Linda T" sort="Hiraki, Linda T" uniqKey="Hiraki L" first="Linda T." last="Hiraki">Linda T. Hiraki</name><affiliation><nlm:aff id="aff19">Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="Tayo, Bamidele O" sort="Tayo, Bamidele O" uniqKey="Tayo B" first="Bamidele O." last="Tayo">Bamidele O. Tayo</name><affiliation><nlm:aff id="aff20">Loyola University Chicago, Maywood, IL</nlm:aff></affiliation></author><author><name sortKey="Fuchsberger, Christian" sort="Fuchsberger, Christian" uniqKey="Fuchsberger C" first="Christian" last="Fuchsberger">Christian Fuchsberger</name><affiliation><nlm:aff id="aff13">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Dieffenbach, Aida Karina" sort="Dieffenbach, Aida Karina" uniqKey="Dieffenbach A" first="Aida Karina" last="Dieffenbach">Aida Karina Dieffenbach</name><affiliation><nlm:aff id="aff21">Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Shuldiner, Alan R" sort="Shuldiner, Alan R" uniqKey="Shuldiner A" first="Alan R." last="Shuldiner">Alan R. Shuldiner</name><affiliation><nlm:aff id="aff23">Department of Medicine, University of Maryland School of Medicine, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Smith, Albert V" sort="Smith, Albert V" uniqKey="Smith A" first="Albert V." last="Smith">Albert V. Smith</name><affiliation><nlm:aff id="aff24">Icelandic Heart Association, Kópavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="aff25">Faculty of Medicine, University of Iceland, Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Zappa, Allison M" sort="Zappa, Allison M" uniqKey="Zappa A" first="Allison M." last="Zappa">Allison M. Zappa</name><affiliation><nlm:aff id="aff26">Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Lupo, Antonio" sort="Lupo, Antonio" uniqKey="Lupo A" first="Antonio" last="Lupo">Antonio Lupo</name><affiliation><nlm:aff id="aff27">Renal Unit, Department of Medicine, University of Verona, Verona, Italy</nlm:aff></affiliation></author><author><name sortKey="Kollerits, Barbara" sort="Kollerits, Barbara" uniqKey="Kollerits B" first="Barbara" last="Kollerits">Barbara Kollerits</name><affiliation><nlm:aff id="aff28">Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Ponte, Belen" sort="Ponte, Belen" uniqKey="Ponte B" first="Belen" last="Ponte">Belen Ponte</name><affiliation><nlm:aff id="aff29">Nephrology Division, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Stengel, Benedicte" sort="Stengel, Benedicte" uniqKey="Stengel B" first="Bénédicte" last="Stengel">Bénédicte Stengel</name><affiliation><nlm:aff id="aff30">INSERM U-1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Villejuif, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">UMRS 1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Univ Paris Sud, Univ Versailles, St. Quentin, France</nlm:aff></affiliation></author><author><name sortKey="Kr Mer, Bernhard K" sort="Kr Mer, Bernhard K" uniqKey="Kr Mer B" first="Bernhard K." last="Kr Mer">Bernhard K. Kr Mer</name><affiliation><nlm:aff id="aff32">Fifth Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany</nlm:aff></affiliation></author><author><name sortKey="Paulweber, Bernhard" sort="Paulweber, Bernhard" uniqKey="Paulweber B" first="Bernhard" last="Paulweber">Bernhard Paulweber</name><affiliation><nlm:aff id="aff33">First Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria</nlm:aff></affiliation></author><author><name sortKey="Mitchell, Braxton D" sort="Mitchell, Braxton D" uniqKey="Mitchell B" first="Braxton D." last="Mitchell">Braxton D. Mitchell</name><affiliation><nlm:aff id="aff23">Department of Medicine, University of Maryland School of Medicine, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Hayward, Caroline" sort="Hayward, Caroline" uniqKey="Hayward C" first="Caroline" last="Hayward">Caroline Hayward</name><affiliation><nlm:aff id="aff34">Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, U.K.</nlm:aff></affiliation></author><author><name sortKey="Helmer, Catherine" sort="Helmer, Catherine" uniqKey="Helmer C" first="Catherine" last="Helmer">Catherine Helmer</name><affiliation><nlm:aff id="aff35">INSERM U897, Bordeaux University, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Bordeaux, France</nlm:aff></affiliation></author><author><name sortKey="Meisinger, Christa" sort="Meisinger, Christa" uniqKey="Meisinger C" first="Christa" last="Meisinger">Christa Meisinger</name><affiliation><nlm:aff id="aff36">Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Gieger, Christian" sort="Gieger, Christian" uniqKey="Gieger C" first="Christian" last="Gieger">Christian Gieger</name><affiliation><nlm:aff id="aff37">Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Shaffer, Christian M" sort="Shaffer, Christian M" uniqKey="Shaffer C" first="Christian M." last="Shaffer">Christian M. Shaffer</name><affiliation><nlm:aff id="aff38">Vanderbilt University School of Medicine, Nashville, TN</nlm:aff></affiliation></author><author><name sortKey="Muller, Christian" sort="Muller, Christian" uniqKey="Muller C" first="Christian" last="Müller">Christian Müller</name><affiliation><nlm:aff id="aff39">University Heart Center Hamburg, Hamburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff40">German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Langenberg, Claudia" sort="Langenberg, Claudia" uniqKey="Langenberg C" first="Claudia" last="Langenberg">Claudia Langenberg</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Ackermann, Daniel" sort="Ackermann, Daniel" uniqKey="Ackermann D" first="Daniel" last="Ackermann">Daniel Ackermann</name><affiliation><nlm:aff id="aff42">University Clinic for Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Siscovick, David" sort="Siscovick, David" uniqKey="Siscovick D" first="David" last="Siscovick">David Siscovick</name><affiliation><nlm:aff id="aff43">Cardiovascular Health Research Unit, Departments of Epidemiology and Medicine, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Boerwinkle, Eric" sort="Boerwinkle, Eric" uniqKey="Boerwinkle E" first="Eric" last="Boerwinkle">Eric Boerwinkle</name><affiliation><nlm:aff id="aff45">Human Genetics Center, University of Texas Health Science Center, Houston, TX</nlm:aff></affiliation></author><author><name sortKey="Kronenberg, Florian" sort="Kronenberg, Florian" uniqKey="Kronenberg F" first="Florian" last="Kronenberg">Florian Kronenberg</name><affiliation><nlm:aff id="aff28">Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Ehret, Georg B" sort="Ehret, Georg B" uniqKey="Ehret G" first="Georg B." last="Ehret">Georg B. Ehret</name><affiliation><nlm:aff id="aff46">Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Homuth, Georg" sort="Homuth, Georg" uniqKey="Homuth G" first="Georg" last="Homuth">Georg Homuth</name><affiliation><nlm:aff id="aff47">Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Waeber, Gerard" sort="Waeber, Gerard" uniqKey="Waeber G" first="Gerard" last="Waeber">Gerard Waeber</name><affiliation><nlm:aff id="aff48">Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Navis, Gerjan" sort="Navis, Gerjan" uniqKey="Navis G" first="Gerjan" last="Navis">Gerjan Navis</name><affiliation><nlm:aff id="aff49">Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Gambaro, Giovanni" sort="Gambaro, Giovanni" uniqKey="Gambaro G" first="Giovanni" last="Gambaro">Giovanni Gambaro</name><affiliation><nlm:aff id="aff50">Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Malerba, Giovanni" sort="Malerba, Giovanni" uniqKey="Malerba G" first="Giovanni" last="Malerba">Giovanni Malerba</name><affiliation><nlm:aff id="aff11">Department of Life and Reproduction Sciences, University of Verona, Verona, Italy</nlm:aff></affiliation></author><author><name sortKey="Eiriksdottir, Gudny" sort="Eiriksdottir, Gudny" uniqKey="Eiriksdottir G" first="Gudny" last="Eiriksdottir">Gudny Eiriksdottir</name><affiliation><nlm:aff id="aff24">Icelandic Heart Association, Kópavogur, Iceland</nlm:aff></affiliation></author><author><name sortKey="Li, Guo" sort="Li, Guo" uniqKey="Li G" first="Guo" last="Li">Guo Li</name><affiliation><nlm:aff id="aff43">Cardiovascular Health Research Unit, Departments of Epidemiology and Medicine, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Wichmann, H Erich" sort="Wichmann, H Erich" uniqKey="Wichmann H" first="H. Erich" last="Wichmann">H. Erich Wichmann</name><affiliation><nlm:aff id="aff51">Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff52">Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff53">Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Grallert, Harald" sort="Grallert, Harald" uniqKey="Grallert H" first="Harald" last="Grallert">Harald Grallert</name><affiliation><nlm:aff id="aff36">Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff54">Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff55">German Center for Diabetes Research (DZD), Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Wallaschofski, Henri" sort="Wallaschofski, Henri" uniqKey="Wallaschofski H" first="Henri" last="Wallaschofski">Henri Wallaschofski</name><affiliation><nlm:aff id="aff56">Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volzke, Henry" sort="Volzke, Henry" uniqKey="Volzke H" first="Henry" last="Völzke">Henry Völzke</name><affiliation><nlm:aff id="aff1">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Brenner, Herrmann" sort="Brenner, Herrmann" uniqKey="Brenner H" first="Herrmann" last="Brenner">Herrmann Brenner</name><affiliation><nlm:aff id="aff21">Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Kramer, Holly" sort="Kramer, Holly" uniqKey="Kramer H" first="Holly" last="Kramer">Holly Kramer</name><affiliation><nlm:aff id="aff20">Loyola University Chicago, Maywood, IL</nlm:aff></affiliation></author><author><name sortKey="Leach, I Mateo" sort="Leach, I Mateo" uniqKey="Leach I" first="I. Mateo" last="Leach">I. Mateo Leach</name><affiliation><nlm:aff id="aff57">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rudan, Igor" sort="Rudan, Igor" uniqKey="Rudan I" first="Igor" last="Rudan">Igor Rudan</name><affiliation><nlm:aff id="aff58">Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.</nlm:aff></affiliation></author><author><name sortKey="Hillege, Hans L" sort="Hillege, Hans L" uniqKey="Hillege H" first="Hans L." last="Hillege">Hans L. Hillege</name><affiliation><nlm:aff id="aff59">Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Beckmann, Jacques S" sort="Beckmann, Jacques S" uniqKey="Beckmann J" first="Jacques S." last="Beckmann">Jacques S. Beckmann</name><affiliation><nlm:aff id="aff60">Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="aff61">Swiss Institute of Bioinformatics, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean Charles" last="Lambert">Jean Charles Lambert</name><affiliation><nlm:aff id="aff62">INSERM UMR 1167 “Risk factors and molecular determinants of aging-related diseases,” Institut Pasteur de Lille, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Luan, Jian An" sort="Luan, Jian An" uniqKey="Luan J" first="Jian'An" last="Luan">Jian'An Luan</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Zhao, Jing Hua" sort="Zhao, Jing Hua" uniqKey="Zhao J" first="Jing Hua" last="Zhao">Jing Hua Zhao</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Chalmers, John" sort="Chalmers, John" uniqKey="Chalmers J" first="John" last="Chalmers">John Chalmers</name><affiliation><nlm:aff id="aff63">The George Institute for Global Health, University of Sydney, Camperdown, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Coresh, Josef" sort="Coresh, Josef" uniqKey="Coresh J" first="Josef" last="Coresh">Josef Coresh</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation><affiliation><nlm:aff id="aff64">Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Denny, Joshua C" sort="Denny, Joshua C" uniqKey="Denny J" first="Joshua C." last="Denny">Joshua C. Denny</name><affiliation><nlm:aff id="aff65">Vanderbilt University School of Medicine, Nashville, TN</nlm:aff></affiliation></author><author><name sortKey="Butterbach, Katja" sort="Butterbach, Katja" uniqKey="Butterbach K" first="Katja" last="Butterbach">Katja Butterbach</name><affiliation><nlm:aff id="aff21">Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Launer, Lenore J" sort="Launer, Lenore J" uniqKey="Launer L" first="Lenore J." last="Launer">Lenore J. Launer</name><affiliation><nlm:aff id="aff66">Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD</nlm:aff></affiliation></author><author><name sortKey="Ferrucci, Luigi" sort="Ferrucci, Luigi" uniqKey="Ferrucci L" first="Luigi" last="Ferrucci">Luigi Ferrucci</name><affiliation><nlm:aff id="aff67">Clinical Research Branch, National Institute on Aging, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Kedenko, Lyudmyla" sort="Kedenko, Lyudmyla" uniqKey="Kedenko L" first="Lyudmyla" last="Kedenko">Lyudmyla Kedenko</name><affiliation><nlm:aff id="aff33">First Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria</nlm:aff></affiliation></author><author><name sortKey="Haun, Margot" sort="Haun, Margot" uniqKey="Haun M" first="Margot" last="Haun">Margot Haun</name><affiliation><nlm:aff id="aff28">Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Metzger, Marie" sort="Metzger, Marie" uniqKey="Metzger M" first="Marie" last="Metzger">Marie Metzger</name><affiliation><nlm:aff id="aff30">INSERM U-1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Villejuif, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">UMRS 1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Univ Paris Sud, Univ Versailles, St. Quentin, France</nlm:aff></affiliation></author><author><name sortKey="Woodward, Mark" sort="Woodward, Mark" uniqKey="Woodward M" first="Mark" last="Woodward">Mark Woodward</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation><affiliation><nlm:aff id="aff63">The George Institute for Global Health, University of Sydney, Camperdown, New South Wales, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff68">The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.</nlm:aff></affiliation></author><author><name sortKey="Hoffman, Matthew J" sort="Hoffman, Matthew J" uniqKey="Hoffman M" first="Matthew J." last="Hoffman">Matthew J. Hoffman</name><affiliation><nlm:aff id="aff7">Department of Physiology, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Nauck, Matthias" sort="Nauck, Matthias" uniqKey="Nauck M" first="Matthias" last="Nauck">Matthias Nauck</name><affiliation><nlm:aff id="aff2">German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff56">Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Waldenberger, Melanie" sort="Waldenberger, Melanie" uniqKey="Waldenberger M" first="Melanie" last="Waldenberger">Melanie Waldenberger</name><affiliation><nlm:aff id="aff36">Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Pruijm, Menno" sort="Pruijm, Menno" uniqKey="Pruijm M" first="Menno" last="Pruijm">Menno Pruijm</name><affiliation><nlm:aff id="aff69">Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Bochud, Murielle" sort="Bochud, Murielle" uniqKey="Bochud M" first="Murielle" last="Bochud">Murielle Bochud</name><affiliation><nlm:aff id="aff70">University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Épalinges, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Rheinberger, Myriam" sort="Rheinberger, Myriam" uniqKey="Rheinberger M" first="Myriam" last="Rheinberger">Myriam Rheinberger</name><affiliation><nlm:aff id="aff71">Department of Nephrology, University Hospital Regensburg, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Verweij, Niek" sort="Verweij, Niek" uniqKey="Verweij N" first="Niek" last="Verweij">Niek Verweij</name><affiliation><nlm:aff id="aff57">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Wareham, Nicholas J" sort="Wareham, Nicholas J" uniqKey="Wareham N" first="Nicholas J." last="Wareham">Nicholas J. Wareham</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Endlich, Nicole" sort="Endlich, Nicole" uniqKey="Endlich N" first="Nicole" last="Endlich">Nicole Endlich</name><affiliation><nlm:aff id="aff72">Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Soranzo, Nicole" sort="Soranzo, Nicole" uniqKey="Soranzo N" first="Nicole" last="Soranzo">Nicole Soranzo</name><affiliation><nlm:aff id="aff73">Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.</nlm:aff></affiliation><affiliation><nlm:aff id="aff74">Department of Haematology, University of Cambridge, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Polasek, Ozren" sort="Polasek, Ozren" uniqKey="Polasek O" first="Ozren" last="Polasek">Ozren Polasek</name><affiliation><nlm:aff id="aff75">Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split, Croatia</nlm:aff></affiliation></author><author><name sortKey="Van Der Harst, Pim" sort="Van Der Harst, Pim" uniqKey="Van Der Harst P" first="Pim" last="Van Der Harst">Pim Van Der Harst</name><affiliation><nlm:aff id="aff59">Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Pramstaller, Peter Paul" sort="Pramstaller, Peter Paul" uniqKey="Pramstaller P" first="Peter Paul" last="Pramstaller">Peter Paul Pramstaller</name><affiliation><nlm:aff id="aff13">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Vollenweider, Peter" sort="Vollenweider, Peter" uniqKey="Vollenweider P" first="Peter" last="Vollenweider">Peter Vollenweider</name><affiliation><nlm:aff id="aff48">Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Wild, Philipp S" sort="Wild, Philipp S" uniqKey="Wild P" first="Philipp S." last="Wild">Philipp S. Wild</name><affiliation><nlm:aff id="aff76">Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff77">Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff78">German Center for Cardiovascular Research (DZHK), Mainz, Germany</nlm:aff></affiliation></author><author><name sortKey="Gansevoort, Ron T" sort="Gansevoort, Ron T" uniqKey="Gansevoort R" first="Ron T." last="Gansevoort">Ron T. Gansevoort</name><affiliation><nlm:aff id="aff59">Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rettig, Rainer" sort="Rettig, Rainer" uniqKey="Rettig R" first="Rainer" last="Rettig">Rainer Rettig</name><affiliation><nlm:aff id="aff79">Institute of Physiology, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Biffar, Reiner" sort="Biffar, Reiner" uniqKey="Biffar R" first="Reiner" last="Biffar">Reiner Biffar</name><affiliation><nlm:aff id="aff80">Clinic for Prosthetic Dentistry, Gerostomatology and Material Science, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Carroll, Robert J" sort="Carroll, Robert J" uniqKey="Carroll R" first="Robert J." last="Carroll">Robert J. Carroll</name><affiliation><nlm:aff id="aff65">Vanderbilt University School of Medicine, Nashville, TN</nlm:aff></affiliation></author><author><name sortKey="Katz, Ronit" sort="Katz, Ronit" uniqKey="Katz R" first="Ronit" last="Katz">Ronit Katz</name><affiliation><nlm:aff id="aff81">Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Loos, Ruth J F" sort="Loos, Ruth J F" uniqKey="Loos R" first="Ruth J. F." last="Loos">Ruth J. F. Loos</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation><affiliation><nlm:aff id="aff82">Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY</nlm:aff></affiliation></author><author><name sortKey="Hwang, Shih Jen" sort="Hwang, Shih Jen" uniqKey="Hwang S" first="Shih-Jen" last="Hwang">Shih-Jen Hwang</name><affiliation><nlm:aff id="aff9">National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA</nlm:aff></affiliation></author><author><name sortKey="Coassin, Stefan" sort="Coassin, Stefan" uniqKey="Coassin S" first="Stefan" last="Coassin">Stefan Coassin</name><affiliation><nlm:aff id="aff28">Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Bergmann, Sven" sort="Bergmann, Sven" uniqKey="Bergmann S" first="Sven" last="Bergmann">Sven Bergmann</name><affiliation><nlm:aff id="aff83">Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Rosas, Sylvia E" sort="Rosas, Sylvia E" uniqKey="Rosas S" first="Sylvia E." last="Rosas">Sylvia E. Rosas</name><affiliation><nlm:aff id="aff84">Kidney and Hypertension Section, Joslin Diabetes Center and Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Stracke, Sylvia" sort="Stracke, Sylvia" uniqKey="Stracke S" first="Sylvia" last="Stracke">Sylvia Stracke</name><affiliation><nlm:aff id="aff85">Clinic for Internal Medicine A, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Harris, Tamara B" sort="Harris, Tamara B" uniqKey="Harris T" first="Tamara B." last="Harris">Tamara B. Harris</name><affiliation><nlm:aff id="aff66">Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD</nlm:aff></affiliation></author><author><name sortKey="Corre, Tanguy" sort="Corre, Tanguy" uniqKey="Corre T" first="Tanguy" last="Corre">Tanguy Corre</name><affiliation><nlm:aff id="aff83">Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Zeller, Tanja" sort="Zeller, Tanja" uniqKey="Zeller T" first="Tanja" last="Zeller">Tanja Zeller</name><affiliation><nlm:aff id="aff39">University Heart Center Hamburg, Hamburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff40">German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name><affiliation><nlm:aff id="aff36">Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff86">Institute for Human Genetics, Hannover Medical School, Hannover, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff87">Hannover Unified Biobank, Hannover Medical School, Hannover, Germany</nlm:aff></affiliation></author><author><name sortKey="Aspelund, Thor" sort="Aspelund, Thor" uniqKey="Aspelund T" first="Thor" last="Aspelund">Thor Aspelund</name><affiliation><nlm:aff id="aff24">Icelandic Heart Association, Kópavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="aff25">Faculty of Medicine, University of Iceland, Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Tanaka, Toshiko" sort="Tanaka, Toshiko" uniqKey="Tanaka T" first="Toshiko" last="Tanaka">Toshiko Tanaka</name><affiliation><nlm:aff id="aff67">Clinical Research Branch, National Institute on Aging, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Lendeckel, Uwe" sort="Lendeckel, Uwe" uniqKey="Lendeckel U" first="Uwe" last="Lendeckel">Uwe Lendeckel</name><affiliation><nlm:aff id="aff88">Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volker, Uwe" sort="Volker, Uwe" uniqKey="Volker U" first="Uwe" last="Völker">Uwe Völker</name><affiliation><nlm:aff id="aff2">German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff47">Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Gudnason, Vilmundur" sort="Gudnason, Vilmundur" uniqKey="Gudnason V" first="Vilmundur" last="Gudnason">Vilmundur Gudnason</name><affiliation><nlm:aff id="aff24">Icelandic Heart Association, Kópavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="aff25">Faculty of Medicine, University of Iceland, Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Chouraki, Vincent" sort="Chouraki, Vincent" uniqKey="Chouraki V" first="Vincent" last="Chouraki">Vincent Chouraki</name><affiliation><nlm:aff id="aff62">INSERM UMR 1167 “Risk factors and molecular determinants of aging-related diseases,” Institut Pasteur de Lille, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Koenig, Wolfgang" sort="Koenig, Wolfgang" uniqKey="Koenig W" first="Wolfgang" last="Koenig">Wolfgang Koenig</name><affiliation><nlm:aff id="aff89">Abteilung Innere II, Universitätsklinikum Ulm, Ulm, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff90">Deutsches Herzzentrum München, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff91">German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Kutalik, Zoltan" sort="Kutalik, Zoltan" uniqKey="Kutalik Z" first="Zoltan" last="Kutalik">Zoltan Kutalik</name><affiliation><nlm:aff id="aff61">Swiss Institute of Bioinformatics, Lausanne, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="aff83">Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="aff92">University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="O Connell, Jeffrey R" sort="O Connell, Jeffrey R" uniqKey="O Connell J" first="Jeffrey R." last="O'Connell">Jeffrey R. O'Connell</name><affiliation><nlm:aff id="aff23">Department of Medicine, University of Maryland School of Medicine, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Parsa, Afshin" sort="Parsa, Afshin" uniqKey="Parsa A" first="Afshin" last="Parsa">Afshin Parsa</name><affiliation><nlm:aff id="aff23">Department of Medicine, University of Maryland School of Medicine, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Heid, Iris M" sort="Heid, Iris M" uniqKey="Heid I" first="Iris M." last="Heid">Iris M. Heid</name><affiliation><nlm:aff id="aff5">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff37">Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Paterson, Andrew D" sort="Paterson, Andrew D" uniqKey="Paterson A" first="Andrew D." last="Paterson">Andrew D. Paterson</name><affiliation><nlm:aff id="aff19">Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff93">Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="De Boer, Ian H" sort="De Boer, Ian H" uniqKey="De Boer I" first="Ian H." last="De Boer">Ian H. De Boer</name><affiliation><nlm:aff id="aff81">Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Devuyst, Olivier" sort="Devuyst, Olivier" uniqKey="Devuyst O" first="Olivier" last="Devuyst">Olivier Devuyst</name><affiliation><nlm:aff id="aff14">Institute of Physiology, Mechanisms of Inherited Kidney Disorders Group, University of Zürich, Zürich, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Lazar, Jozef" sort="Lazar, Jozef" uniqKey="Lazar J" first="Jozef" last="Lazar">Jozef Lazar</name><affiliation><nlm:aff id="aff94">Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Endlich, Karlhans" sort="Endlich, Karlhans" uniqKey="Endlich K" first="Karlhans" last="Endlich">Karlhans Endlich</name><affiliation><nlm:aff id="aff72">Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Susztak, Katalin" sort="Susztak, Katalin" uniqKey="Susztak K" first="Katalin" last="Susztak">Katalin Susztak</name><affiliation><nlm:aff id="aff12">Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Tremblay, Johanne" sort="Tremblay, Johanne" uniqKey="Tremblay J" first="Johanne" last="Tremblay">Johanne Tremblay</name><affiliation><nlm:aff id="aff95">Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), University of Montreal, CHUM Research Center, Technopìle Angus, Montreal, Quebec, Canada.</nlm:aff></affiliation></author><author><name sortKey="Hamet, Pavel" sort="Hamet, Pavel" uniqKey="Hamet P" first="Pavel" last="Hamet">Pavel Hamet</name><affiliation><nlm:aff id="aff95">Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), University of Montreal, CHUM Research Center, Technopìle Angus, Montreal, Quebec, Canada.</nlm:aff></affiliation></author><author><name sortKey="Jacob, Howard J" sort="Jacob, Howard J" uniqKey="Jacob H" first="Howard J." last="Jacob">Howard J. Jacob</name><affiliation><nlm:aff id="aff7">Department of Physiology, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Boger, Carsten A" sort="Boger, Carsten A" uniqKey="Boger C" first="Carsten A." last="Böger">Carsten A. Böger</name><affiliation><nlm:aff id="aff6">Department of Nephrology, University Hospital Regensburg, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Fox, Caroline S" sort="Fox, Caroline S" uniqKey="Fox C" first="Caroline S." last="Fox">Caroline S. Fox</name><affiliation><nlm:aff id="aff9">National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA</nlm:aff></affiliation><affiliation><nlm:aff id="aff96">Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Pattaro, Cristian" sort="Pattaro, Cristian" uniqKey="Pattaro C" first="Cristian" last="Pattaro">Cristian Pattaro</name><affiliation><nlm:aff id="aff13">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Kottgen, Anna" sort="Kottgen, Anna" uniqKey="Kottgen A" first="Anna" last="Köttgen">Anna Köttgen</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation><affiliation><nlm:aff id="aff10">Renal Division, Medical Center, University of Freiburg, Freiburg, Germany</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26631737</idno><idno type="pmc">4764151</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764151</idno><idno type="RBID">PMC:4764151</idno><idno type="doi">10.2337/db15-1313</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000527</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000527</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes</title><author><name sortKey="Teumer, Alexander" sort="Teumer, Alexander" uniqKey="Teumer A" first="Alexander" last="Teumer">Alexander Teumer</name><affiliation><nlm:aff id="aff1">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Tin, Adrienne" sort="Tin, Adrienne" uniqKey="Tin A" first="Adrienne" last="Tin">Adrienne Tin</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Sorice, Rossella" sort="Sorice, Rossella" uniqKey="Sorice R" first="Rossella" last="Sorice">Rossella Sorice</name><affiliation><nlm:aff id="aff4">Institute of Genetics and Biophysics, “Adriano-Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples, Italy</nlm:aff></affiliation></author><author><name sortKey="Gorski, Mathias" sort="Gorski, Mathias" uniqKey="Gorski M" first="Mathias" last="Gorski">Mathias Gorski</name><affiliation><nlm:aff id="aff5">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Department of Nephrology, University Hospital Regensburg, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Yeo, Nan Cher" sort="Yeo, Nan Cher" uniqKey="Yeo N" first="Nan Cher" last="Yeo">Nan Cher Yeo</name><affiliation><nlm:aff id="aff7">Department of Physiology, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Chu, Audrey Y" sort="Chu, Audrey Y" uniqKey="Chu A" first="Audrey Y." last="Chu">Audrey Y. Chu</name><affiliation><nlm:aff id="aff8">Preventive Medicine, Brigham and Women's Hospital, Boston, MA</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA</nlm:aff></affiliation></author><author><name sortKey="Li, Man" sort="Li, Man" uniqKey="Li M" first="Man" last="Li">Man Li</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Li, Yong" sort="Li, Yong" uniqKey="Li Y" first="Yong" last="Li">Yong Li</name><affiliation><nlm:aff id="aff10">Renal Division, Medical Center, University of Freiburg, Freiburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Mijatovic, Vladan" sort="Mijatovic, Vladan" uniqKey="Mijatovic V" first="Vladan" last="Mijatovic">Vladan Mijatovic</name><affiliation><nlm:aff id="aff11">Department of Life and Reproduction Sciences, University of Verona, Verona, Italy</nlm:aff></affiliation></author><author><name sortKey="Ko, Yi An" sort="Ko, Yi An" uniqKey="Ko Y" first="Yi-An" last="Ko">Yi-An Ko</name><affiliation><nlm:aff id="aff12">Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Taliun, Daniel" sort="Taliun, Daniel" uniqKey="Taliun D" first="Daniel" last="Taliun">Daniel Taliun</name><affiliation><nlm:aff id="aff13">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Luciani, Alessandro" sort="Luciani, Alessandro" uniqKey="Luciani A" first="Alessandro" last="Luciani">Alessandro Luciani</name><affiliation><nlm:aff id="aff14">Institute of Physiology, Mechanisms of Inherited Kidney Disorders Group, University of Zürich, Zürich, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Chen, Ming Huei" sort="Chen, Ming Huei" uniqKey="Chen M" first="Ming-Huei" last="Chen">Ming-Huei Chen</name><affiliation><nlm:aff id="aff15">Department of Neurology, Boston University School of Medicine, Boston, MA</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Department of Biostatistics, Boston University School of Public Health, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Yang, Qiong" sort="Yang, Qiong" uniqKey="Yang Q" first="Qiong" last="Yang">Qiong Yang</name><affiliation><nlm:aff id="aff16">Department of Biostatistics, Boston University School of Public Health, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Foster, Meredith C" sort="Foster, Meredith C" uniqKey="Foster M" first="Meredith C." last="Foster">Meredith C. Foster</name><affiliation><nlm:aff id="aff17">Tufts Medical Center, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Olden, Matthias" sort="Olden, Matthias" uniqKey="Olden M" first="Matthias" last="Olden">Matthias Olden</name><affiliation><nlm:aff id="aff5">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff18">Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Hiraki, Linda T" sort="Hiraki, Linda T" uniqKey="Hiraki L" first="Linda T." last="Hiraki">Linda T. Hiraki</name><affiliation><nlm:aff id="aff19">Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="Tayo, Bamidele O" sort="Tayo, Bamidele O" uniqKey="Tayo B" first="Bamidele O." last="Tayo">Bamidele O. Tayo</name><affiliation><nlm:aff id="aff20">Loyola University Chicago, Maywood, IL</nlm:aff></affiliation></author><author><name sortKey="Fuchsberger, Christian" sort="Fuchsberger, Christian" uniqKey="Fuchsberger C" first="Christian" last="Fuchsberger">Christian Fuchsberger</name><affiliation><nlm:aff id="aff13">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Dieffenbach, Aida Karina" sort="Dieffenbach, Aida Karina" uniqKey="Dieffenbach A" first="Aida Karina" last="Dieffenbach">Aida Karina Dieffenbach</name><affiliation><nlm:aff id="aff21">Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Shuldiner, Alan R" sort="Shuldiner, Alan R" uniqKey="Shuldiner A" first="Alan R." last="Shuldiner">Alan R. Shuldiner</name><affiliation><nlm:aff id="aff23">Department of Medicine, University of Maryland School of Medicine, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Smith, Albert V" sort="Smith, Albert V" uniqKey="Smith A" first="Albert V." last="Smith">Albert V. Smith</name><affiliation><nlm:aff id="aff24">Icelandic Heart Association, Kópavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="aff25">Faculty of Medicine, University of Iceland, Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Zappa, Allison M" sort="Zappa, Allison M" uniqKey="Zappa A" first="Allison M." last="Zappa">Allison M. Zappa</name><affiliation><nlm:aff id="aff26">Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Lupo, Antonio" sort="Lupo, Antonio" uniqKey="Lupo A" first="Antonio" last="Lupo">Antonio Lupo</name><affiliation><nlm:aff id="aff27">Renal Unit, Department of Medicine, University of Verona, Verona, Italy</nlm:aff></affiliation></author><author><name sortKey="Kollerits, Barbara" sort="Kollerits, Barbara" uniqKey="Kollerits B" first="Barbara" last="Kollerits">Barbara Kollerits</name><affiliation><nlm:aff id="aff28">Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Ponte, Belen" sort="Ponte, Belen" uniqKey="Ponte B" first="Belen" last="Ponte">Belen Ponte</name><affiliation><nlm:aff id="aff29">Nephrology Division, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Stengel, Benedicte" sort="Stengel, Benedicte" uniqKey="Stengel B" first="Bénédicte" last="Stengel">Bénédicte Stengel</name><affiliation><nlm:aff id="aff30">INSERM U-1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Villejuif, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">UMRS 1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Univ Paris Sud, Univ Versailles, St. Quentin, France</nlm:aff></affiliation></author><author><name sortKey="Kr Mer, Bernhard K" sort="Kr Mer, Bernhard K" uniqKey="Kr Mer B" first="Bernhard K." last="Kr Mer">Bernhard K. Kr Mer</name><affiliation><nlm:aff id="aff32">Fifth Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany</nlm:aff></affiliation></author><author><name sortKey="Paulweber, Bernhard" sort="Paulweber, Bernhard" uniqKey="Paulweber B" first="Bernhard" last="Paulweber">Bernhard Paulweber</name><affiliation><nlm:aff id="aff33">First Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria</nlm:aff></affiliation></author><author><name sortKey="Mitchell, Braxton D" sort="Mitchell, Braxton D" uniqKey="Mitchell B" first="Braxton D." last="Mitchell">Braxton D. Mitchell</name><affiliation><nlm:aff id="aff23">Department of Medicine, University of Maryland School of Medicine, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Hayward, Caroline" sort="Hayward, Caroline" uniqKey="Hayward C" first="Caroline" last="Hayward">Caroline Hayward</name><affiliation><nlm:aff id="aff34">Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, U.K.</nlm:aff></affiliation></author><author><name sortKey="Helmer, Catherine" sort="Helmer, Catherine" uniqKey="Helmer C" first="Catherine" last="Helmer">Catherine Helmer</name><affiliation><nlm:aff id="aff35">INSERM U897, Bordeaux University, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Bordeaux, France</nlm:aff></affiliation></author><author><name sortKey="Meisinger, Christa" sort="Meisinger, Christa" uniqKey="Meisinger C" first="Christa" last="Meisinger">Christa Meisinger</name><affiliation><nlm:aff id="aff36">Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Gieger, Christian" sort="Gieger, Christian" uniqKey="Gieger C" first="Christian" last="Gieger">Christian Gieger</name><affiliation><nlm:aff id="aff37">Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Shaffer, Christian M" sort="Shaffer, Christian M" uniqKey="Shaffer C" first="Christian M." last="Shaffer">Christian M. Shaffer</name><affiliation><nlm:aff id="aff38">Vanderbilt University School of Medicine, Nashville, TN</nlm:aff></affiliation></author><author><name sortKey="Muller, Christian" sort="Muller, Christian" uniqKey="Muller C" first="Christian" last="Müller">Christian Müller</name><affiliation><nlm:aff id="aff39">University Heart Center Hamburg, Hamburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff40">German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Langenberg, Claudia" sort="Langenberg, Claudia" uniqKey="Langenberg C" first="Claudia" last="Langenberg">Claudia Langenberg</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Ackermann, Daniel" sort="Ackermann, Daniel" uniqKey="Ackermann D" first="Daniel" last="Ackermann">Daniel Ackermann</name><affiliation><nlm:aff id="aff42">University Clinic for Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Siscovick, David" sort="Siscovick, David" uniqKey="Siscovick D" first="David" last="Siscovick">David Siscovick</name><affiliation><nlm:aff id="aff43">Cardiovascular Health Research Unit, Departments of Epidemiology and Medicine, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Boerwinkle, Eric" sort="Boerwinkle, Eric" uniqKey="Boerwinkle E" first="Eric" last="Boerwinkle">Eric Boerwinkle</name><affiliation><nlm:aff id="aff45">Human Genetics Center, University of Texas Health Science Center, Houston, TX</nlm:aff></affiliation></author><author><name sortKey="Kronenberg, Florian" sort="Kronenberg, Florian" uniqKey="Kronenberg F" first="Florian" last="Kronenberg">Florian Kronenberg</name><affiliation><nlm:aff id="aff28">Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Ehret, Georg B" sort="Ehret, Georg B" uniqKey="Ehret G" first="Georg B." last="Ehret">Georg B. Ehret</name><affiliation><nlm:aff id="aff46">Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Homuth, Georg" sort="Homuth, Georg" uniqKey="Homuth G" first="Georg" last="Homuth">Georg Homuth</name><affiliation><nlm:aff id="aff47">Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Waeber, Gerard" sort="Waeber, Gerard" uniqKey="Waeber G" first="Gerard" last="Waeber">Gerard Waeber</name><affiliation><nlm:aff id="aff48">Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Navis, Gerjan" sort="Navis, Gerjan" uniqKey="Navis G" first="Gerjan" last="Navis">Gerjan Navis</name><affiliation><nlm:aff id="aff49">Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Gambaro, Giovanni" sort="Gambaro, Giovanni" uniqKey="Gambaro G" first="Giovanni" last="Gambaro">Giovanni Gambaro</name><affiliation><nlm:aff id="aff50">Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Malerba, Giovanni" sort="Malerba, Giovanni" uniqKey="Malerba G" first="Giovanni" last="Malerba">Giovanni Malerba</name><affiliation><nlm:aff id="aff11">Department of Life and Reproduction Sciences, University of Verona, Verona, Italy</nlm:aff></affiliation></author><author><name sortKey="Eiriksdottir, Gudny" sort="Eiriksdottir, Gudny" uniqKey="Eiriksdottir G" first="Gudny" last="Eiriksdottir">Gudny Eiriksdottir</name><affiliation><nlm:aff id="aff24">Icelandic Heart Association, Kópavogur, Iceland</nlm:aff></affiliation></author><author><name sortKey="Li, Guo" sort="Li, Guo" uniqKey="Li G" first="Guo" last="Li">Guo Li</name><affiliation><nlm:aff id="aff43">Cardiovascular Health Research Unit, Departments of Epidemiology and Medicine, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Wichmann, H Erich" sort="Wichmann, H Erich" uniqKey="Wichmann H" first="H. Erich" last="Wichmann">H. Erich Wichmann</name><affiliation><nlm:aff id="aff51">Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff52">Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff53">Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Grallert, Harald" sort="Grallert, Harald" uniqKey="Grallert H" first="Harald" last="Grallert">Harald Grallert</name><affiliation><nlm:aff id="aff36">Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff54">Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff55">German Center for Diabetes Research (DZD), Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Wallaschofski, Henri" sort="Wallaschofski, Henri" uniqKey="Wallaschofski H" first="Henri" last="Wallaschofski">Henri Wallaschofski</name><affiliation><nlm:aff id="aff56">Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volzke, Henry" sort="Volzke, Henry" uniqKey="Volzke H" first="Henry" last="Völzke">Henry Völzke</name><affiliation><nlm:aff id="aff1">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Brenner, Herrmann" sort="Brenner, Herrmann" uniqKey="Brenner H" first="Herrmann" last="Brenner">Herrmann Brenner</name><affiliation><nlm:aff id="aff21">Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Kramer, Holly" sort="Kramer, Holly" uniqKey="Kramer H" first="Holly" last="Kramer">Holly Kramer</name><affiliation><nlm:aff id="aff20">Loyola University Chicago, Maywood, IL</nlm:aff></affiliation></author><author><name sortKey="Leach, I Mateo" sort="Leach, I Mateo" uniqKey="Leach I" first="I. Mateo" last="Leach">I. Mateo Leach</name><affiliation><nlm:aff id="aff57">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rudan, Igor" sort="Rudan, Igor" uniqKey="Rudan I" first="Igor" last="Rudan">Igor Rudan</name><affiliation><nlm:aff id="aff58">Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.</nlm:aff></affiliation></author><author><name sortKey="Hillege, Hans L" sort="Hillege, Hans L" uniqKey="Hillege H" first="Hans L." last="Hillege">Hans L. Hillege</name><affiliation><nlm:aff id="aff59">Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Beckmann, Jacques S" sort="Beckmann, Jacques S" uniqKey="Beckmann J" first="Jacques S." last="Beckmann">Jacques S. Beckmann</name><affiliation><nlm:aff id="aff60">Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="aff61">Swiss Institute of Bioinformatics, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean Charles" last="Lambert">Jean Charles Lambert</name><affiliation><nlm:aff id="aff62">INSERM UMR 1167 “Risk factors and molecular determinants of aging-related diseases,” Institut Pasteur de Lille, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Luan, Jian An" sort="Luan, Jian An" uniqKey="Luan J" first="Jian'An" last="Luan">Jian'An Luan</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Zhao, Jing Hua" sort="Zhao, Jing Hua" uniqKey="Zhao J" first="Jing Hua" last="Zhao">Jing Hua Zhao</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Chalmers, John" sort="Chalmers, John" uniqKey="Chalmers J" first="John" last="Chalmers">John Chalmers</name><affiliation><nlm:aff id="aff63">The George Institute for Global Health, University of Sydney, Camperdown, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Coresh, Josef" sort="Coresh, Josef" uniqKey="Coresh J" first="Josef" last="Coresh">Josef Coresh</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation><affiliation><nlm:aff id="aff64">Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Denny, Joshua C" sort="Denny, Joshua C" uniqKey="Denny J" first="Joshua C." last="Denny">Joshua C. Denny</name><affiliation><nlm:aff id="aff65">Vanderbilt University School of Medicine, Nashville, TN</nlm:aff></affiliation></author><author><name sortKey="Butterbach, Katja" sort="Butterbach, Katja" uniqKey="Butterbach K" first="Katja" last="Butterbach">Katja Butterbach</name><affiliation><nlm:aff id="aff21">Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Launer, Lenore J" sort="Launer, Lenore J" uniqKey="Launer L" first="Lenore J." last="Launer">Lenore J. Launer</name><affiliation><nlm:aff id="aff66">Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD</nlm:aff></affiliation></author><author><name sortKey="Ferrucci, Luigi" sort="Ferrucci, Luigi" uniqKey="Ferrucci L" first="Luigi" last="Ferrucci">Luigi Ferrucci</name><affiliation><nlm:aff id="aff67">Clinical Research Branch, National Institute on Aging, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Kedenko, Lyudmyla" sort="Kedenko, Lyudmyla" uniqKey="Kedenko L" first="Lyudmyla" last="Kedenko">Lyudmyla Kedenko</name><affiliation><nlm:aff id="aff33">First Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria</nlm:aff></affiliation></author><author><name sortKey="Haun, Margot" sort="Haun, Margot" uniqKey="Haun M" first="Margot" last="Haun">Margot Haun</name><affiliation><nlm:aff id="aff28">Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Metzger, Marie" sort="Metzger, Marie" uniqKey="Metzger M" first="Marie" last="Metzger">Marie Metzger</name><affiliation><nlm:aff id="aff30">INSERM U-1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Villejuif, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">UMRS 1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Univ Paris Sud, Univ Versailles, St. Quentin, France</nlm:aff></affiliation></author><author><name sortKey="Woodward, Mark" sort="Woodward, Mark" uniqKey="Woodward M" first="Mark" last="Woodward">Mark Woodward</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation><affiliation><nlm:aff id="aff63">The George Institute for Global Health, University of Sydney, Camperdown, New South Wales, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff68">The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.</nlm:aff></affiliation></author><author><name sortKey="Hoffman, Matthew J" sort="Hoffman, Matthew J" uniqKey="Hoffman M" first="Matthew J." last="Hoffman">Matthew J. Hoffman</name><affiliation><nlm:aff id="aff7">Department of Physiology, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Nauck, Matthias" sort="Nauck, Matthias" uniqKey="Nauck M" first="Matthias" last="Nauck">Matthias Nauck</name><affiliation><nlm:aff id="aff2">German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff56">Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Waldenberger, Melanie" sort="Waldenberger, Melanie" uniqKey="Waldenberger M" first="Melanie" last="Waldenberger">Melanie Waldenberger</name><affiliation><nlm:aff id="aff36">Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Pruijm, Menno" sort="Pruijm, Menno" uniqKey="Pruijm M" first="Menno" last="Pruijm">Menno Pruijm</name><affiliation><nlm:aff id="aff69">Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Bochud, Murielle" sort="Bochud, Murielle" uniqKey="Bochud M" first="Murielle" last="Bochud">Murielle Bochud</name><affiliation><nlm:aff id="aff70">University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Épalinges, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Rheinberger, Myriam" sort="Rheinberger, Myriam" uniqKey="Rheinberger M" first="Myriam" last="Rheinberger">Myriam Rheinberger</name><affiliation><nlm:aff id="aff71">Department of Nephrology, University Hospital Regensburg, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Verweij, Niek" sort="Verweij, Niek" uniqKey="Verweij N" first="Niek" last="Verweij">Niek Verweij</name><affiliation><nlm:aff id="aff57">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Wareham, Nicholas J" sort="Wareham, Nicholas J" uniqKey="Wareham N" first="Nicholas J." last="Wareham">Nicholas J. Wareham</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Endlich, Nicole" sort="Endlich, Nicole" uniqKey="Endlich N" first="Nicole" last="Endlich">Nicole Endlich</name><affiliation><nlm:aff id="aff72">Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Soranzo, Nicole" sort="Soranzo, Nicole" uniqKey="Soranzo N" first="Nicole" last="Soranzo">Nicole Soranzo</name><affiliation><nlm:aff id="aff73">Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.</nlm:aff></affiliation><affiliation><nlm:aff id="aff74">Department of Haematology, University of Cambridge, Cambridge, U.K.</nlm:aff></affiliation></author><author><name sortKey="Polasek, Ozren" sort="Polasek, Ozren" uniqKey="Polasek O" first="Ozren" last="Polasek">Ozren Polasek</name><affiliation><nlm:aff id="aff75">Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split, Croatia</nlm:aff></affiliation></author><author><name sortKey="Van Der Harst, Pim" sort="Van Der Harst, Pim" uniqKey="Van Der Harst P" first="Pim" last="Van Der Harst">Pim Van Der Harst</name><affiliation><nlm:aff id="aff59">Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Pramstaller, Peter Paul" sort="Pramstaller, Peter Paul" uniqKey="Pramstaller P" first="Peter Paul" last="Pramstaller">Peter Paul Pramstaller</name><affiliation><nlm:aff id="aff13">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Vollenweider, Peter" sort="Vollenweider, Peter" uniqKey="Vollenweider P" first="Peter" last="Vollenweider">Peter Vollenweider</name><affiliation><nlm:aff id="aff48">Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Wild, Philipp S" sort="Wild, Philipp S" uniqKey="Wild P" first="Philipp S." last="Wild">Philipp S. Wild</name><affiliation><nlm:aff id="aff76">Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff77">Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff78">German Center for Cardiovascular Research (DZHK), Mainz, Germany</nlm:aff></affiliation></author><author><name sortKey="Gansevoort, Ron T" sort="Gansevoort, Ron T" uniqKey="Gansevoort R" first="Ron T." last="Gansevoort">Ron T. Gansevoort</name><affiliation><nlm:aff id="aff59">Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rettig, Rainer" sort="Rettig, Rainer" uniqKey="Rettig R" first="Rainer" last="Rettig">Rainer Rettig</name><affiliation><nlm:aff id="aff79">Institute of Physiology, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Biffar, Reiner" sort="Biffar, Reiner" uniqKey="Biffar R" first="Reiner" last="Biffar">Reiner Biffar</name><affiliation><nlm:aff id="aff80">Clinic for Prosthetic Dentistry, Gerostomatology and Material Science, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Carroll, Robert J" sort="Carroll, Robert J" uniqKey="Carroll R" first="Robert J." last="Carroll">Robert J. Carroll</name><affiliation><nlm:aff id="aff65">Vanderbilt University School of Medicine, Nashville, TN</nlm:aff></affiliation></author><author><name sortKey="Katz, Ronit" sort="Katz, Ronit" uniqKey="Katz R" first="Ronit" last="Katz">Ronit Katz</name><affiliation><nlm:aff id="aff81">Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Loos, Ruth J F" sort="Loos, Ruth J F" uniqKey="Loos R" first="Ruth J. F." last="Loos">Ruth J. F. Loos</name><affiliation><nlm:aff id="aff41">Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</nlm:aff></affiliation><affiliation><nlm:aff id="aff82">Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY</nlm:aff></affiliation></author><author><name sortKey="Hwang, Shih Jen" sort="Hwang, Shih Jen" uniqKey="Hwang S" first="Shih-Jen" last="Hwang">Shih-Jen Hwang</name><affiliation><nlm:aff id="aff9">National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA</nlm:aff></affiliation></author><author><name sortKey="Coassin, Stefan" sort="Coassin, Stefan" uniqKey="Coassin S" first="Stefan" last="Coassin">Stefan Coassin</name><affiliation><nlm:aff id="aff28">Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Bergmann, Sven" sort="Bergmann, Sven" uniqKey="Bergmann S" first="Sven" last="Bergmann">Sven Bergmann</name><affiliation><nlm:aff id="aff83">Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Rosas, Sylvia E" sort="Rosas, Sylvia E" uniqKey="Rosas S" first="Sylvia E." last="Rosas">Sylvia E. Rosas</name><affiliation><nlm:aff id="aff84">Kidney and Hypertension Section, Joslin Diabetes Center and Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Stracke, Sylvia" sort="Stracke, Sylvia" uniqKey="Stracke S" first="Sylvia" last="Stracke">Sylvia Stracke</name><affiliation><nlm:aff id="aff85">Clinic for Internal Medicine A, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Harris, Tamara B" sort="Harris, Tamara B" uniqKey="Harris T" first="Tamara B." last="Harris">Tamara B. Harris</name><affiliation><nlm:aff id="aff66">Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD</nlm:aff></affiliation></author><author><name sortKey="Corre, Tanguy" sort="Corre, Tanguy" uniqKey="Corre T" first="Tanguy" last="Corre">Tanguy Corre</name><affiliation><nlm:aff id="aff83">Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Zeller, Tanja" sort="Zeller, Tanja" uniqKey="Zeller T" first="Tanja" last="Zeller">Tanja Zeller</name><affiliation><nlm:aff id="aff39">University Heart Center Hamburg, Hamburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff40">German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name><affiliation><nlm:aff id="aff36">Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff86">Institute for Human Genetics, Hannover Medical School, Hannover, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff87">Hannover Unified Biobank, Hannover Medical School, Hannover, Germany</nlm:aff></affiliation></author><author><name sortKey="Aspelund, Thor" sort="Aspelund, Thor" uniqKey="Aspelund T" first="Thor" last="Aspelund">Thor Aspelund</name><affiliation><nlm:aff id="aff24">Icelandic Heart Association, Kópavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="aff25">Faculty of Medicine, University of Iceland, Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Tanaka, Toshiko" sort="Tanaka, Toshiko" uniqKey="Tanaka T" first="Toshiko" last="Tanaka">Toshiko Tanaka</name><affiliation><nlm:aff id="aff67">Clinical Research Branch, National Institute on Aging, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Lendeckel, Uwe" sort="Lendeckel, Uwe" uniqKey="Lendeckel U" first="Uwe" last="Lendeckel">Uwe Lendeckel</name><affiliation><nlm:aff id="aff88">Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volker, Uwe" sort="Volker, Uwe" uniqKey="Volker U" first="Uwe" last="Völker">Uwe Völker</name><affiliation><nlm:aff id="aff2">German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff47">Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Gudnason, Vilmundur" sort="Gudnason, Vilmundur" uniqKey="Gudnason V" first="Vilmundur" last="Gudnason">Vilmundur Gudnason</name><affiliation><nlm:aff id="aff24">Icelandic Heart Association, Kópavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="aff25">Faculty of Medicine, University of Iceland, Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Chouraki, Vincent" sort="Chouraki, Vincent" uniqKey="Chouraki V" first="Vincent" last="Chouraki">Vincent Chouraki</name><affiliation><nlm:aff id="aff62">INSERM UMR 1167 “Risk factors and molecular determinants of aging-related diseases,” Institut Pasteur de Lille, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Koenig, Wolfgang" sort="Koenig, Wolfgang" uniqKey="Koenig W" first="Wolfgang" last="Koenig">Wolfgang Koenig</name><affiliation><nlm:aff id="aff89">Abteilung Innere II, Universitätsklinikum Ulm, Ulm, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff90">Deutsches Herzzentrum München, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff91">German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Kutalik, Zoltan" sort="Kutalik, Zoltan" uniqKey="Kutalik Z" first="Zoltan" last="Kutalik">Zoltan Kutalik</name><affiliation><nlm:aff id="aff61">Swiss Institute of Bioinformatics, Lausanne, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="aff83">Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="aff92">University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="O Connell, Jeffrey R" sort="O Connell, Jeffrey R" uniqKey="O Connell J" first="Jeffrey R." last="O'Connell">Jeffrey R. O'Connell</name><affiliation><nlm:aff id="aff23">Department of Medicine, University of Maryland School of Medicine, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Parsa, Afshin" sort="Parsa, Afshin" uniqKey="Parsa A" first="Afshin" last="Parsa">Afshin Parsa</name><affiliation><nlm:aff id="aff23">Department of Medicine, University of Maryland School of Medicine, Baltimore, MD</nlm:aff></affiliation></author><author><name sortKey="Heid, Iris M" sort="Heid, Iris M" uniqKey="Heid I" first="Iris M." last="Heid">Iris M. Heid</name><affiliation><nlm:aff id="aff5">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff37">Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Paterson, Andrew D" sort="Paterson, Andrew D" uniqKey="Paterson A" first="Andrew D." last="Paterson">Andrew D. Paterson</name><affiliation><nlm:aff id="aff19">Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff93">Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="De Boer, Ian H" sort="De Boer, Ian H" uniqKey="De Boer I" first="Ian H." last="De Boer">Ian H. De Boer</name><affiliation><nlm:aff id="aff81">Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Devuyst, Olivier" sort="Devuyst, Olivier" uniqKey="Devuyst O" first="Olivier" last="Devuyst">Olivier Devuyst</name><affiliation><nlm:aff id="aff14">Institute of Physiology, Mechanisms of Inherited Kidney Disorders Group, University of Zürich, Zürich, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Lazar, Jozef" sort="Lazar, Jozef" uniqKey="Lazar J" first="Jozef" last="Lazar">Jozef Lazar</name><affiliation><nlm:aff id="aff94">Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Endlich, Karlhans" sort="Endlich, Karlhans" uniqKey="Endlich K" first="Karlhans" last="Endlich">Karlhans Endlich</name><affiliation><nlm:aff id="aff72">Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Susztak, Katalin" sort="Susztak, Katalin" uniqKey="Susztak K" first="Katalin" last="Susztak">Katalin Susztak</name><affiliation><nlm:aff id="aff12">Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Tremblay, Johanne" sort="Tremblay, Johanne" uniqKey="Tremblay J" first="Johanne" last="Tremblay">Johanne Tremblay</name><affiliation><nlm:aff id="aff95">Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), University of Montreal, CHUM Research Center, Technopìle Angus, Montreal, Quebec, Canada.</nlm:aff></affiliation></author><author><name sortKey="Hamet, Pavel" sort="Hamet, Pavel" uniqKey="Hamet P" first="Pavel" last="Hamet">Pavel Hamet</name><affiliation><nlm:aff id="aff95">Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), University of Montreal, CHUM Research Center, Technopìle Angus, Montreal, Quebec, Canada.</nlm:aff></affiliation></author><author><name sortKey="Jacob, Howard J" sort="Jacob, Howard J" uniqKey="Jacob H" first="Howard J." last="Jacob">Howard J. Jacob</name><affiliation><nlm:aff id="aff7">Department of Physiology, Medical College of Wisconsin, Milwaukee, WI</nlm:aff></affiliation></author><author><name sortKey="Boger, Carsten A" sort="Boger, Carsten A" uniqKey="Boger C" first="Carsten A." last="Böger">Carsten A. Böger</name><affiliation><nlm:aff id="aff6">Department of Nephrology, University Hospital Regensburg, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Fox, Caroline S" sort="Fox, Caroline S" uniqKey="Fox C" first="Caroline S." last="Fox">Caroline S. Fox</name><affiliation><nlm:aff id="aff9">National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA</nlm:aff></affiliation><affiliation><nlm:aff id="aff96">Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Pattaro, Cristian" sort="Pattaro, Cristian" uniqKey="Pattaro C" first="Cristian" last="Pattaro">Cristian Pattaro</name><affiliation><nlm:aff id="aff13">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Kottgen, Anna" sort="Kottgen, Anna" uniqKey="Kottgen A" first="Anna" last="Köttgen">Anna Köttgen</name><affiliation><nlm:aff id="aff3">Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</nlm:aff></affiliation><affiliation><nlm:aff id="aff10">Renal Division, Medical Center, University of Freiburg, Freiburg, Germany</nlm:aff></affiliation></author></analytic><series><title level="j">Diabetes</title><idno type="ISSN">0012-1797</idno><idno type="eISSN">1939-327X</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in <italic>CUBN</italic>, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (<italic>P</italic> = 2.4 × 10<sup>−10</sup>). Gene-by-diabetes interactions were detected and confirmed for variants in <italic>HS6ST1</italic> and near <italic>RAB38</italic>/<italic>CTSC</italic>. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for <italic>HS6ST1</italic> (<italic>P</italic> = 6.3 × 10<sup>–7</sup>) and 13% for <italic>RAB38</italic>/<italic>CTSC</italic> (<italic>P</italic> = 5.8 × 10<sup>−7</sup>). Experiments using streptozotocin-induced diabetic <italic>Rab38</italic> knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in <italic>Rab38</italic> knockout versus control rats. Relative expression of <italic>RAB38</italic> was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Fuchsberger, C" uniqKey="Fuchsberger C">C Fuchsberger</name></author><author><name sortKey="Taliun, D" uniqKey="Taliun D">D Taliun</name></author><author><name sortKey="Pramstaller, Pp" uniqKey="Pramstaller P">PP Pramstaller</name></author><author><name sortKey="Pattaro, C" uniqKey="Pattaro C">C Pattaro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Devlin, B" uniqKey="Devlin B">B Devlin</name></author><author><name sortKey="Roeder, K" uniqKey="Roeder K">K Roeder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Willer, Cj" uniqKey="Willer C">CJ Willer</name></author><author><name sortKey="Li, Y" uniqKey="Li Y">Y Li</name></author><author><name sortKey="Abecasis, Gr" uniqKey="Abecasis G">GR Abecasis</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Boger, Ca" uniqKey="Boger C">CA Böger</name></author><author><name sortKey="Gorski, M" uniqKey="Gorski M">M Gorski</name></author><author><name sortKey="Li, M" uniqKey="Li M">M Li</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Woroniecka, Ki" uniqKey="Woroniecka K">KI Woroniecka</name></author><author><name sortKey="Park, Asd" uniqKey="Park A">ASD Park</name></author><author><name sortKey="Mohtat, D" uniqKey="Mohtat D">D Mohtat</name></author><author><name sortKey="Thomas, Db" uniqKey="Thomas D">DB Thomas</name></author><author><name sortKey="Pullman, Jm" uniqKey="Pullman J">JM Pullman</name></author><author><name sortKey="Susztak, K" uniqKey="Susztak K">K Susztak</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Welter, D" uniqKey="Welter D">D Welter</name></author><author><name sortKey="Macarthur, J" uniqKey="Macarthur J">J MacArthur</name></author><author><name sortKey="Morales, J" uniqKey="Morales J">J Morales</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
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contrib-type="author"><name><surname>Corre</surname><given-names>Tanguy</given-names></name><xref ref-type="aff" rid="aff83"><sup>83</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zeller</surname><given-names>Tanja</given-names></name><xref ref-type="aff" rid="aff39"><sup>39</sup></xref><xref ref-type="aff" rid="aff40"><sup>40</sup></xref></contrib><contrib contrib-type="author"><name><surname>Illig</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="aff36"><sup>36</sup></xref><xref ref-type="aff" rid="aff86"><sup>86</sup></xref><xref ref-type="aff" rid="aff87"><sup>87</sup></xref></contrib><contrib contrib-type="author"><name><surname>Aspelund</surname><given-names>Thor</given-names></name><xref ref-type="aff" rid="aff24"><sup>24</sup></xref><xref ref-type="aff" rid="aff25"><sup>25</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tanaka</surname><given-names>Toshiko</given-names></name><xref ref-type="aff" rid="aff67"><sup>67</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lendeckel</surname><given-names>Uwe</given-names></name><xref ref-type="aff" rid="aff88"><sup>88</sup></xref></contrib><contrib contrib-type="author"><name><surname>Völker</surname><given-names>Uwe</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff47"><sup>47</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gudnason</surname><given-names>Vilmundur</given-names></name><xref ref-type="aff" rid="aff24"><sup>24</sup></xref><xref ref-type="aff" rid="aff25"><sup>25</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chouraki</surname><given-names>Vincent</given-names></name><xref ref-type="aff" rid="aff62"><sup>62</sup></xref></contrib><contrib contrib-type="author"><name><surname>Koenig</surname><given-names>Wolfgang</given-names></name><xref ref-type="aff" rid="aff89"><sup>89</sup></xref><xref ref-type="aff" rid="aff90"><sup>90</sup></xref><xref ref-type="aff" rid="aff91"><sup>91</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kutalik</surname><given-names>Zoltan</given-names></name><xref ref-type="aff" rid="aff61"><sup>61</sup></xref><xref ref-type="aff" rid="aff83"><sup>83</sup></xref><xref ref-type="aff" rid="aff92"><sup>92</sup></xref></contrib><contrib contrib-type="author"><name><surname>O'Connell</surname><given-names>Jeffrey R.</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Parsa</surname><given-names>Afshin</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Heid</surname><given-names>Iris M.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="aff" rid="aff37"><sup>37</sup></xref></contrib><contrib contrib-type="author"><name><surname>Paterson</surname><given-names>Andrew D.</given-names></name><xref ref-type="aff" rid="aff19"><sup>19</sup></xref><xref ref-type="aff" rid="aff93"><sup>93</sup></xref></contrib><contrib contrib-type="author"><name><surname>de Boer</surname><given-names>Ian H.</given-names></name><xref ref-type="aff" rid="aff81"><sup>81</sup></xref></contrib><contrib contrib-type="author"><name><surname>Devuyst</surname><given-names>Olivier</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lazar</surname><given-names>Jozef</given-names></name><xref ref-type="aff" rid="aff94"><sup>94</sup></xref></contrib><contrib contrib-type="author"><name><surname>Endlich</surname><given-names>Karlhans</given-names></name><xref ref-type="aff" rid="aff72"><sup>72</sup></xref></contrib><contrib contrib-type="author"><name><surname>Susztak</surname><given-names>Katalin</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tremblay</surname><given-names>Johanne</given-names></name><xref ref-type="aff" rid="aff95"><sup>95</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hamet</surname><given-names>Pavel</given-names></name><xref ref-type="aff" rid="aff95"><sup>95</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jacob</surname><given-names>Howard J.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Böger</surname><given-names>Carsten A.</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Fox</surname><given-names>Caroline S.</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref><xref ref-type="aff" rid="aff96"><sup>96</sup></xref><xref ref-type="corresp" rid="cor1"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Pattaro</surname><given-names>Cristian</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref><xref ref-type="corresp" rid="cor1"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Köttgen</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff10"><sup>10</sup></xref><xref ref-type="corresp" rid="cor1"></xref></contrib><aff id="aff1"><sup>1</sup>Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff2"><sup>2</sup>German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany</aff><aff id="aff3"><sup>3</sup>Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</aff><aff id="aff4"><sup>4</sup>Institute of Genetics and Biophysics, “Adriano-Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples, Italy</aff><aff id="aff5"><sup>5</sup>Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</aff><aff id="aff6"><sup>6</sup>Department of Nephrology, University Hospital Regensburg, Regensburg, Germany</aff><aff id="aff7"><sup>7</sup>Department of Physiology, Medical College of Wisconsin, Milwaukee, WI</aff><aff id="aff8"><sup>8</sup>Preventive Medicine, Brigham and Women's Hospital, Boston, MA</aff><aff id="aff9"><sup>9</sup>National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA</aff><aff id="aff10"><sup>10</sup>Renal Division, Medical Center, University of Freiburg, Freiburg, Germany</aff><aff id="aff11"><sup>11</sup>Department of Life and Reproduction Sciences, University of Verona, Verona, Italy</aff><aff id="aff12"><sup>12</sup>Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA</aff><aff id="aff13"><sup>13</sup>Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy</aff><aff id="aff14"><sup>14</sup>Institute of Physiology, Mechanisms of Inherited Kidney Disorders Group, University of Zürich, Zürich, Switzerland</aff><aff id="aff15"><sup>15</sup>Department of Neurology, Boston University School of Medicine, Boston, MA</aff><aff id="aff16"><sup>16</sup>Department of Biostatistics, Boston University School of Public Health, Boston, MA</aff><aff id="aff17"><sup>17</sup>Tufts Medical Center, Boston, MA</aff><aff id="aff18"><sup>18</sup>Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Regensburg, Germany</aff><aff id="aff19"><sup>19</sup>Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada</aff><aff id="aff20"><sup>20</sup>Loyola University Chicago, Maywood, IL</aff><aff id="aff21"><sup>21</sup>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</aff><aff id="aff22"><sup>22</sup>German Cancer Consortium (DKTK), Heidelberg, Germany</aff><aff id="aff23"><sup>23</sup>Department of Medicine, University of Maryland School of Medicine, Baltimore, MD</aff><aff id="aff24"><sup>24</sup>Icelandic Heart Association, Kópavogur, Iceland</aff><aff id="aff25"><sup>25</sup>Faculty of Medicine, University of Iceland, Reykjavik, Iceland</aff><aff id="aff26"><sup>26</sup>Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI</aff><aff id="aff27"><sup>27</sup>Renal Unit, Department of Medicine, University of Verona, Verona, Italy</aff><aff id="aff28"><sup>28</sup>Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria</aff><aff id="aff29"><sup>29</sup>Nephrology Division, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland</aff><aff id="aff30"><sup>30</sup>INSERM U-1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Villejuif, France</aff><aff id="aff31"><sup>31</sup>UMRS 1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Univ Paris Sud, Univ Versailles, St. Quentin, France</aff><aff id="aff32"><sup>32</sup>Fifth Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany</aff><aff id="aff33"><sup>33</sup>First Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria</aff><aff id="aff34"><sup>34</sup>Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, U.K.</aff><aff id="aff35"><sup>35</sup>INSERM U897, Bordeaux University, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Bordeaux, France</aff><aff id="aff36"><sup>36</sup>Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</aff><aff id="aff37"><sup>37</sup>Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</aff><aff id="aff38"><sup>38</sup>Vanderbilt University School of Medicine, Nashville, TN</aff><aff id="aff39"><sup>39</sup>University Heart Center Hamburg, Hamburg, Germany</aff><aff id="aff40"><sup>40</sup>German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany</aff><aff id="aff41"><sup>41</sup>Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.</aff><aff id="aff42"><sup>42</sup>University Clinic for Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland</aff><aff id="aff43"><sup>43</sup>Cardiovascular Health Research Unit, Departments of Epidemiology and Medicine, University of Washington, Seattle, WA</aff><aff id="aff44"><sup>44</sup>Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group</aff><aff id="aff45"><sup>45</sup>Human Genetics Center, University of Texas Health Science Center, Houston, TX</aff><aff id="aff46"><sup>46</sup>Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland</aff><aff id="aff47"><sup>47</sup>Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff48"><sup>48</sup>Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland</aff><aff id="aff49"><sup>49</sup>Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</aff><aff id="aff50"><sup>50</sup>Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy</aff><aff id="aff51"><sup>51</sup>Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</aff><aff id="aff52"><sup>52</sup>Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany</aff><aff id="aff53"><sup>53</sup>Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany</aff><aff id="aff54"><sup>54</sup>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</aff><aff id="aff55"><sup>55</sup>German Center for Diabetes Research (DZD), Neuherberg, Germany</aff><aff id="aff56"><sup>56</sup>Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff57"><sup>57</sup>Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</aff><aff id="aff58"><sup>58</sup>Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.</aff><aff id="aff59"><sup>59</sup>Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands</aff><aff id="aff60"><sup>60</sup>Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland</aff><aff id="aff61"><sup>61</sup>Swiss Institute of Bioinformatics, Lausanne, Switzerland</aff><aff id="aff62"><sup>62</sup>INSERM UMR 1167 “Risk factors and molecular determinants of aging-related diseases,” Institut Pasteur de Lille, Lille, France.</aff><aff id="aff63"><sup>63</sup>The George Institute for Global Health, University of Sydney, Camperdown, New South Wales, Australia</aff><aff id="aff64"><sup>64</sup>Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, MD</aff><aff id="aff65"><sup>65</sup>Vanderbilt University School of Medicine, Nashville, TN</aff><aff id="aff66"><sup>66</sup>Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD</aff><aff id="aff67"><sup>67</sup>Clinical Research Branch, National Institute on Aging, Baltimore, MD</aff><aff id="aff68"><sup>68</sup>The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.</aff><aff id="aff69"><sup>69</sup>Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland</aff><aff id="aff70"><sup>70</sup>University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Épalinges, Switzerland</aff><aff id="aff71"><sup>71</sup>Department of Nephrology, University Hospital Regensburg, Regensburg, Germany</aff><aff id="aff72"><sup>72</sup>Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff73"><sup>73</sup>Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.</aff><aff id="aff74"><sup>74</sup>Department of Haematology, University of Cambridge, Cambridge, U.K.</aff><aff id="aff75"><sup>75</sup>Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split, Croatia</aff><aff id="aff76"><sup>76</sup>Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany</aff><aff id="aff77"><sup>77</sup>Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany</aff><aff id="aff78"><sup>78</sup>German Center for Cardiovascular Research (DZHK), Mainz, Germany</aff><aff id="aff79"><sup>79</sup>Institute of Physiology, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff80"><sup>80</sup>Clinic for Prosthetic Dentistry, Gerostomatology and Material Science, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff81"><sup>81</sup>Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA</aff><aff id="aff82"><sup>82</sup>Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY</aff><aff id="aff83"><sup>83</sup>Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland</aff><aff id="aff84"><sup>84</sup>Kidney and Hypertension Section, Joslin Diabetes Center and Harvard Medical School, Boston, MA</aff><aff id="aff85"><sup>85</sup>Clinic for Internal Medicine A, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff86"><sup>86</sup>Institute for Human Genetics, Hannover Medical School, Hannover, Germany</aff><aff id="aff87"><sup>87</sup>Hannover Unified Biobank, Hannover Medical School, Hannover, Germany</aff><aff id="aff88"><sup>88</sup>Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff89"><sup>89</sup>Abteilung Innere II, Universitätsklinikum Ulm, Ulm, Germany</aff><aff id="aff90"><sup>90</sup>Deutsches Herzzentrum München, Technische Universität München, Munich, Germany</aff><aff id="aff91"><sup>91</sup>German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany</aff><aff id="aff92"><sup>92</sup>University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland</aff><aff id="aff93"><sup>93</sup>Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</aff><aff id="aff94"><sup>94</sup>Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI</aff><aff id="aff95"><sup>95</sup>Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), University of Montreal, CHUM Research Center, Technopìle Angus, Montreal, Quebec, Canada.</aff><aff id="aff96"><sup>96</sup>Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA</aff></contrib-group><author-notes><corresp id="cor1">Corresponding authors: Anna Köttgen, <email>anna.koettgen@uniklinik-freiburg.de</email>, Alexander Teumer, <email>ateumer@uni-greifswald.de</email>, Caroline S. Fox, <email>foxca@nhlbi.nih.gov</email>, and Cristian Pattaro, <email>cristian.pattaro@eurac.edu</email>.</corresp><fn fn-type="equal"><p>A.Te., A.Ti., R.S., M.G., and N.C.Y. contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><month>3</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>2</day><month>12</month><year>2015</year></pub-date><volume>65</volume><issue>3</issue><fpage>803</fpage><lpage>817</lpage><history><date date-type="received"><day>21</day><month>9</month><year>2015</year></date><date date-type="accepted"><day>25</day><month>11</month><year>2015</year></date></history><permissions><copyright-statement>© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.</copyright-statement><copyright-year>2016</copyright-year></permissions><self-uri xlink:title="pdf" xlink:href="db151313.pdf"></self-uri><abstract><p>Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in <italic>CUBN</italic>, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (<italic>P</italic> = 2.4 × 10<sup>−10</sup>). Gene-by-diabetes interactions were detected and confirmed for variants in <italic>HS6ST1</italic> and near <italic>RAB38</italic>/<italic>CTSC</italic>. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for <italic>HS6ST1</italic> (<italic>P</italic> = 6.3 × 10<sup>–7</sup>) and 13% for <italic>RAB38</italic>/<italic>CTSC</italic> (<italic>P</italic> = 5.8 × 10<sup>−7</sup>). Experiments using streptozotocin-induced diabetic <italic>Rab38</italic> knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in <italic>Rab38</italic> knockout versus control rats. Relative expression of <italic>RAB38</italic> was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.</p></abstract><funding-group><award-group id="sp1"><funding-source>National Institutes of Health (NIH)<named-content content-type="funder-id">http://dx.doi.org/10.13039/100000002</named-content></funding-source><award-id rid="sp1">N01-AG-1-2100</award-id><award-id rid="sp1">HHSN271201200022C</award-id></award-group></funding-group><funding-group><award-group id="sp2"><funding-source>NIH</funding-source><award-id rid="sp2">R01-AG-18728</award-id><award-id rid="sp2">R01-HL-088119</award-id><award-id rid="sp2">U01-GM-074518-04</award-id><award-id rid="sp2">U01- HL0-72515-06</award-id><award-id rid="sp2">U01-HL0-84756</award-id><award-id rid="sp2">K12-RR0-23250</award-id><award-id rid="sp2">M01-RR-16500</award-id></award-group></funding-group><funding-group><award-group id="sp3"><funding-source>German Research Foundation<named-content content-type="funder-id">http://dx.doi.org/xxx</named-content></funding-source><award-id rid="sp3">KO 3598/2-1</award-id></award-group></funding-group><funding-group><award-group id="sp4"><funding-source>NIH<named-content content-type="funder-id">http://dx.doi.org/10.13039/100000002</named-content></funding-source><award-id rid="sp4">2R01-LM0-10098</award-id></award-group></funding-group><counts><fig-count count="3"></fig-count><table-count count="2"></table-count><equation-count count="0"></equation-count><ref-count count="42"></ref-count><page-count count="15"></page-count></counts></article-meta></front><body><sec sec-type="intro" id="s1"><title>Introduction</title><p>Urinary albumin and serum creatinine are two biomarkers recommended for the routine assessment of chronic kidney disease (CKD) (<xref rid="B1" ref-type="bibr">1</xref>). Even at physiological rates of glomerular filtration, small elevations in urinary albumin concentrations are associated with an increased risk for CKD progression, end-stage renal disease (ESRD), cardiovascular events, and cardiovascular and all-cause mortality (<xref rid="B2" ref-type="bibr">2</xref>–<xref rid="B4" ref-type="bibr">4</xref>). Patients with diabetes are at a particularly high risk for CKD and its sequelae: the prevalence of CKD among individuals with diabetes is >40% compared with ∼10% in the general U.S. adult population (<xref rid="B5" ref-type="bibr">5</xref>), and the presence of CKD is an important contributor to the excess mortality in diabetes (<xref rid="B6" ref-type="bibr">6</xref>). The appearance of significant amounts of albumin in the urine (albuminuria) is a hallmark of diabetic kidney disease (DKD), the incidence of which continues to rise along with type 2 diabetes worldwide (<xref rid="B7" ref-type="bibr">7</xref>). Residual diabetes-related microvascular risk represents an important challenge even in treated individuals (<xref rid="B8" ref-type="bibr">8</xref>), and DKD remains the leading cause of ESRD. No new effective treatments for DKD have been approved in more than two decades (<xref rid="B9" ref-type="bibr">9</xref>), highlighting the importance to better understand its underlying mechanisms.</p><p>Using genome-wide association study (GWAS) meta-analysis in general population cohorts, we previously identified a missense single nucleotide polymorphism (SNP) in the gene encoding cubilin (<italic>CUBN</italic>) in association with the urinary albumin-to-creatinine ratio (UACR) (<xref rid="B10" ref-type="bibr">10</xref>). <italic>CUBN</italic> is currently the only genome-wide significant locus for UACR. However, this variant explains only a small fraction of the previously reported heritability of albuminuria, ranging from 0.2 to 0.46 in the general population and in those with diabetes (<xref rid="B11" ref-type="bibr">11</xref>–<xref rid="B13" ref-type="bibr">13</xref>), suggesting that additional genetic variants remain to be found. Here we report the results of a GWAS meta-analysis of albuminuria traits in the general population performed in almost twice the sample size of our previous study (<xref rid="B10" ref-type="bibr">10</xref>), with a special focus on those with diabetes, replication in additional independent individuals, and follow-up investigations in human tissues and a genetically modified animal model of diabetes.</p></sec><sec id="s2"><title>Research Design and Methods</title><sec id="s3"><title>Study Populations</title><p>Our study was based on 30 discovery and replication studies mostly from the general population, with the exception of Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) and Genetics of Diabetic Nephropathy (GENDIAN), which enrolled exclusively individuals with type 2 diabetes, totaling 67,452 participants of European ancestry across the different analyses (up to 7,787 with diabetes in discovery and replication). The study characteristics, including the distribution of albuminuria and diabetes, are reported in <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Table 1</ext-link>. Study protocols were approved by each local institutional review board or ethics committee, and all human participants gave written informed consent.</p></sec><sec id="s4"><title>Phenotype Definitions and Analytical Strategy</title><p>The measurement of urinary albumin and creatinine in each study is reported in <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Table 2</ext-link>. Urinary albumin values below the detection limit of the used assays were set to the lower limit of detection. Rather than using urinary albumin, the UACR was calculated as urinary albumin/urinary creatinine (mg/g) to account for differences in urine concentration. Microalbuminuria (MA) was defined as UACR >25 mg/g in women and >17 mg/g in men (<xref rid="B10" ref-type="bibr">10</xref>). Diabetes was defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or treatment for diabetes, or by self-report if this information was not available. Across studies, we evaluated two traits, UACR and MA, and performed four GWAS meta-analyses: MA and UACR in the overall sample, as well as UACR—a continuous trait with higher statistical power—separately among those with and without diabetes. Diabetes-stratified genome-wide association analyses of MA were not performed due to limited sample size. Detailed information on the design, genotyping, imputation, and data management of each study is provided in <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Tables 2 and 3</ext-link>.</p></sec><sec id="s5"><title>Discovery Meta-Analysis, Replication, and Power</title><p>Stringent quality control of the genetic data was performed at the individual study level and again at the meta-analysis level using state-of-the-art methods. Missing genotypes were imputed using the HapMap reference panels in 19 studies and the 1000 Genomes reference panels in two studies. Details of genotyping, imputation software, reference panels, and quality filters in each study are reported in <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Table 3</ext-link>.</p><p>All GWAS were performed following a standardized analysis protocol. In each study, the natural logarithm of UACR was taken. Subsequently, sex-specific residuals were obtained from linear regression models of ln (UACR) on age and study-specific covariates, including study center and genetic principal components, to adjust for possible population stratification, if applicable. The continuous sex-specific residuals were then combined and used as the dependent variable that was regressed on imputed allelic dosages for each SNP in the GWAS.</p><p>Before the meta-analyses, all study-specific GWAS summary files underwent quality control using the GWAtoolbox (<xref rid="B14" ref-type="bibr">14</xref>). Genomic-control (GC) (<xref rid="B15" ref-type="bibr">15</xref>) correction was applied when the GC factor was >1. Inverse variance weighted fixed-effects meta-analyses were conducted using METAL (<xref rid="B16" ref-type="bibr">16</xref>). The <italic>I</italic><sup>2</sup> statistic was used to evaluate between-study heterogeneity (<xref rid="B17" ref-type="bibr">17</xref>). All meta-analyses were performed in duplicate by two independent researchers.</p><p>After meta-analysis, SNPs with average minor allele frequency (MAF) <0.01 were excluded, and another GC correction was applied. There were 2,191,945 SNPs with average MAF >0.05 and present in >50% of the studies, which were then clustered based on correlation (linkage disequilibrium pruning using <italic>r</italic><sup>2</sup> ≤ 0.2) with the respective index SNP (the SNP with the lowest <italic>P</italic> value) within windows of ± 1 MB to identify independent SNPs with suggestive association (<italic>P</italic> < 10<sup>−5</sup>) in one or more of the four analyses.</p><p>Replication testing was then performed for signals that were genome-wide significant (<italic>P</italic> < 5 × 10<sup>−8</sup>) in any analysis or that showed suggestive association among those with diabetes, motivated by the clinical importance of DKD and the stronger association of the known and validated <italic>CUBN</italic> variant on UACR among those with diabetes (<xref rid="B18" ref-type="bibr">18</xref>). Replication was defined as a one-sided <italic>P</italic> value <0.05 in the meta-analysis of independent replication studies. Five of the nine studies that contributed to replication used imputed dosage, and four studies performed replication genotyping of the index SNPs. A meta-analysis of the replication results was performed. The double GC-corrected results from the discovery meta-analysis and the results of the nine replication studies were meta-analyzed to obtain the overall statistical significance. Unless stated otherwise, all reported <italic>P</italic> values are two-sided.</p><p>Assuming that associated SNPs explain a respective 0.6% and 0.5% of the UACR variance in diabetes (<xref ref-type="table" rid="T1">Table 1</xref>), there was 95% and 91% power, respectively, to replicate the seven suggestive loci from the discovery stage in an additional 1,800 samples with a one-sided <italic>P</italic> value of <0.05.</p><table-wrap id="T1" orientation="portrait" position="float"><label>Table 1</label><caption><p>Replicated SNP associations with UACR in individuals with diabetes</p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th align="left" scope="col" rowspan="1" colspan="1"></th><th align="center" scope="col" rowspan="1" colspan="1">Sample size (<italic>n</italic>)</th><th align="center" scope="col" rowspan="1" colspan="1">Effect on log(UACR) mg/g</th><th align="center" scope="col" rowspan="1" colspan="1">SE</th><th align="center" scope="col" rowspan="1" colspan="1"><italic>P</italic> value</th><th align="center" scope="col" rowspan="1" colspan="1"><italic>I</italic><sup>2</sup> %</th></tr></thead><tbody><tr><td colspan="2" align="left" scope="col" rowspan="1">rs649529, <italic>RAB38</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1"> Discovery</td><td align="center" rowspan="1" colspan="1">5,825</td><td align="center" rowspan="1" colspan="1">−0.15</td><td align="center" rowspan="1" colspan="1">0.03</td><td align="center" rowspan="1" colspan="1">9.3 × 10<sup>−6</sup></td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1"> Replication</td><td align="center" rowspan="1" colspan="1">1,962</td><td align="center" rowspan="1" colspan="1">−0.12</td><td align="center" rowspan="1" colspan="1">0.05</td><td align="center" rowspan="1" colspan="1">0.02</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1"> Combined</td><td align="center" rowspan="1" colspan="1">7,787</td><td align="center" rowspan="1" colspan="1">−0.14</td><td align="center" rowspan="1" colspan="1">0.03</td><td align="center" rowspan="1" colspan="1">5.8 × 10<sup>−7</sup></td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td colspan="2" align="left" scope="col" rowspan="1">rs13427836, <italic>HS6ST1</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1"> Discovery</td><td align="center" rowspan="1" colspan="1">5,509</td><td align="center" rowspan="1" colspan="1">0.20</td><td align="center" rowspan="1" colspan="1">0.04</td><td align="center" rowspan="1" colspan="1">6.1 × 10<sup>−6</sup></td><td align="center" rowspan="1" colspan="1">10</td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1"> Replication</td><td align="center" rowspan="1" colspan="1">1,890</td><td align="center" rowspan="1" colspan="1">0.16</td><td align="center" rowspan="1" colspan="1">0.07</td><td align="center" rowspan="1" colspan="1">0.03</td><td align="center" rowspan="1" colspan="1">58</td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1"> Combined</td><td align="center" rowspan="1" colspan="1">7,399</td><td align="center" rowspan="1" colspan="1">0.19</td><td align="center" rowspan="1" colspan="1">0.04</td><td align="center" rowspan="1" colspan="1">6.3 × 10<sup>−7</sup></td><td align="center" rowspan="1" colspan="1">30</td></tr></tbody></table><table-wrap-foot><fn><p>For both variants, the effect of each additional copy of the minor allele (T) on UACR was modeled in an additive fashion. <italic>I</italic><sup>2</sup> is provided as a measure of heterogeneity across studies. Imputation quality ranged from 0.41 to 1.0 for rs649529 and from 0.44 to 1.0 for rs13427836. The variants were directly genotyped in four of the replication studies, with a call rate ranging from 0.98 to 1.0 for rs649529 and from 0.99 to 1.0 for rs13427836. The estimated proportion of explained variance in UACR among those with diabetes is 0.6% for rs649529 and 0.5% for rs13427836, using the formula 2 × MAF × (1-MAF) × effect<sup>2</sup>/var(log[UACR]), based on the combined effect estimates from <xref ref-type="table" rid="T1">Table 1</xref> and the phenotypic variance in the large population-based ARIC Study.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s6"><title>Additional Analyses to Characterize Novel Loci</title><p>Replicated SNPs were further evaluated even in the absence of genome-wide significance because, in addition to the significant replication <italic>P</italic> value, the low heterogeneity across cohorts and the biological plausibility of the <italic>RAB38</italic> locus further increased confidence in the findings. The SNPs were evaluated in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study for association with a primary clinical end point defined as time from the DCCT baseline until time to persistent MA or a secondary end point of time to incident albumin excretion rate >300 mg/24 h or ESRD (<xref rid="B10" ref-type="bibr">10</xref>). Time to outcome development or censoring was determined as the number of visit years from the DCCT baseline up to and including the 12th year of EDIC follow-up. Subjects with persistent MA at DCCT baseline and DCCT year 1 were excluded from analyses of that outcome.</p><p>Epigenomic map analyses were performed, as described previously (<xref rid="B19" ref-type="bibr">19</xref>), by using data from human kidney and kidney proximal tubule epithelial cells that can be accessed at Gene Expression Omnibus (GSE49637).</p><p>Genetic associations with additional renal function traits, estimated glomerular filtration rate (eGFR), and CKD, were evaluated based on results from GWAS meta-analysis of the corresponding traits within the CKDGen Consortium (C.P., personal communication).</p></sec><sec id="s7"><title>Gene Expression Analyses in Human Tissues</title><p>Quantification of transcript abundance in microdissected fractions of human glomeruli and tubuli from surgical nephrectomies, living allograft donors, and portions of diagnostic kidney biopsies (<xref rid="B20" ref-type="bibr">20</xref>) was performed using RNA sequencing. Tissue from different renal compartments was separated using microdissection, homogenized, and stored at −80°C. Total RNA of human proximal tubule fractions (<italic>n</italic> = 256) and glomerular cells (<italic>n</italic> = 48) was isolated using the RNeasy Mini Kit (Qiagen) according to the manufacturer's instructions. RNA quality was assessed with the Agilent Bioanalyzer 2100, and RNA preparations exhibiting RNA integrity number scores >7 were used for cDNA synthesis (library preparation at DNA Sequencing Core at UT Southwestern Medical Center). In short, 1 μg total RNA was used to isolate poly A purified mRNA using the Illumina TruSeq RNA Preparation Kit. Single-end 100 bp sequencing was performed, and the annotated RNA counts (fastq) were calculated by CASAVA 1.8.2 (Illumina). Reads were mapped to the reference genome (National Center for Biotechnology Information build 37, hg19) using Spliced Transcripts Alignment to a Reference (STAR). Reads per kilobase of transcript per million mapped for <italic>HS6ST1</italic> and <italic>RAB38</italic> were compared between glomerular and tubular fractions using a two-sided <italic>t</italic> test.</p><p>Comparison of candidate gene expression between case subjects with DKD proven by biopsy specimen and healthy control subjects was based on publicly available microarray data from human microdissected glomeruli and tubuli (Gene Expression Omnibus, GSE 30122) (<xref rid="B20" ref-type="bibr">20</xref>). Raw data were analyzed using the R package “Affy” version 1.44.0, and expression levels were normalized using robust multiarray average. Transcript abundance between patients and control subjects was compared using two-sided <italic>t</italic> tests; statistical significance was defined as <italic>P</italic> < 8.3 × 10<sup>−3</sup> (α = 0.05 corrected for six comparisons).</p></sec><sec id="s8"><title>Studies of <italic>Rab38</italic> in Rats</title><p>To better understand the association of <italic>RAB38</italic> with albuminuria in diabetes, we studied genetically modified rat models of diabetes. Eight <italic>Rab38</italic> knockout (KO) rats on a fawn-hooded hypertensive (FHH) background, seven rats transgenic for the wild-type Brown Norway rat <italic>Rab38</italic> allele, and seven congenic rats were generated and raised as described previously (<xref rid="B21" ref-type="bibr">21</xref>–<xref rid="B23" ref-type="bibr">23</xref>). <italic>Rab38</italic> KO rats did not express the protein (<xref rid="B22" ref-type="bibr">22</xref>). These references also describe the recording of blood pressure and the measurement of glucose and albuminuria. Diabetes was induced by administering streptozotocin (STZ) (STZ; 50 mg/kg i.p.; Sigma-Aldrich, St. Louis, MO) to 9-week-old male rats.</p><p>Paraffin blocks of rat kidney samples were sectioned (6-μm thickness) with a Leica RM2255 rotary microtome (Thermo-Fisher Scientific, Waltham, MA) on Superfrost Plus glass slides (12-550-15, Thermo-Fisher Scientific). Before staining, slides were deparaffinized in changes of CitriSolv (22-143-975, Thermo-Fisher Scientific) and 70% isopropanol. Antigen retrieval was accomplished by incubating in sodium citrate buffer (1.8% 0.1 mol/L citric acid, 8.2% 0.1 mol/L sodium citrate, in distillated water, pH 6.0) in a rice cooker for 30 min. Slides were blocked with PBS blocking buffer (1% BSA, 0.2% nonfat dry milk in PBS) for 30 min and stained with primary antibodies specific for megalin or cubilin diluted in blocking buffer overnight at 4°C. Sheep anti-megalin and rabbit anti-cubilin were provided by Dr. P. Verroust, INSERM, Paris, France. After two washes in 0.1% Tween 20 (v/v in PBS), slides were incubated with corresponding fluorophore-conjugated secondary antibodies (Invitrogen), diluted in blocking buffer at room temperature for 1 h, and counterstained with 10 μmol/L Hoechst 33342 (Molecular Probes-Invitrogen, H1399). Slides were subsequently mounted in Prolong Gold Antifade reagent (Invitrogen), and images were acquired with a Leica SP5 confocal laser scanning microscope (Center for Microscopy and Image Analysis, University of Zurich) equipped with a Leica APO ×63 NA 1.4 oil immersion objective.</p><p>All experiments were performed in compliance with National Institutes of Health <italic>Guide for Care and Use of Laboratory Animals</italic>, and all used protocols were approved by the local institutional animal care and use committee.</p></sec></sec><sec sec-type="results" id="s9"><title>Results</title><sec id="s10"><title>Discovery of Genomic Loci Associated With Albuminuria Traits</title><p>The discovery GWAS meta-analyses for the four traits included up to 20 studies and up to 54,450 individuals per trait. The median UACR in the 20 individual studies that contributed to the UACR meta-analysis ranged from 2.5 to 15.6 mg/g. Across all studies, the mean proportion of women was 53%, and the median of average age was 57 years. The prevalence of diabetes in the population-based studies ranged from 1 to 14% (<ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Table 1</ext-link>).</p><p>There was no evidence of systematic biases influencing the genome-wide association results, as indicated by low genomic control parameters (<ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Fig. 1</ext-link>). Only SNPs in the previously identified <italic>CUBN</italic> locus showed genome-wide significant association with both UACR (<italic>P</italic> = 2.4 × 10<sup>−10</sup>, <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Table 4</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Fig. 2</ext-link>) and MA (<italic>P</italic> = 1.3 × 10<sup>−10</sup>, <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Table 5</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Fig. 2</ext-link>). The effect of the minor C allele of the index SNP rs10795433 on logarithmic UACR values was fourfold larger among 5,825 individuals with diabetes (0.19 log[mg/g], <italic>P</italic> = 2.0 × 10<sup>−5</sup>) compared with 46,061 individuals without diabetes (0.045 log[mg/g], <italic>P</italic> = 8.7 × 10<sup>−6</sup>; <italic>P</italic> = 8.2 × 10<sup>−4</sup> for difference). This corresponds, for each additional C allele, to a 5% higher geometric mean of UACR (exp[0.045]) in individuals without diabetes compared with 21% higher average UACR in those with diabetes (exp[0.19]).</p><p>Suggestive associations were identified for all four analyses (<ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Tables 4–7</ext-link> and regional association plots in <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Fig. 3</ext-link>). Among the clinically important group of individuals with diabetes, seven genomic loci contained one or more SNPs showing a suggestive association with UACR. These were exclusively identified in the meta-analysis of individuals with diabetes and mapped into or near <italic>HS6ST1</italic>, <italic>CNTN4</italic>, <italic>KBTBD8</italic>, <italic>TFAP2B</italic>/<italic>PKHD1</italic>, <italic>CHN2</italic>, <italic>WDR11</italic>/<italic>FGFR2</italic>, and <italic>RAB38</italic>/<italic>CTSC</italic> (<ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Table 7</ext-link>). Following our analytical strategy, we selected the index SNP in each of these seven regions for follow-up among up to 1,962 independent individuals with diabetes.</p><p>The <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary PDF</ext-link> document contains the QQ and Manhattan plots of all GWAS meta-analyses, the regional association plots, tables with cohort descriptions, and association results of SNPs at <italic>P</italic> < 10<sup>−5</sup>. Results from discovery GWAS meta-analysis are publicly available at <ext-link ext-link-type="uri" xlink:href="http://fox.nhlbi.nih.gov/CKDGen/">http://fox.nhlbi.nih.gov/CKDGen/</ext-link>.</p></sec><sec id="s11"><title>Replication Analyses Implicate <italic>RAB38/CTSC</italic> and <italic>HS6ST1</italic> as Novel Loci for UACR in Diabetes</title><p>The replication analyses included nine studies and up to 1,962 individuals with diabetes. The median UACR across replication studies ranged from 3.8 to 14.5 mg/g. The mean proportion of women was 49%, and the median of average age was 55 years. For the seven SNPs tested for replication (<ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Table 8</ext-link>), we assessed whether the one-sided <italic>P</italic> value was <0.05 in the combined replication studies (see <sc>research design and methods</sc>). This was the case for two SNPs: intergenic rs649529 upstream of <italic>RAB38</italic>/downstream of <italic>CTSC</italic> on chromosome 11q14 (<xref ref-type="fig" rid="F1">Fig. 1<italic>A</italic></xref>) and the intronic variant rs13427836 in <italic>HS6ST1</italic> on chromosome 2q21 (<xref ref-type="fig" rid="F1">Fig. 1<italic>B</italic></xref>). As illustrated in <xref ref-type="fig" rid="F1">Fig. 1<italic>C</italic></xref>, each additional copy of the minor T allele of rs649529 at <italic>RAB38</italic>/<italic>CTSC</italic> was consistently associated with lower UACR among the 5,825 individuals in the discovery and 1,962 in the replication cohorts (combined <italic>P</italic> = 5.8 × 10<sup>−7</sup>) (<xref ref-type="table" rid="T1">Table 1</xref>), with no evidence of heterogeneity across cohorts (<italic>I</italic><sup>2</sup> = 0%). This effect corresponded to 13% lower geometric mean of UACR per copy of the T allele. Similarly, rs13427836 in <italic>HS6ST1</italic> showed consistent effects across cohorts (combined <italic>P</italic> = 6.3 × 10<sup>−7</sup>) (<xref ref-type="table" rid="T1">Table 1</xref>), with each copy of the T allele associated with an ∼21% higher mean UACR but moderate heterogeneity (<italic>I</italic><sup>2</sup> = 29.9%) (<xref ref-type="fig" rid="F1">Fig. 1<italic>D</italic></xref>).</p><fig id="F1" fig-type="figure" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Overview of associated genomic loci at <italic>RAB38</italic>/<italic>CTSC</italic> and <italic>HS6ST1</italic> and consistent association with albuminuria in diabetes across the contributing studies. <italic>A</italic>: Regional association plot of the <italic>RAB38</italic>/<italic>CTSC</italic> locus on chromosome 11. <italic>B</italic>: The T allele at rs649529 is associated with lower UACR across discovery and replication studies. <italic>C</italic>: Regional association plot of the <italic>HS6ST1</italic> locus on chromosome 10. <italic>D</italic>: The T allele of intronic rs13427836 is associated with higher UACR across discovery and replication studies. The solid squares indicate the mean difference and are proportional to the weights used in the meta-analysis. The solid vertical line indicates no effect. The diamond indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated CIs. The horizontal lines represent the 95% CI.</p></caption><graphic xlink:href="db151313f1"></graphic></fig><p>The association of rs649529 near <italic>RAB38</italic>/<italic>CTSC</italic> and rs13427836 in <italic>HS6ST1</italic> was not found in individuals without diabetes (<italic>P</italic> = 0.64 and <italic>P</italic> = 0.38, respectively) (<xref ref-type="table" rid="T2">Table 2</xref>). Differences in the association with UACR among those with and without diabetes were significant (<italic>t</italic> test for difference: <italic>P</italic> = 6.9 × 10<sup>−6</sup> for rs649529 and <italic>P</italic> = 1.7 × 10<sup>−5</sup> for rs13427836). Effects for the index variant in <italic>CUBN</italic> are provided for comparison. We also evaluated the association of the replicated SNPs with MA in the setting of diabetes. Information was obtained from a subset of studies with sufficiently high numbers of individuals with diabetes and MA (<italic>n</italic> = 2,552; Atherosclerosis Risk in Communities Study [ARIC], Cardiovascular Health Study [CHS], Cohorte Lausannoise [CoLaus], European Prospective Investigation into Cancer and Nutrition [EPIC], Framingham Heart Study [FHS], Kooperative Gesundheitsforschung in der Region Augsburg [KORA] F3, KORAF4, and Study of Health in Pomerania [SHIP]). Across cohorts, the odds ratio for MA for each copy of the minor allele was 0.84 for rs649529 near <italic>RAB38</italic> (<italic>P</italic> = 0.019) and 1.39 for rs13427836 in <italic>HS6ST1</italic> (<italic>P</italic> = 7.8 × 10<sup>−4</sup>), consistent with the direction of the SNP effects on UACR.</p><table-wrap id="T2" orientation="portrait" position="float"><label>Table 2</label><caption><p>Replicated SNP associations with additional kidney function and diabetes-related traits</p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th align="left" scope="col" rowspan="1" colspan="1">Trait<hr></hr></th><th align="center" scope="col" rowspan="1" colspan="1"><italic>n</italic><hr></hr></th><th align="center" scope="col" rowspan="1" colspan="1">Effect (OR)<hr></hr></th><th align="center" scope="col" rowspan="1" colspan="1">SE<hr></hr></th><th align="center" scope="col" rowspan="1" colspan="1"><italic>P</italic> value<hr></hr></th><th align="center" scope="col" rowspan="1" colspan="1"><italic>P</italic> difference<xref ref-type="table-fn" rid="t2n1">*</xref><hr></hr></th></tr></thead><tbody><tr><td colspan="6" align="center" scope="col" rowspan="1">rs649529, <italic>RAB38</italic>/<italic>CTSC</italic></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">UACR, diabetes; log(mg/g)</td><td align="center" rowspan="1" colspan="1">7,787</td><td align="center" rowspan="1" colspan="1">−0.14</td><td align="center" rowspan="1" colspan="1">0.03</td><td align="center" rowspan="1" colspan="1">5.8 × 10<sup>−7</sup></td><td rowspan="2" align="center" colspan="1">6.9 × 10<sup>−6</sup></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">UACR, no diabetes; log(mg/g)</td><td align="center" rowspan="1" colspan="1">45,094</td><td align="center" rowspan="1" colspan="1">−0.004</td><td align="center" rowspan="1" colspan="1">0.008</td><td align="center" rowspan="1" colspan="1">0.64</td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">eGFRcrea, diabetes; log(mL/min/1.73 m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">11,527</td><td align="center" rowspan="1" colspan="1">0.003</td><td align="center" rowspan="1" colspan="1">0.004</td><td align="center" rowspan="1" colspan="1">0.46</td><td rowspan="2" align="center" colspan="1">2.8 × 10<sup>−1</sup></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">eGFRcrea, no diabetes; log(mL/min/1.73 m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">118,427</td><td align="center" rowspan="1" colspan="1">−0.001</td><td align="center" rowspan="1" colspan="1">0.001</td><td align="center" rowspan="1" colspan="1">0.59</td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1">CKD (eGFR <60 mL/min/1.73 m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">118,114</td><td align="center" rowspan="1" colspan="1">(1.01)</td><td align="center" rowspan="1" colspan="1">0.02</td><td align="center" rowspan="1" colspan="1">0.57</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1">Type 2 diabetes</td><td align="center" rowspan="1" colspan="1">63,390</td><td align="center" rowspan="1" colspan="1">(1.02)</td><td align="center" rowspan="1" colspan="1">0.02</td><td align="center" rowspan="1" colspan="1">0.32</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">Fasting glucose (mmol/L)</td><td align="center" rowspan="1" colspan="1">46,186</td><td align="center" rowspan="1" colspan="1">0.003</td><td align="center" rowspan="1" colspan="1">0.006</td><td align="center" rowspan="1" colspan="1">0.65</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">HbA<sub>1c</sub> (%)</td><td align="center" rowspan="1" colspan="1">46,368</td><td align="center" rowspan="1" colspan="1">0.004</td><td align="center" rowspan="1" colspan="1">0.004</td><td align="center" rowspan="1" colspan="1">0.31</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td colspan="6" align="center" scope="col" rowspan="1">rs13427836, <italic>HS6ST1</italic></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">UACR, diabetes; log(mg/g)</td><td align="center" rowspan="1" colspan="1">7,399</td><td align="center" rowspan="1" colspan="1">0.19</td><td align="center" rowspan="1" colspan="1">0.04</td><td align="center" rowspan="1" colspan="1">6.3 × 10<sup>−7</sup></td><td rowspan="2" align="center" colspan="1">1.7 × 10<sup>−5</sup></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">UACR, no diabetes; log(mg/g)</td><td align="center" rowspan="1" colspan="1">34,830</td><td align="center" rowspan="1" colspan="1">0.010</td><td align="center" rowspan="1" colspan="1">0.012</td><td align="center" rowspan="1" colspan="1">0.38</td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">eGFRcrea, diabetes; log(mL/min/1.73 m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">11,092</td><td align="center" rowspan="1" colspan="1">0.008</td><td align="center" rowspan="1" colspan="1">0.006</td><td align="center" rowspan="1" colspan="1">0.13</td><td rowspan="2" align="center" colspan="1">1.3 × 10<sup>−1</sup></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">eGFRcrea, no diabetes; log(mL/min/1.73 m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">114,247</td><td align="center" rowspan="1" colspan="1">0.000</td><td align="center" rowspan="1" colspan="1">0.001</td><td align="center" rowspan="1" colspan="1">0.94</td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1">CKD (eGFR <60 mL/min/1.73m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">113,612</td><td align="center" rowspan="1" colspan="1">(0.97)</td><td align="center" rowspan="1" colspan="1">0.02</td><td align="center" rowspan="1" colspan="1">0.23</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1">Type 2 diabetes</td><td align="center" rowspan="1" colspan="1">63,390</td><td align="center" rowspan="1" colspan="1">(1.00)</td><td align="center" rowspan="1" colspan="1">0.03</td><td align="center" rowspan="1" colspan="1">0.94</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">Fasting glucose (mmol/L)</td><td align="center" rowspan="1" colspan="1">46,186</td><td align="center" rowspan="1" colspan="1">−0.005</td><td align="center" rowspan="1" colspan="1">0.004</td><td align="center" rowspan="1" colspan="1">0.22</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">HbA<sub>1c</sub> (%)</td><td align="center" rowspan="1" colspan="1">46,368</td><td align="center" rowspan="1" colspan="1">0.003</td><td align="center" rowspan="1" colspan="1">0.005</td><td align="center" rowspan="1" colspan="1">0.61</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td colspan="6" align="center" scope="col" rowspan="1">rs10795433, <italic>CUBN</italic><xref ref-type="table-fn" rid="t2n2">†</xref></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">UACR, diabetes; log(mg/g)</td><td align="center" rowspan="1" colspan="1">5,825</td><td align="center" rowspan="1" colspan="1">0.19</td><td align="center" rowspan="1" colspan="1">0.04</td><td align="center" rowspan="1" colspan="1">2.0 × 10<sup>−5</sup></td><td rowspan="2" align="center" colspan="1">8.2 × 10<sup>−4</sup></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">UACR, no diabetes; log(mg/g)</td><td align="center" rowspan="1" colspan="1">46,061</td><td align="center" rowspan="1" colspan="1">0.045</td><td align="center" rowspan="1" colspan="1">0.01</td><td align="center" rowspan="1" colspan="1">8.7 × 10<sup>−6</sup></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">eGFRcrea, diabetes; log(mL/min/1.73 m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">11,522</td><td align="center" rowspan="1" colspan="1">0.007</td><td align="center" rowspan="1" colspan="1">0.005</td><td align="center" rowspan="1" colspan="1">0.18</td><td rowspan="2" align="center" colspan="1">1.9 × 10<sup>−1</sup></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">eGFRcrea, no diabetes; log(mL/min/1.73 m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">118,299</td><td align="center" rowspan="1" colspan="1">0.0007</td><td align="center" rowspan="1" colspan="1">0.001</td><td align="center" rowspan="1" colspan="1">0.61</td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1">CKD (eGFR <60 mL/min/1.73 m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">118,121</td><td align="center" rowspan="1" colspan="1">(1.04)</td><td align="center" rowspan="1" colspan="1">0.02</td><td align="center" rowspan="1" colspan="1">0.08</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" scope="row" rowspan="1" colspan="1">Type 2 diabetes</td><td align="center" rowspan="1" colspan="1">63,390</td><td align="center" rowspan="1" colspan="1">(1.00)</td><td align="center" rowspan="1" colspan="1">0.03</td><td align="center" rowspan="1" colspan="1">0.88</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">Fasting glucose (mmol/L)</td><td align="center" rowspan="1" colspan="1">46,186</td><td align="center" rowspan="1" colspan="1">−0.003</td><td align="center" rowspan="1" colspan="1">0.005</td><td align="center" rowspan="1" colspan="1">0.52</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td valign="middle" align="left" scope="row" rowspan="1" colspan="1">HbA<sub>1c</sub> (%)</td><td align="center" rowspan="1" colspan="1">46,368</td><td align="center" rowspan="1" colspan="1">−0.002</td><td align="center" rowspan="1" colspan="1">0.005</td><td align="center" rowspan="1" colspan="1">0.73</td><td align="left" rowspan="1" colspan="1"></td></tr></tbody></table><table-wrap-foot><fn><p>DM, diabetes mellitus; eGFRcrea, GFR estimated by serum creatinine levels; OR, odds ratio.</p></fn><fn><p>Effects represent the change in trait associated with each additional copy of the minor allele for each of the SNPs. For continuous traits, units are provided; the effect for binary outcomes, shown in parentheses, represents the OR. Except for UACR in diabetes, estimates refer to the discovery samples of the respective trait and to the published resources for the glycemic traits. Fasting glucose and HbA<sub>1c</sub> were evaluated among individuals free of diabetes. For the kidney traits, <italic>P</italic> values and SEs are corrected using genomic control.</p></fn><fn id="t2n1"><p>*<italic>P</italic> value for difference from a two-sample <italic>t</italic> test: <italic>t</italic> = (effect<sub>DM</sub> − effect<sub>nonDM</sub>)/(SE<sub>DM</sub><sup>2</sup> + SE<sub>nonDM</sub><sup>2</sup>)<sup>0.5</sup> which, for large sample sizes is distributed as a normal (0,1). The correlation between effect<sub>DM</sub> and effect<sub>nonDM</sub> is assumed to be 0.</p></fn><fn><p>Associations with type 2 diabetes were tested using the publicly available summary statistics dataset from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) Consortium (12,171 case subjects and 56,862 control subjects) (<xref rid="B40" ref-type="bibr">40</xref>). Associations with fasting glucose and plasma hemoglobin A<sub>1c</sub> concentrations were evaluated using the publicly available results from the MAGIC Consortium (<ext-link ext-link-type="uri" xlink:href="http://www.magicinvestigators.org">www.magicinvestigators.org</ext-link>) (<xref rid="B41" ref-type="bibr">41</xref>,<xref rid="B42" ref-type="bibr">42</xref>).</p></fn><fn id="t2n2"><p>†UACR effect estimates for UACR in diabetes for <italic>CUBN</italic> are provided from the discovery stage.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s12"><title>Characterization of Genetic Effects by Markers of Kidney Function and Diabetes</title><p>We next investigated whether the gene-by-environment interaction was also observed for the eGFR, another measure of kidney function, and/or diabetes or glycemic traits. No statistically significant associations were found between rs649529, rs13427836, rs10795433, and eGFR in those with or without diabetes (<xref ref-type="table" rid="T2">Table 2</xref>) and no associations were found with CKD. There were also no statistically significant associations of these variants with type 2 diabetes, fasting blood glucose, or plasma hemoglobin A<sub>1c</sub> concentrations (<xref ref-type="table" rid="T2">Table 2</xref>), indicating that the observed associations pertain to albuminuria in the setting of diabetes rather than to diabetes or impaired glucose metabolism per se. A comprehensive search in the National Human Genome Research Institute GWAS Catalog (<xref rid="B24" ref-type="bibr">24</xref>) did not reveal any significant associations between the two validated SNPs or their proxies with other diseases or traits.</p></sec><sec id="s13"><title>Variant Evaluation</title><p>Using publicly available data of genetic effects on gene expression (<xref rid="B25" ref-type="bibr">25</xref>), we found an association in <italic>cis</italic> between rs649529 and transcript levels of <italic>RAB38</italic> (<italic>P</italic> = 5.4 × 10<sup>−6</sup>) and the neighboring <italic>CTSC</italic> (<italic>P</italic> = 7.6 × 10<sup>−7</sup>), consistent with a regulatory effect of this variant in whole blood. Corresponding data for kidney-specific tissues are currently not available, but we used epigenetic maps generated from human adult kidney tissue (<xref rid="B19" ref-type="bibr">19</xref>) (see <sc>research design and methods</sc>) to further examine the regulatory potential of index SNPs. The intronic index SNP in <italic>HS6ST1</italic> and several proxies mapped into enhancer regions. Similarly, the <italic>CUBN</italic> index variant rs10795433 mapped into an intronic enhancer region. The region in which the index variant at <italic>RAB38</italic>/<italic>CTSC</italic> is located was annotated as not mapped/repressed in these cells, thus preventing further examination. All proxies in strong linkage disequilibrium with these three index SNPs (<italic>r</italic><sup>2</sup> > 0.6, 1000G v5 reference panel) (<xref rid="B26" ref-type="bibr">26</xref>) were intronic (<italic>CUBN</italic> and <italic>HS6ST1</italic>) or intergenic (<italic>RAB38</italic>/<italic>CTSC</italic>).</p></sec><sec id="s14"><title>Clinical Characterization Including Gene Expression of Replicated Loci</title><p>To evaluate target tissues within the kidney, we characterized the identified loci using data for tissue-specific gene expression. Clinical characterization was conducted using data from patients with DKD and healthy control subjects (<xref rid="B27" ref-type="bibr">27</xref>) and a prospective study of individuals with type 1 diabetes (<xref rid="B28" ref-type="bibr">28</xref>).</p><p>We used publicly available data (<xref rid="B27" ref-type="bibr">27</xref>) to compare relative expression of <italic>RAB38</italic>, <italic>CTSC</italic>, and <italic>HS6ST1</italic> between patients with DKD confirmed by biopsy specimen and healthy control subjects (see <sc>research design and methods</sc>). After multiple testing correction, only <italic>RAB38</italic> expression levels were significantly different, with higher expression in tubuli of DKD patients compared with control subjects (<italic>P</italic> = 1.3 × 10<sup>−4</sup>) (<xref ref-type="fig" rid="F2">Fig. 2<italic>A</italic></xref>). We also used RNA sequencing data from microdissected human kidney samples to quantify <italic>RAB38</italic> and <italic>HS6ST1</italic> expression in human glomeruli and tubuli. <italic>HS6ST1</italic> showed higher expression levels than <italic>RAB38</italic>, and both genes showed higher expression in tubuli than in glomeruli (<xref ref-type="fig" rid="F2">Fig. 2<italic>B</italic></xref>). The difference between tubular and glomerular expression was more pronounced for <italic>RAB38</italic> (<italic>P</italic> = 1.1 × 10<sup>−8</sup>) than for <italic>HS6ST1</italic> (<italic>P</italic> = 0.015).</p><fig id="F2" fig-type="figure" orientation="portrait" position="float"><label>Figure 2</label><caption><p><italic>RAB38</italic> and <italic>HS6ST1</italic> expression across kidney tissues. <italic>A</italic>: Comparison of <italic>RAB38</italic> and <italic>HS6ST1</italic> expression (microarray) in tubuli and glomeruli of patients with DKD and control subjects shows significantly higher <italic>RAB38</italic> expression in tubuli of DKD patients than in tubuli of control subjects (significance threshold 0.05/6 = 8.3 × 10<sup>−3</sup> for investigating <italic>RAB38</italic>, <italic>CTSC</italic>, and <italic>HS6ST1</italic> in tubuli and glomeruli). <italic>CTSC</italic> expression was not significantly different between DKD case subjects and control subjects in tubuli (<italic>P</italic> = 0.11) or glomeruli (<italic>P</italic> = 0.03). Expression levels are shown as robust multiarray average–processed gene intensity values. <italic>B</italic>: <italic>RAB38</italic> and <italic>HS6ST1</italic> transcript abundance quantified from RNA sequencing (RNAseq) is detected at high levels in human tubuli but also in glomerular cells. Transcripts were quantified by reads per kilobase of transcript per million mapped (RPKM). The error bars in <italic>A</italic> and <italic>B</italic> correspond to the SEM.</p></caption><graphic xlink:href="db151313f2"></graphic></fig><p>To investigate whether the effect of the replicated SNPs extended to kidney disease progression in the setting of type 1 diabetes, the SNPs were tested for association with incident MA (268 case subjects, primary end point) and a combined end point of time to macroalbuminuria or ESRD (133 case subjects, secondary end point) among up to 1,304 participants with type 1 diabetes in the DCCT/EDIC study (<xref rid="B28" ref-type="bibr">28</xref>). Neither SNP showed a significant association (<ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Table 9</ext-link>).</p></sec><sec id="s15"><title>Diabetic <italic>Rab38</italic> KO Rats Show Increased Urinary Albumin Excretion</title><p>We aimed to further substantiate our findings by obtaining experimental support. We focused on the examination of <italic>RAB38</italic> because it was the gene implicated by higher gene expression in tubuli of DKD patients compared with control subjects and because previous studies of <italic>Rab38</italic> KO and transgenic rats have confirmed its role in albuminuria in FHH rats and highlighted a role in tubular albumin reuptake (<xref rid="B21" ref-type="bibr">21</xref>,<xref rid="B22" ref-type="bibr">22</xref>). We thus examined these animals in the setting of diabetes as outlined in <xref ref-type="fig" rid="F3">Fig. 3<italic>A</italic></xref>. Injection of STZ in 9-week-old rats successfully induced diabetes in all strains (<xref ref-type="fig" rid="F3">Fig. 3<italic>B</italic></xref>). Blood glucose rose from normal values before injection of STZ (congenic, 205 ± 3 mg/dL; transgenic, 227 ± 11 mg/dL; KO, 198 ± 7 mg/dL) to high values that indicate severe hyperglycemia 1 week after STZ (congenic, 422 ± 35 mg/dL; transgenic, 406 ± 27 mg/dL; KO, 420 ± 21 mg/dL). Blood glucose levels remained high at age 11, 12, and 13 weeks and showed no significant differences among strains (<xref ref-type="fig" rid="F3">Fig. 3<italic>B</italic></xref>). There were no significant differences in mean arterial blood pressure among congenic, transgenic, and KO animals freely moving around the cage. All animal strains showed a tendency toward decreased blood pressure 3–4 weeks after injection of STZ (<xref ref-type="fig" rid="F3">Fig. 3<italic>C</italic></xref>).</p><fig id="F3" fig-type="figure" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Comparison of <italic>Rab38</italic> congenic, transgenic, and KO rats after induction of diabetes. <italic>A</italic>: Experimental setup and timeline. BP, blood pressure measurement via radio telemetry; MC, metabolic cage. <italic>B</italic>: Comparison of blood glucose concentrations. <italic>C</italic>: Comparison of mean arterial pressure. <italic>D</italic>: Comparison of urinary albumin concentrations. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01 KO vs. transgenic, ##<italic>P</italic> < 0.01 KO vs. congenic. <italic>E</italic>: Expression of endocytic markers. Immunofluorescence staining for megalin (green, top panel) and cubilin (red, bottom panel) in kidneys from all three rat strains. Nuclei counterstained with DAPI (blue). Scale bar, 50 μm. Data are presented as mean ± SEM. The results for blood pressure measurement, urinary albumin excretion, and blood glucose were analyzed by two-way ANOVA, followed by the Tukey post hoc test.</p></caption><graphic xlink:href="db151313f3"></graphic></fig><p>As illustrated in <xref ref-type="fig" rid="F3">Fig. 3<italic>D</italic></xref>, <italic>Rab38</italic> KO animals showed a progressive increase in urinary albumin excretion that became statistically significant 2 weeks after injection of STZ. At 4 weeks after injection, <italic>Rab38</italic> KO animals had an albumin excretion of 79 ± 14 mg/day, whereas albumin excretion was only 28 ± 8 mg/day in transgenic (<italic>P</italic> < 0.01) and 41 ± 13 mg/day in congenic animals (<italic>P</italic> < 0.01). These data indicate that diabetic rats without Rab38 are more susceptible to the development of albuminuria than congenic and transgenic animals with functional <italic>Rab38</italic> despite a similar degree of hyperglycemia in all animals. Kidney sections obtained from a subset of animals showed a higher average glomerulosclerosis score (2.9 ± 0.3) compared with congenic (2.2 ± 0.1) and transgenic (2.2 ± 0.1) rats (<italic>P</italic> < 0.05) (<ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">Supplementary Fig. 4</ext-link>), but differences were subtler than those observed for urinary albumin excretion.</p><p>To further clarify how loss of <italic>Rab38</italic> may lead to albuminuria, we performed immunohistochemistry staining of megalin and cubilin, known to mediate albumin reuptake in the proximal tubulus, in kidney sections of all three animal strains. Cubilin and megalin were markedly reduced at the luminal membrane of proximal tubular cells in <italic>Rab38</italic> KO rats compared with congenic and transgenic control animals (<xref ref-type="fig" rid="F3">Fig. 3<italic>E</italic></xref>), consistent with a role of Rab38 in regulating the abundance of cubilin and megalin at the cell surface. In contrast, there was no significant difference in the number of structures positive for the lysosomal marker LAMP1 among the three strains.</p></sec></sec><sec sec-type="discussion" id="s16"><title>Discussion</title><p>In this GWAS discovery meta-analysis of 2,191,945 SNPs in up to 54,450 participants of 20 studies, we replicated the association of the previously identified <italic>CUBN</italic> locus and UACR as well as MA at genome-wide significance and identified several suggestive signals among individuals with diabetes. Two of these loci, <italic>RAB38/CTSC</italic> and <italic>HS6ST1</italic>, showed evidence of independent replication, and <italic>RAB38</italic> was further supported by functional studies in a rat model. Our findings point to mechanisms in renal handling of albumin that associate with albuminuria in humans in the setting of diabetes. They thus represent examples of gene-by-diabetes interactions resulting in a complex trait that manifests when environmental exposure and genetic susceptibility variants occur together (<xref rid="B29" ref-type="bibr">29</xref>).</p><p>Not all individuals with diabetes develop DKD, suggesting that neither the presence of hyperglycemia nor genetic variants alone are sufficient to elicit the renal damage that typically manifests itself as albuminuria in diabetes. Our observations therefore raise the question of how the diabetic environment may result in the manifestation of genetic effects on albuminuria. The lack of association between both genetic variants and type 2 diabetes or specific glycemic measures in humans indicates that their effects occur without influencing diabetes per se<italic>.</italic> This notion is further substantiated by the fact that diabetic <italic>Rab38</italic> KO rats showed higher urinary albumin concentrations compared with controls despite the presence of similar blood glucose concentrations.</p><p>A difference between our observations in humans and rats is that the effect of genetic variation near <italic>RAB38</italic> on albuminuria was only found in humans with but not without diabetes, whereas <italic>Rab38</italic> KO rats without diabetes also progress to albuminuria (<xref rid="B22" ref-type="bibr">22</xref>). A potential explanation is that KO rats represent a null mutation, allowing for the genetic component to take full effect without needing further aggravation by environmental factors. Conversely, many human susceptibility variants of complex traits do not result in a complete loss of function but instead are of a regulatory nature. The effect of such variants may become apparent only upon an environmental challenge, such that genetically determined alterations in renal albumin handling could manifest themselves in the setting of hyperglycemia and/or diabetes due to a number of mechanisms that secondarily affect albumin reabsorption, including an increased load of filtered albumin due to hyperfiltration or impairment of the glomerular filter. Along these lines, our observation of significantly higher <italic>RAB38</italic> transcript abundance in tubuli of DKD patients than control subjects may indicate an adaption of the tubular machinery for albumin reabsorption in this setting. Moreover, genetics effects of the index SNP at the <italic>CUBN</italic> locus on albuminuria were four times as large in individuals with diabetes compared with those without diabetes, supporting alterations of tubular albumin handling in the setting of diabetes.</p><p><italic>RAB38</italic> encodes a member of the small Rab GTPase protein family that regulates intracellular vesicle trafficking between organelles and is important in exo-, endo-, and transcytosis (<xref rid="B30" ref-type="bibr">30</xref>). Expression of Rab38 at the mRNA and protein level was observed in proximal tubule cells of wild-type rats (<xref rid="B31" ref-type="bibr">31</xref>). FHH rats, a natural <italic>Rab38</italic>-null mutation, show increased urinary albumin excretion without changes in glomerular permeability (<xref rid="B21" ref-type="bibr">21</xref>). In these animals, the expression of a Brown Norway <italic>Rab38</italic> transgene led to phenotypic rescue, and knockdown of <italic>Rab38</italic> in a proximal tubule cell system significantly decreased albumin endocytosis (<xref rid="B22" ref-type="bibr">22</xref>). Together, these observations support an important role for the small Rab GTPase RAB38 in the reabsorption of filtered albumin.</p><p>Impaired RAB38 function may lead to increased albumin excretion via different mechanisms: altered intracellular vesicle transport may affect albumin reabsorption or recycling of reabsorbed albumin back to the plasma membrane (<xref rid="B32" ref-type="bibr">32</xref>). Alternatively, altered RAB38 function may affect the delivery of proteins required, such as cubilin or megalin, for albumin endocytosis, the mechanism underlying albuminuria in Dent disease (<xref rid="B33" ref-type="bibr">33</xref>). Our experimental data showing reduced abundance of cubilin and megalin in <italic>Rab38</italic> KO but not in control rats are consistent with the latter hypothesis. Finally, that impaired RAB38 function may directly cause glomerular damage, in turn leading to increased concentrations of urinary albumin, is also conceivable.</p><p>Although the combined evidence from <italic>Rab38</italic> KO rats along with the gene expression and GWAS data strongly implicate <italic>RAB38</italic> as the gene underlying albuminuria in humans, the intergenic index SNP mapped upstream of <italic>RAB38</italic> and downstream of <italic>CTSC</italic> and was associated with transcript levels of both genes in whole blood. We can therefore not exclude the possibility that <italic>CTSC</italic> may be the causal gene underlying the observed associations or that it contributes to the phenotype in addition to <italic>RAB38</italic>. <italic>CTSC</italic> encodes for a lysosomal cysteine protease. Rare mutations in the gene cause autosomal-recessive Papillon-Lefèvre syndrome. No renal abnormalities have been reported in affected patients (<xref rid="B34" ref-type="bibr">34</xref>), <italic>Ctsc</italic> KO mice do not show kidney abnormalities (<xref rid="B35" ref-type="bibr">35</xref>), and the gene has not been linked to albuminuria or kidney disease.</p><p>The other genomic locus associated with albuminuria in diabetes contains <italic>HS6ST1</italic>, encoding the enzyme heparan sulfate (HS) 6-<italic>O</italic>-sulfotransferase that catalyzes the 6-<italic>O</italic>-sulfation of HS and heparin (<xref rid="B36" ref-type="bibr">36</xref>,<xref rid="B37" ref-type="bibr">37</xref>). HS are anionic side chains of HS proteoglycans, which are components of basement membranes, extracellular matrix, and cell surfaces. Several studies have reported that inactivation or removal of HS leads to proteinuria, and biopsy specimens from patients with diabetes revealed changes in HS sulfation patterns compared with control subjects (<xref rid="B38" ref-type="bibr">38</xref>). Thus, a genetic variant altering the activity or abundance of the enzyme may lead to altered albuminuria. The underlying mechanisms could be manifold, because HS has been reported to affect not only glomerular filtration but also growth factor signaling, composition, and functions of the glomerular basement membrane as well as functions at the endothelial surface layer (<xref rid="B38" ref-type="bibr">38</xref>) and the proximal tubule (<xref rid="B39" ref-type="bibr">39</xref>).</p><p>Strengths of our study include its large sample size, specific examination of individuals with diabetes, and consistent effects across a variety of studies underscoring the relevance of our findings at the general population level. In addition, we performed careful characterization of a replicated finding through in vivo experiments in <italic>RAB38</italic> KO and control rats that cannot, however, elucidate the exact mechanism by which genetic variation at this locus influences albuminuria in humans.</p><p>Limitations include the fact that the replicated SNPs did not achieve genome-wide significance, necessitating future confirmation in even larger studies, and that we could not assess allele-specific gene expression in human kidney tissues. We focused on European ancestry study participants and mostly on individuals with type 2 diabetes. Future studies should therefore examine these associations among individuals of additional ancestries and in well-powered studies of patients with type 1 diabetes. Although results were combined after study-specific analyses, biological variation in UACR and different urine collection and storage methods may have resulted in increased variation and thus reduced statistical power to reveal significant associations.</p><p>Additional studies are required to determine the causal variants and the exact underlying molecular mechanism by which genetic variation at <italic>RAB38</italic>/<italic>CTSC</italic> and <italic>HS6ST1</italic> associates with albuminuria in humans. An elucidation of the underlying mechanisms and the contributions and differences of albuminuria of glomerular and tubular origin may improve our understanding of proteinuric kidney diseases in general but may be especially relevant to DKD, the most common cause of ESRD.</p></sec><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material id="PMC_1" content-type="local-data"><caption><title>Supplementary Data</title></caption><media mimetype="text" mime-subtype="html" xlink:href="supp_65_3_803__index.html"></media><media xlink:role="associated-file" mimetype="application" mime-subtype="pdf" xlink:href="supp_db15-1313_DB151313SupplementaryData.pdf"></media></supplementary-material></sec></body><back><fn-group><fn id="fn1" fn-type="supplementary-material"><p>This article contains Supplementary Data online at <ext-link ext-link-type="uri" xlink:href="http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1">http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1313/-/DC1</ext-link>.</p></fn><fn id="fn2"><p>H.J.J., C.A.B., C.S.F., C.P., and A.K. provided joint oversight of this work.</p></fn></fn-group><ack><title>Article Information</title><p><bold>Acknowledgments and Funding.</bold> 3C Study: The work was made possible by the generous participation of the control subjects, the patients, and their families. The authors thank Dr. Anne Boland, Centre National de Génotypage, for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille, and the Centre National de Génotypage. The Three-City (3C) Study was performed as part of a collaboration between INSERM, the Victor Segalen Bordeaux II University, and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France, and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Lille Génopôle received an unconditional grant from Eisai.</p><p>ADVANCE Study: The genetic epidemiological work was funded by Prognomix, Inc., and by grants from Genome Quebec and Canadian Institutes of Health Research (CIHR). The clinical study was managed by The George Institute for Global Health (University of Sydney, Sydney, New South Wales, Australia) with grants received from Les Laboratoires Servier, France, and from the National Health and Medical Research Council of Australia. The genotyping was performed at the genomic platform of Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM). The authors acknowledge the technical help of Carole Long and Mounsif Haloui and the bioinformatic analyses performed by Gilles Godefroid, François-Christophe Blanchet-Marois, and François Harvey (CRCHUM, Université de Montréal, Montreal, Quebec, Canada). Also acknowledged are the members of the genetic substudy of ADVANCE, Stephen Harrap (Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia) and Michel Marre (Diabétologie, Endocrinologie, Nutrition at Hôpital Bichat, Paris, France). M.W. did not participate in animal experiments.</p><p>AGES Study: The study has been funded by National Institutes of Health (NIH) contracts N01-AG-1-2100 and HHSN271201200022C, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.</p><p>Amish Study: The authors thank the Amish research volunteers for their long-standing partnership in research and the research staff at the Amish Research Clinic for their hard work and dedication. The study is supported by grants and contracts from the NIH, including R01-AG-18728 (Amish Longevity Study), R01-HL-088119 (Amish Calcification Study), U01-GM-074518-04 (Pharmacogenomics of Anti-Platelet Intervention [PAPI] Study), U01-HL0-72515-06 (Heredity and Phenotype Intervention [HAPI] Study), U01-HL0-84756, and K12-RR0-23250 (University of Maryland Multidisciplinary Clinical Research Career Development Program), the University of Maryland General Clinical Research Center, grant M01-RR-16500, the Baltimore Veterans Administration Medical Center Geriatric Research Education and Clinical Center, and the Paul Beeson Physician Faculty Scholars in Aging Research Program. Partial funding was also provided by the Mid-Atlantic Nutrition Obesity Research Center (P30-DK0-72488).</p><p>ARIC Study: The ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01-HL0-87641, R01-HL-9367 and R01-HL0-86694, National Human Genome Research Institute contract U01-HG0-04402, and NIH contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant number UL1-RR0-25005, a component of the NIH and NIH Roadmap for Medical Research. This work as well as Y.L. and A.K. were supported by the Emmy Noether Programme of the German Research Foundation (KO 3598/2-1 to A.K.).</p><p>Baltimore Longitudinal Study of Aging (BLSA): BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.</p><p>CHS: The CHS research reported in this article was supported by National Heart, Lung, and Blood Institute contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, and grant numbers U01-HL0-80295 and R01-HL0-87652, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at <ext-link ext-link-type="uri" xlink:href="http://www.chs-nhlbi.org/pi">http://www.chs-nhlbi.org/pi</ext-link>. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR-00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK-063491 to the Southern California Diabetes Endocrinology Research Center.</p><p>CoLaus Study: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (33CSCO-122661).</p><p>CROATIA-Split Study: The CROATIA-Split study was supported through grants from the Medical Research Council U.K., and Ministry of Science, Education and Sport of the Republic of Croatia (No. 108-1080315-0302). The authors acknowledge the invaluable contributions of the recruitment team from the Croatian Centre for Global Health, University of Split, the administrative teams in Croatia and Edinburgh, and the people of Split. The SNP genotyping for the Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark.</p><p>EPIC-Norfolk Study: The EPIC-Norfolk Study is supported by program grants from the Medical Research Council, and Cancer Research U.K. The authors acknowledge the contribution of the staff and participants of the EPIC-Norfolk Study.</p><p>ESTHER Study: The authors thank all the individuals who took part in the ESTHER (Epidemiological investigations of the chances of preventing, recognizing early and optimally treating chronic diseases in an elderly population) study and all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out. This work was supported in part by the Baden-Württemberg State Ministry of Science, Research and Arts, by the German Federal Ministry of Education and Research (grant number 01ET0717), and by the CHANCES (Consortium on Health and Ageing: Network of Cohorts in Europe and the United States) project funded in the Seventh Framework Programme of the Directorate-General for Research and Innovation in the European Commission (grant number 242244).</p><p>Fenland Study: The Fenland study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust. The authors are grateful to all the volunteers for their time and help and to the general practitioners and practice staff for assistance with recruitment. The authors thank the Fenland Study Investigators, Fenland Study Co-ordination team, and the Epidemiology Field, Data and Laboratory teams.</p><p>Framingham Heart Study: This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart, Lung, and Blood Institute of the NIH and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Boston University School of Medicine Department of Medicine and Boston Medical Center.</p><p>GENDIAN Study: The support of the physicians, the patients, and the staff of the Diabetes Zentrum Mergentheim (Head: Prof. Dr. Thomas Haak), the diabetes outpatient clinic Dr. Nusser – Dr. Kreisel, the dialysis centers KfH Amberg, KfH Bayreuth, KfH Deggendorf, KfH Donauwörth, KfH Freising, KfH Freyung, KfH Fürth, KfH Hof, KfH Ingolstadt, KfH Kelheim, KfH München Elsenheimerstraße, KfH München-Schwabing, KfH Neumarkt, KfH Neusäß, KfH Oberschleißheim, KfH Passau, KfH Plauen, KfH Regensburg Günzstraße, KfH Regensburg Caritas-Krankenhaus, KfH Straubing, KfH Sulzbach-Rosenberg, KfH Weiden, Dialysezentrum Augsburg Dr. Kirschner, Dialysezentrum Bad Alexandersbad, KfH Bamberg, Dialysezentrum Emmering, Dialysezentrum Klinikum Landshut, Dialysezentrum Landshut, Dialysezentrum Pfarrkirchen, Dialysezentrum Schwandorf, Dr. Angela Götz, the medical doctoral student Johanna Christ, and the study nurse Ingrid Lugauer. The expert technical assistance of Claudia Strohmeier is gratefully acknowledged. Phenotyping was funded by the Dr. Robert Pfleger-Stiftung (C.A.B.), the MSD Stipend Diabetes (C.A.B.), and the University Hospital of Regensburg (intramural grant ReForM A to Dr. Angela Götz, ReForM C to C.A.B.). Genome-wide genotyping was funded by the KfH Stiftung Präventivmedizin e.V. (C.A.B., Dr. Jens Brüning), the Else Kröner-Fresenius-Stiftung (2012_A147 to C.A.B. and I.M.H.), and the University Hospital Regensburg (C.A.B.). Data analysis was funded by the Else Kröner-Fresenius Stiftung (2012_A147 to I.M.H. and C.A.B. and P48/08//A11/08 to C.A.B. and B.K.K.). GENDIAN Study Group: M.G., I.M.H., B.K.K., M.R., Michael Broll, Alexander Lammert, Jens Brüning, M.O., Klaus Stark, Claudia Strohmeier, Simone Neumeier, Sarah Hufnagel, Petra Jackermeier, Emilia Ruff, Johanna Christ, Peter Nürnberg, Thomas Haak, and C.A.B.</p><p>INCIPE Study: The INCIPE (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points) study was cosponsored by Fondazione Cassa di Risparmio di Verona, Azienda Ospedaliera di Verona, and University of Verona, Italy. N.S.’s research is supported by the Wellcome Trust (grant codes WT098051 and WT091310), the European Union Framework Program 7 (EPIGENESYS grant code 257082 and BLUEPRINT grant code HEALTH-F5-2011-282510).</p><p>KORA-F3/KORA-F4 Study: The genetic epidemiological work was funded by the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and by the Else Kröner-Fresenius-Stiftung (P48/08//A11/08 to C.A.B., B.K.K. and 2012_A147 to C.A.B. and I.M.H.). The kidney parameter measurements in F3 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.) and the Regensburg University Medical Center, Germany, and in F4 by the University of Ulm, Germany (W.K.). De novo genotyping as well as partly genome-wide genotyping costs in F3 and F4 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). The KORA research platform and the MONICA (Multinational MONItoring of Trends and Determinants in CArdiovascular Disease) Augsburg studies were initiated and financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research and by the State of Bavaria. Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum München. The LINUX platform for computation were funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center.</p><p>LifeLines Study: The LifeLines Cohort Study and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO grant 175.010.2007.006, the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation, and Dutch Diabetes Research Foundation. LifeLines is a multidisciplinary prospective population-based cohort study examining in a unique three-generation design the health and health-related behaviors of 165,000 individuals living in the Northeast region of the Netherlands. It uses a broad range of investigative procedures in assessing the biomedical, sociodemographic, behavioral, physical, and psychological factors that contribute to the health and disease of the general population, with a special focus on multimorbidity and complex genetics.</p><p>MESA (The Multi-Ethnic Study of Atherosclerosis) Study: University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL-071205).</p><p>MICROS (Microisolates in South Tyrol) Study: The authors are grateful to all participants. The authors thank the primary care practitioners Raffaela Stocker, Stefan Waldner, Toni Pizzecco, Josef Plangger, Ugo Marcadent, and the personnel of the Hospital of Silandro Department of Laboratory Medicine for their participation and collaboration in the research project. The authors thank Dr. Peter Riegler (Hemodialysis Unit, Hospital of Merano) for the important discussions. In South Tyrol, the study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, and the European Union Framework Program 6 EUROSPAN project (contract No. LSHG-CT-2006-018947).</p><p>PREVEND Study: PREVEND (Prevention of Renal and Vascular End-stage Disease) genetics is supported by the Dutch Kidney Foundation grant E033; the EU project grant GENECURE (FP-6 LSHM CT 2006 037697); the NIH grant 2R01-LM0-10098; The Netherlands Organisation for Health Research and Development NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70, ZonMw grant 90.700.441; and the Dutch Inter University Cardiology Institute Netherlands (ICIN).</p><p>SAPHIR Study: The SAPHIR (Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk) study was partially supported by a grant from the Kamillo Eisner Stiftung to B.P. and by grants from the Genomics of Lipid-associated Disorders (GOLD) of the “Austrian Genome Research Programme GEN-AU” to F.K.</p><p>SHIP/SHIP-Trend/GANI_MED Study: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research grants 01ZZ9603, 01ZZ0103, and 01ZZ0403; the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research grant 03IS2061A. Genome-wide data have been supported by the Federal Ministry of Education and Research grant 03ZIK012 and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens AG, the German Centre for Diabetes Research (DZD), and the Caché Campus program of the InterSystems GmbH. The SHIP authors are grateful to Mario Stanke for the opportunity to use his Server Cluster for the SNP imputation as well as to Holger Prokisch and Thomas Meitinger (Helmholtz Zentrum München) for the genotyping of the SHIP-Trend cohort.</p><p>SKIPOGH (Swiss Kidney Project on Genes in Hypertension) Study: This research was funded by grant 33CM30-124087 from the Swiss National Science Foundation. The study also received support from Lausanne University Hospital, Geneva University Hospital, and Bern University Hospital, Switzerland. M.B. received support from the Swiss School of Public Health Plus (SSPH+).</p><p>Vanderbilt Study: Genotyping was supported by National Institute of General Medical Sciences (NIGMS) RC2-GM092318 (Omni1 and Omni5 array). This work was supported by the Electronic Medical Records and Genomics (eMERGE) Network, initiated and funded by the National Human Genome Research Institute, with additional funding from the NIGMS, through U01-HG04603 (660 array).</p><p>Susztak Laboratory: Work in the laboratory of K.S. was supported by NIH R01-DK0-76077 and DK0-87635.</p><p>Jacobs Laboratory: Work in the H.J.J. and J.L. laboratories was supported by 2R01-069321 to H.J.J.</p><p>Devuyst Laboratory: This work was supported by the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 305608 (EURenOmics) and the Swiss National Science Foundation project grant 310030_146490.</p><p>Additional Data Resources: Data on glycemic traits have been contributed by MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) investigators and have been downloaded from <ext-link ext-link-type="uri" xlink:href="http://www.magicinvestigators.org">www.magicinvestigators.org</ext-link>.</p><p><bold>Duality of Interest</bold>. C.He. received honoraria from Novartis. J.Ch., J.T., and P.H. received research grants and honoraria from Servier. M.W. had consultancies with Amgen and Novartis and received support from Sanofi. K.S. received research support from Boehringer Ingelheim and was on the advisory board of Abbvie. No other potential conflicts of interest relevant to this article were reported.</p><p>The sponsors had no role in the study design, analyses, drafting of the manuscript, or the decision to publish.</p><p><bold>Author Contributions.</bold> A.L., B.S., B.K.K., B.P., C.He., C.Me., C.G., G.G., G.E., H.E.W., H.V., J.C.D., L.J.L., M.J.H., M.N., N.J.W., P.P.P., P.S.W., R.R., R.B., R.J.C., T.B.H., V.G., A.D.P., J.La., J.T., P.H., H.J.J., C.S.F., and A.K. designed this study. A.K.D., A.R.S., B.K., B.Po., B.K.K., B.Pa., B.D.M., C.Ha., C.He., C.Me., C.G., D.A., D.S., E.B., F.K., G.B.E., G.W., G.N., G.G., G.E., H.E.W., H.G., H.V., H.B., H.K., I.M.L., I.R., J.L.H., J.S.B., J.H.Z., J.Ch., J.Co., K.B., L.J.L., L.F., L.K., M.Wo., M.J.H., M.Wa., M.P., M.B., N.J.W., N.E., O.P., P.v.d.H., P.P.P., P.V., P.S.W., R.T.G., R.R., R.K., S.C., S.B., T.B.H., T.C., T.I., T.T., U.L., U.V., V.G., W.K., I.H.d.B., J.La., P.H., C.S.F., C.P., and A.K. were involved in the study management. A.R.S., A.L., B.K.K., B.Pa., C.He., C.Me., C.G., G.G., G.E., H.E.W., H.W., H.V., J.L.H., J.Co., M.N., L.K., N.J.W., O.P., P.v.d.H., P.P.P., P.S.W., R.J.C., R.T.G., S.S., V.G., O.D., P.H., and C.S.F. recruited the subjects. A.Te., A.Ti., R.S., M.G., N.C.Y., M.L., Y.L., V.M., B.O.T., A.V.S., B.Pa., F.K., J.Co., L.K., M.J.H., M.R., S.C., T.A., A.D.P., J.La., K.E., J.T., P.H., C.S.F., C.P., and A.K. interpreted the results. A.Te., A.Ti., M.G., N.C.Y., M.L., Y.-A.K., M.J.H., I.M.H., J.La., K.E., K.S., J.T., P.H., H.J.J., C.A.B., C.P., and A.K. drafted the manuscript. A.Te., A.Ti., R.S., M.G., N.C.Y., A.Y.C., M.L., Y.L., V.M., Y.-A.K., D.T., M.-H.C., Q.Y., M.C.F., M.O., L.T.H., B.O.T., C.F., A.V.S., B.K., C.Ha., C.M.S., C.Mü., G.L., J.Lu., M.M., M.J.H., M.R., N.V., R.J.C., R.K., S.-J.H., S.E.R., T.A., Z.K., J.R.O., A.P., I.M.H., C.A.B., A.D.P., K.E., K.S., C.P., and A.K. developed statistical methods and performed the analyses. A.R.S., A.M.Z., B.D.M., C.Ha., C.L., E.B., G.H., H.G., M.H., M.Wa., M.R., N.S., O.P., R.J.F.L., S.C., T.Z., T.I., and U.V. performed the genotyping. M.G., Y.L., V.M., Y.-A.K., D.T., C.M.S., C.Mü., G.M., J.C.L., J.Lu., N.V., P.v.d.H., V.C., J.R.O., I.M.H., K.S., and C.A.B. conducted the bioinformatics analyses. N.C.Y., A.L., A.M.Z., M.J.H., O.D., J.La., and H.J.J. did the animal work or provided functional data. All authors critically reviewed the manuscript. A.Te., C.S.F., C.P., and A.K. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.</p><p><bold>Prior Presentation.</bold> Findings from this study were presented at the 51st Congress of the European Renal Association (ERA)-European Diabetes and Transplant Association (EDTA), Amsterdam, the Netherlands, 31 May–3 June 2014, and at the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Investigator Meeting, Jackson, MS, 1–2 July 2015. An abstract and platform presentation of this work was presented at the American Society of Human Genetics (ASHG) 2015 Annual Meeting, Baltimore, MD, 6–10 October 2015.</p></ack><ref-list><title>References</title><ref id="B1"><label>1</label><mixed-citation publication-type="web">Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. 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