PROX1 gene CC genotype as a major determinant of early onset of type 2 diabetes in slavic study participants from Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation study
Identifieur interne : 000457 ( Pmc/Checkpoint ); précédent : 000456; suivant : 000458PROX1 gene CC genotype as a major determinant of early onset of type 2 diabetes in slavic study participants from Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation study
Auteurs : Pavel Hamet ; Mounsif Haloui ; François Harvey ; François-Christophe Marois-Blanchet ; Marie-Pierre Sylvestre ; Muhammad-Ramzan Tahir ; Paul H. G. Simon ; Beatriz Sonja Kanzki [Canada] ; John Raelson ; Carole Long ; John Chalmers [Australie] ; Mark Woodward [Australie] ; Michel Marre [France] ; Stephen Harrap [Australie] ; Johanne TremblaySource :
- Journal of Hypertension [ 0263-6352 ] ; 2017.
Abstract
The prevalence of diabetic nephropathy varies according to ethnicity. Environmental as well as genetic factors contribute to the heterogeneity in the presentation of diabetic nephropathy. Our objective was to evaluate this heterogeneity within the Caucasian population.
The geo-ethnic origin of the 3409 genotyped Caucasian type 2 diabetes (T2D) patients of Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation was determined using principal component analysis. Genome-wide association studies analyses of age of onset of T2D were performed for geo-ethnic groups separately and combined.
The first principal component separated the Caucasian study participants into Slavic and Celtic ethnic origins. Age of onset of diabetes was significantly lower in Slavic patients (
These results reveal the presence of distinct genetic architectures between Caucasian ethnic groups that likely have clinical relevance, among them
Url:
DOI: 10.1097/HJH.0000000000001241
PubMed: 28060188
PubMed Central: 5377997
Affiliations:
- Australie, Canada, France
- Nouvelle-Galles du Sud, Victoria (État), Île-de-France
- Melbourne, Paris, Sydney
- Université de Melbourne, Université de Sydney
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G." last="Simon">Paul H. G. Simon</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Kanzki, Beatriz Sonja" sort="Kanzki, Beatriz Sonja" uniqKey="Kanzki B" first="Beatriz Sonja" last="Kanzki">Beatriz Sonja Kanzki</name><affiliation wicri:level="1"><nlm:aff id="aff4">Department of Software Engineering and the Information Technology, École de Technologie Supérieure, Montreal, Quebec, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Software Engineering and the Information Technology, École de Technologie Supérieure, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Raelson, John" sort="Raelson, John" uniqKey="Raelson J" first="John" last="Raelson">John Raelson</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Long, Carole" sort="Long, Carole" uniqKey="Long C" first="Carole" last="Long">Carole Long</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Chalmers, John" sort="Chalmers, John" uniqKey="Chalmers J" first="John" last="Chalmers">John Chalmers</name><affiliation wicri:level="4"><nlm:aff id="aff5">The George Institute for Global Health, University of Sydney, Sydney, New South Wales, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>The George Institute for Global Health, University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Woodward, Mark" sort="Woodward, Mark" uniqKey="Woodward M" first="Mark" last="Woodward">Mark Woodward</name><affiliation wicri:level="4"><nlm:aff id="aff5">The George Institute for Global Health, University of Sydney, Sydney, New South Wales, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>The George Institute for Global Health, University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Marre, Michel" sort="Marre, Michel" uniqKey="Marre M" first="Michel" last="Marre">Michel Marre</name><affiliation wicri:level="3"><nlm:aff id="aff6">Hôpital Bichat, Claude Bernard, Université Paris 7, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Hôpital Bichat, Claude Bernard, Université Paris 7, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Harrap, Stephen" sort="Harrap, Stephen" uniqKey="Harrap S" first="Stephen" last="Harrap">Stephen Harrap</name><affiliation wicri:level="4"><nlm:aff id="aff7">Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Tremblay, Johanne" sort="Tremblay, Johanne" uniqKey="Tremblay J" first="Johanne" last="Tremblay">Johanne Tremblay</name><affiliation><nlm:aff id="aff1">Department of Medicine, Gene Medicine Services</nlm:aff><wicri:noCountry code="subfield">Gene Medicine Services</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28060188</idno><idno type="pmc">5377997</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377997</idno><idno type="RBID">PMC:5377997</idno><idno type="doi">10.1097/HJH.0000000000001241</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002681</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002681</idno><idno type="wicri:Area/Pmc/Curation">002531</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002531</idno><idno type="wicri:Area/Pmc/Checkpoint">000457</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000457</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>PROX1</italic> gene CC genotype as a major determinant of early onset of type 2 diabetes in slavic study participants from Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation study</title><author><name sortKey="Hamet, Pavel" sort="Hamet, Pavel" uniqKey="Hamet P" first="Pavel" last="Hamet">Pavel Hamet</name><affiliation><nlm:aff id="aff1">Department of Medicine, Gene Medicine Services</nlm:aff><wicri:noCountry code="subfield">Gene Medicine Services</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Haloui, Mounsif" sort="Haloui, Mounsif" uniqKey="Haloui M" first="Mounsif" last="Haloui">Mounsif Haloui</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Harvey, Francois" sort="Harvey, Francois" uniqKey="Harvey F" first="François" last="Harvey">François Harvey</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Marois Blanchet, Francois Christophe" sort="Marois Blanchet, Francois Christophe" uniqKey="Marois Blanchet F" first="François-Christophe" last="Marois-Blanchet">François-Christophe Marois-Blanchet</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Sylvestre, Marie Pierre" sort="Sylvestre, Marie Pierre" uniqKey="Sylvestre M" first="Marie-Pierre" last="Sylvestre">Marie-Pierre Sylvestre</name><affiliation><nlm:aff id="aff3">Department of Social and Preventive Medicine, Université de Montréal, CRCHUM</nlm:aff><wicri:noCountry code="subfield">CRCHUM</wicri:noCountry></affiliation></author><author><name sortKey="Tahir, Muhammad Ramzan" sort="Tahir, Muhammad Ramzan" uniqKey="Tahir M" first="Muhammad-Ramzan" last="Tahir">Muhammad-Ramzan Tahir</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Simon, Paul H G" sort="Simon, Paul H G" uniqKey="Simon P" first="Paul H. G." last="Simon">Paul H. G. Simon</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Kanzki, Beatriz Sonja" sort="Kanzki, Beatriz Sonja" uniqKey="Kanzki B" first="Beatriz Sonja" last="Kanzki">Beatriz Sonja Kanzki</name><affiliation wicri:level="1"><nlm:aff id="aff4">Department of Software Engineering and the Information Technology, École de Technologie Supérieure, Montreal, Quebec, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Software Engineering and the Information Technology, École de Technologie Supérieure, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Raelson, John" sort="Raelson, John" uniqKey="Raelson J" first="John" last="Raelson">John Raelson</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Long, Carole" sort="Long, Carole" uniqKey="Long C" first="Carole" last="Long">Carole Long</name><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="Chalmers, John" sort="Chalmers, John" uniqKey="Chalmers J" first="John" last="Chalmers">John Chalmers</name><affiliation wicri:level="4"><nlm:aff id="aff5">The George Institute for Global Health, University of Sydney, Sydney, New South Wales, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>The George Institute for Global Health, University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Woodward, Mark" sort="Woodward, Mark" uniqKey="Woodward M" first="Mark" last="Woodward">Mark Woodward</name><affiliation wicri:level="4"><nlm:aff id="aff5">The George Institute for Global Health, University of Sydney, Sydney, New South Wales, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>The George Institute for Global Health, University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Marre, Michel" sort="Marre, Michel" uniqKey="Marre M" first="Michel" last="Marre">Michel Marre</name><affiliation wicri:level="3"><nlm:aff id="aff6">Hôpital Bichat, Claude Bernard, Université Paris 7, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Hôpital Bichat, Claude Bernard, Université Paris 7, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Harrap, Stephen" sort="Harrap, Stephen" uniqKey="Harrap S" first="Stephen" last="Harrap">Stephen Harrap</name><affiliation wicri:level="4"><nlm:aff id="aff7">Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Tremblay, Johanne" sort="Tremblay, Johanne" uniqKey="Tremblay J" first="Johanne" last="Tremblay">Johanne Tremblay</name><affiliation><nlm:aff id="aff1">Department of Medicine, Gene Medicine Services</nlm:aff><wicri:noCountry code="subfield">Gene Medicine Services</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Hypertension</title><idno type="ISSN">0263-6352</idno><idno type="eISSN">1473-5598</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec sec-type="background"><title>Background:</title><p>The prevalence of diabetic nephropathy varies according to ethnicity. Environmental as well as genetic factors contribute to the heterogeneity in the presentation of diabetic nephropathy. Our objective was to evaluate this heterogeneity within the Caucasian population.</p></sec><sec sec-type="methods"><title>Methods:</title><p>The geo-ethnic origin of the 3409 genotyped Caucasian type 2 diabetes (T2D) patients of Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation was determined using principal component analysis. Genome-wide association studies analyses of age of onset of T2D were performed for geo-ethnic groups separately and combined.</p></sec><sec sec-type="results"><title>Results:</title><p>The first principal component separated the Caucasian study participants into Slavic and Celtic ethnic origins. Age of onset of diabetes was significantly lower in Slavic patients (<italic>P</italic> = 7.3 × 10<sup>−20</sup>), whereas the prevalence of hypertension (<italic>P</italic> = 4.9 × 10<sup>−31</sup>) and albuminuria (5.1 × 10<sup>−9</sup>) were significantly higher. Age of onset of T2D and albuminuria appear to have an important genetic component as the values of these traits were also different between Slavic and Celtic individuals living in the same countries. Common and geo-ethnic-specific loci were found to be associated to age of onset of diabetes. Among the latter, the <italic>PROX1/PROX1-AS1</italic> genes (rs340841) had the highest impact. Single-nucleotide polymorphism rs340841 CC genotype was associated with a 4.4 year earlier onset of T2D in Slavic patients living or not in countries with predominant Slavic populations.</p></sec><sec sec-type="conclusion"><title>Conclusion:</title><p>These results reveal the presence of distinct genetic architectures between Caucasian ethnic groups that likely have clinical relevance, among them <italic>PROX1</italic> gene is a strong candidate of early onset of diabetes with variations depending on ethnicity.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Groop, Ph" uniqKey="Groop P">PH Groop</name></author><author><name sortKey="Thomas, Mc" uniqKey="Thomas M">MC Thomas</name></author><author><name sortKey="Moran, Jl" uniqKey="Moran J">JL Moran</name></author><author><name sortKey="Waden, J" uniqKey="Waden J">J Waden</name></author><author><name sortKey="Thorn, Lm" uniqKey="Thorn L">LM 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Hypertens</journal-id><journal-id journal-id-type="iso-abbrev">J. Hypertens</journal-id><journal-id journal-id-type="publisher-id">JHYPE</journal-id><journal-title-group><journal-title>Journal of Hypertension</journal-title></journal-title-group><issn pub-type="ppub">0263-6352</issn><issn pub-type="epub">1473-5598</issn><publisher><publisher-name>Lippincott Williams & Wilkins</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28060188</article-id><article-id pub-id-type="pmc">5377997</article-id><article-id pub-id-type="publisher-id">JH-D-16-00806</article-id><article-id pub-id-type="doi">10.1097/HJH.0000000000001241</article-id><article-id pub-id-type="art-access-id">00005</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title><italic>PROX1</italic> gene CC genotype as a major determinant of early onset of type 2 diabetes in slavic study participants from Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation study</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hamet</surname><given-names>Pavel</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="fn" rid="fn1"><sup>∗†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haloui</surname><given-names>Mounsif</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Harvey</surname><given-names>François</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Marois-Blanchet</surname><given-names>François-Christophe</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sylvestre</surname><given-names>Marie-Pierre</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tahir</surname><given-names>Muhammad-Ramzan</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Simon</surname><given-names>Paul H.G.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kanzki</surname><given-names>Beatriz Sonja</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Raelson</surname><given-names>John</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Long</surname><given-names>Carole</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chalmers</surname><given-names>John</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Woodward</surname><given-names>Mark</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Marre</surname><given-names>Michel</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Harrap</surname><given-names>Stephen</given-names></name><xref ref-type="aff" rid="aff7"><sup>g</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tremblay</surname><given-names>Johanne</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="fn" rid="fn2"><sup>∗†</sup></xref></contrib></contrib-group><aff id="aff1"><label>a</label>Department of Medicine, Gene Medicine Services</aff><aff id="aff2"><label>b</label>Department of Medicine</aff><aff id="aff3"><label>c</label>Department of Social and Preventive Medicine, Université de Montréal, CRCHUM</aff><aff id="aff4"><label>d</label>Department of Software Engineering and the Information Technology, École de Technologie Supérieure, Montreal, Quebec, Canada</aff><aff id="aff5"><label>e</label>The George Institute for Global Health, University of Sydney, Sydney, New South Wales, Australia</aff><aff id="aff6"><label>f</label>Hôpital Bichat, Claude Bernard, Université Paris 7, Paris, France</aff><aff id="aff7"><label>g</label>Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia</aff><author-notes><corresp>Correspondence to Pavel Hamet, OQ, MD, PhD, FRCPC, Centre hospitalier de l’Université de Montréal, 900 Saint-Denis, room R14.404, Montréal, Québec, Canada, H2X 0A9. Tel: +1 514 890 8246; e-mail: <email>pavel.hamet@umontreal.ca</email></corresp></author-notes><pub-date pub-type="ppub"><month>5</month><year>2017</year></pub-date><pub-date pub-type="epub"><day>16</day><month>1</month><year>2017</year></pub-date><volume>35</volume><issue>Suppl 1</issue><fpage>S24</fpage><lpage>S32</lpage><history><date date-type="received"><day>22</day><month>8</month><year>2016</year></date><date date-type="rev-recd"><day>10</day><month>11</month><year>2016</year></date><date date-type="accepted"><day>5</day><month>12</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2017</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0">http://creativecommons.org/licenses/by-nc-nd/4.0</ext-link></license-p></license></permissions><self-uri xlink:type="simple" xlink:href="jhype-35-s24.pdf"></self-uri><abstract><sec sec-type="background"><title>Background:</title><p>The prevalence of diabetic nephropathy varies according to ethnicity. Environmental as well as genetic factors contribute to the heterogeneity in the presentation of diabetic nephropathy. Our objective was to evaluate this heterogeneity within the Caucasian population.</p></sec><sec sec-type="methods"><title>Methods:</title><p>The geo-ethnic origin of the 3409 genotyped Caucasian type 2 diabetes (T2D) patients of Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation was determined using principal component analysis. Genome-wide association studies analyses of age of onset of T2D were performed for geo-ethnic groups separately and combined.</p></sec><sec sec-type="results"><title>Results:</title><p>The first principal component separated the Caucasian study participants into Slavic and Celtic ethnic origins. Age of onset of diabetes was significantly lower in Slavic patients (<italic>P</italic> = 7.3 × 10<sup>−20</sup>), whereas the prevalence of hypertension (<italic>P</italic> = 4.9 × 10<sup>−31</sup>) and albuminuria (5.1 × 10<sup>−9</sup>) were significantly higher. Age of onset of T2D and albuminuria appear to have an important genetic component as the values of these traits were also different between Slavic and Celtic individuals living in the same countries. Common and geo-ethnic-specific loci were found to be associated to age of onset of diabetes. Among the latter, the <italic>PROX1/PROX1-AS1</italic> genes (rs340841) had the highest impact. Single-nucleotide polymorphism rs340841 CC genotype was associated with a 4.4 year earlier onset of T2D in Slavic patients living or not in countries with predominant Slavic populations.</p></sec><sec sec-type="conclusion"><title>Conclusion:</title><p>These results reveal the presence of distinct genetic architectures between Caucasian ethnic groups that likely have clinical relevance, among them <italic>PROX1</italic> gene is a strong candidate of early onset of diabetes with variations depending on ethnicity.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>albuminuria</kwd><kwd>diabetic kidney disease</kwd><kwd>environment</kwd><kwd>ethnic groups</kwd><kwd>genetics</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><floats-group><table-wrap id="T1" position="float"><label>TABLE 1</label><caption><p>Demographic and clinical characteristics at baseline of Caucasian ADVANCE genotyped study participants stratified by ethnic origin</p></caption><table frame="hsides" rules="groups"><thead><tr><td rowspan="1" colspan="1">Trait</td><td rowspan="1" colspan="1">All (<italic>n</italic> = 3409) Mean (SD) or %</td><td rowspan="1" colspan="1">Celtic (<italic>n</italic> = 2307) Mean (SD) or %</td><td rowspan="1" colspan="1">Slavic (<italic>n</italic> = 1102) Mean (SD) or %</td><td rowspan="1" colspan="1"><italic>P</italic> Value</td></tr></thead><tbody><tr><td rowspan="1" colspan="1">Age (years)</td><td rowspan="1" colspan="1">67.3 (6.6)</td><td rowspan="1" colspan="1">68.0 (6.6)</td><td rowspan="1" colspan="1">65.9 (6.6)</td><td rowspan="1" colspan="1">1.9 × 10<sup>–16</sup></td></tr><tr><td rowspan="1" colspan="1">Men (sex)</td><td rowspan="1" colspan="1">64.7</td><td rowspan="1" colspan="1">69.8</td><td rowspan="1" colspan="1">54.0</td><td rowspan="1" colspan="1">5.8 × 10<sup>–19</sup></td></tr><tr><td rowspan="1" colspan="1">Age at diagnosis of diabetes (years)</td><td rowspan="1" colspan="1">60.1 (8.5)</td><td rowspan="1" colspan="1">61.0 (6.1)</td><td rowspan="1" colspan="1">58.2 (6.1)</td><td rowspan="1" colspan="1">7.3 × 10<sup>–20</sup></td></tr><tr><td rowspan="1" colspan="1">Diabetes duration (years)</td><td rowspan="1" colspan="1">6.7 (6.1)</td><td rowspan="1" colspan="1">6.4 (6.1)</td><td rowspan="1" colspan="1">7.4 (6.1)</td><td rowspan="1" colspan="1">2.9 × 10<sup>–6</sup></td></tr><tr><td rowspan="1" colspan="1">BMI</td><td rowspan="1" colspan="1">30.1 (5.1)</td><td rowspan="1" colspan="1">30.1 (5.0)</td><td rowspan="1" colspan="1">30.0 (5.0)</td><td rowspan="1" colspan="1">7.6 × 10<sup>–1</sup></td></tr><tr><td colspan="5" rowspan="1">Blood glucose assessment</td></tr><tr><td rowspan="1" colspan="1"> HbA1c (%)</td><td rowspan="1" colspan="1">13.4 (2.7)</td><td rowspan="1" colspan="1">13.4 (2.8)</td><td rowspan="1" colspan="1">13.4 (2.8)</td><td rowspan="1" colspan="1">7.5 × 10<sup>–1</sup></td></tr><tr><td rowspan="1" colspan="1"> Glucose (mmol/l)</td><td rowspan="1" colspan="1">18.8 (4.6)</td><td rowspan="1" colspan="1">18.8 (4.6)</td><td rowspan="1" colspan="1">18.8 (4.7)</td><td rowspan="1" colspan="1">7.2 × 10<sup>–1</sup></td></tr><tr><td colspan="5" rowspan="1">Blood pressure assessment</td></tr><tr><td rowspan="1" colspan="1"> SBP (mmHg)</td><td rowspan="1" colspan="1">185.5 (30.3)</td><td rowspan="1" colspan="1">182.0 (30.0)</td><td rowspan="1" colspan="1">192.8 (30.2)</td><td rowspan="1" colspan="1">4.5 × 10<sup>–22</sup></td></tr><tr><td rowspan="1" colspan="1"> DBP (mmHg)</td><td rowspan="1" colspan="1">103.6 (16.7)</td><td rowspan="1" colspan="1">101.4 (16.5)</td><td rowspan="1" colspan="1">108.3 (16.7)</td><td rowspan="1" colspan="1">5.3 × 10<sup>–29</sup></td></tr><tr><td rowspan="1" colspan="1"> Heart rate (beats/min)</td><td rowspan="1" colspan="1">94 (16)</td><td rowspan="1" colspan="1">92 (16)</td><td rowspan="1" colspan="1">98 (16)</td><td rowspan="1" colspan="1">3.0 × 10<sup>–21</sup></td></tr><tr><td rowspan="1" colspan="1"> Currently treated hypertension<xref ref-type="table-fn" rid="TF1-3"><sup>c</sup></xref></td><td rowspan="1" colspan="1">60.0</td><td rowspan="1" colspan="1">53.0</td><td rowspan="1" colspan="1">74.6</td><td rowspan="1" colspan="1">4.9 × 10<sup>–31</sup></td></tr><tr><td colspan="5" rowspan="1">Renal function assessment</td></tr><tr><td rowspan="1" colspan="1"> eGFR<sub>CKD-EPI</sub> (ml/min per 1.73 m<sup>2</sup>)</td><td rowspan="1" colspan="1">69.6 (17.9)</td><td rowspan="1" colspan="1">70.9 (15.8)</td><td rowspan="1" colspan="1">66.8 (15.9)</td><td rowspan="1" colspan="1">1.2 × 10<sup>–11</sup></td></tr><tr><td rowspan="1" colspan="1"> UACR (μg/mg)</td><td rowspan="1" colspan="1">78.1 (155)</td><td rowspan="1" colspan="1">63.5 (152)</td><td rowspan="1" colspan="1">96.7 (153)</td><td rowspan="1" colspan="1">5.1 × 10<sup>–9</sup></td></tr><tr><td rowspan="1" colspan="1"> Microalbuminuria<xref ref-type="table-fn" rid="TF1-1"><sup>a</sup></xref></td><td rowspan="1" colspan="1">25.4</td><td rowspan="1" colspan="1">23.7</td><td rowspan="1" colspan="1">28.9</td><td rowspan="1" colspan="1">1.7 × 10<sup>–3</sup></td></tr><tr><td rowspan="1" colspan="1"> Macroalbuminuria<xref ref-type="table-fn" rid="TF1-2"><sup>b</sup></xref></td><td rowspan="1" colspan="1">5.4</td><td rowspan="1" colspan="1">4.0</td><td rowspan="1" colspan="1">7.6</td><td rowspan="1" colspan="1">3.6 × 10<sup>–5</sup></td></tr></tbody></table><table-wrap-foot><fn fn-type="other"><p>Age and age at diagnosis of diabetes are adjusted for sex; diabetes duration, BMI, currently treated hypertension and micro and macroalbuminuria are adjusted for age and sex; all others traits are adjusted for age, sex, and respective treatments.</p><p>eGFR<sub>CKD-EPI</sub>, estimated glomerular filtration rate calculated using Chronic Kidney Disease Epidemiology Collaboration equation; HbA1c, serum glycated hemoglobin; UACR, urinary albumin–creatinine ratio.</p></fn><fn fn-type="other" id="TF1-1"><p><sup>a</sup>Urinary albumin–creatinine ratio between 30 and 300 μg/mg.</p></fn><fn fn-type="other" id="TF1-2"><p><sup>b</sup>Urinary albumin–creatinine ratio >300 μg/mg.</p></fn><fn fn-type="other" id="TF1-3"><p><sup>c</sup>Blood pressure >140/90 mmHg or receiving antihypertensive treatment</p></fn></table-wrap-foot></table-wrap><table-wrap id="T2" position="float"><label>TABLE 2</label><caption><p>Summary statistics for association of age of onset of T2D for 25 independent single-nucleotide polymorphisms in Caucasians study participants from ADVANCE. Genome-wide association studies were done for all study participants (<italic>n</italic> = 3409 combined group) and separately for Celtic (<italic>n</italic> = 2307) and Slavic (<italic>n</italic> = 1102) individuals stratified by ethnic origin, which is determined by principal component analysis. Selected single-nucleotide polymorphisms for all groups are associated to age at diagnosis of diabetes with <italic>P</italic> value less than 1 × 10<sup>−5</sup></p></caption><table frame="hsides" rules="groups"><thead><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td colspan="3" rowspan="1">Celtic</td><td colspan="3" rowspan="1">Slavic</td><td colspan="3" rowspan="1">Combined<xref ref-type="table-fn" rid="TF2-3"><sup>c</sup></xref></td></tr><tr><td rowspan="1" colspan="1">SNP ID</td><td rowspan="1" colspan="1">Chr</td><td rowspan="1" colspan="1">Position (bp, hg19)</td><td rowspan="1" colspan="1">RA</td><td rowspan="1" colspan="1">Locus<xref ref-type="table-fn" rid="TF2-1"><sup>a</sup></xref></td><td rowspan="1" colspan="1"><italic>P</italic> value</td><td rowspan="1" colspan="1">RAF%</td><td rowspan="1" colspan="1">Effect size<xref ref-type="table-fn" rid="TF2-2"><sup>b</sup></xref></td><td rowspan="1" colspan="1"><italic>P</italic> value</td><td rowspan="1" colspan="1">RAF%</td><td rowspan="1" colspan="1">Effect size<xref ref-type="table-fn" rid="TF2-2"><sup>b</sup></xref></td><td rowspan="1" colspan="1"><italic>P</italic> value</td><td rowspan="1" colspan="1">RAF%</td><td rowspan="1" colspan="1">Effect size<xref ref-type="table-fn" rid="TF2-2"><sup>b</sup></xref></td></tr></thead><tbody><tr><td colspan="14" rowspan="1">SNPs that are significantly associated in both Celtic and Slavic genetic profiles and that increase in significance in combined group<xref ref-type="table-fn" rid="TF2-3"><sup>c</sup></xref></td></tr><tr><td rowspan="1" colspan="1">rs34428389</td><td rowspan="1" colspan="1">3</td><td rowspan="1" colspan="1">52 894 142</td><td rowspan="1" colspan="1">A</td><td rowspan="1" colspan="1"><bold>TMEM110</bold>, MIR8064, SFMBT1</td><td rowspan="1" colspan="1">3.3 × 10<sup>−4</sup></td><td rowspan="1" colspan="1">19.1</td><td rowspan="1" colspan="1">−2.00</td><td rowspan="1" colspan="1">8.9 × 10<sup>−3</sup></td><td rowspan="1" colspan="1">18.4</td><td rowspan="1" colspan="1">−1.43</td><td rowspan="1" colspan="1"><bold>8.1 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">18.9</td><td rowspan="1" colspan="1">−2.47</td></tr><tr><td rowspan="1" colspan="1">rs17447640</td><td rowspan="1" colspan="1">4</td><td rowspan="1" colspan="1">42 555 811</td><td rowspan="1" colspan="1">G</td><td rowspan="1" colspan="1"><bold>ATP8A1</bold>, SHISA3, GRXCR1</td><td rowspan="1" colspan="1">1.1 × 10<sup>−5</sup></td><td rowspan="1" colspan="1">13.9</td><td rowspan="1" colspan="1">−2.15</td><td rowspan="1" colspan="1">5.6 × 10<sup>−2</sup></td><td rowspan="1" colspan="1">15.7</td><td rowspan="1" colspan="1">−0.98</td><td rowspan="1" colspan="1"><bold>1.5 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">14.5</td><td rowspan="1" colspan="1">−2.39</td></tr><tr><td rowspan="1" colspan="1">rs11298745</td><td rowspan="1" colspan="1">7</td><td rowspan="1" colspan="1">18 548 252</td><td rowspan="1" colspan="1">Del</td><td rowspan="1" colspan="1"><bold>HDAC9</bold>, MIR1302–6, TWIST1</td><td rowspan="1" colspan="1">2.3 × 10<sup>−3</sup></td><td rowspan="1" colspan="1">90.5</td><td rowspan="1" colspan="1">−1.26</td><td rowspan="1" colspan="1">4.6 × 10<sup>−5</sup></td><td rowspan="1" colspan="1">90.0</td><td rowspan="1" colspan="1">−1.73</td><td rowspan="1" colspan="1"><bold>1.6 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">90.3</td><td rowspan="1" colspan="1">−2.01</td></tr><tr><td rowspan="1" colspan="1">rs34620785</td><td rowspan="1" colspan="1">8</td><td rowspan="1" colspan="1">103 452 308</td><td rowspan="1" colspan="1">A</td><td rowspan="1" colspan="1">UBR5, ODF1</td><td rowspan="1" colspan="1">1.6 × 10<sup>−4</sup></td><td rowspan="1" colspan="1">88.4</td><td rowspan="1" colspan="1">−1.71</td><td rowspan="1" colspan="1">1.7 × 10<sup>−3</sup></td><td rowspan="1" colspan="1">84.4</td><td rowspan="1" colspan="1">−1.61</td><td rowspan="1" colspan="1"><bold>1.6 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">87.1</td><td rowspan="1" colspan="1">−2.27</td></tr><tr><td rowspan="1" colspan="1">rs76703216</td><td rowspan="1" colspan="1">10</td><td rowspan="1" colspan="1">9 512 026</td><td rowspan="1" colspan="1">G</td><td rowspan="1" colspan="1">LOC101928272</td><td rowspan="1" colspan="1">3.8 × 10<sup>−5</sup></td><td rowspan="1" colspan="1">94.1</td><td rowspan="1" colspan="1">−1.37</td><td rowspan="1" colspan="1">3.5 × 10<sup>−2</sup></td><td rowspan="1" colspan="1">96.2</td><td rowspan="1" colspan="1">−0.57</td><td rowspan="1" colspan="1"><bold>3.6 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">94.7</td><td rowspan="1" colspan="1">−1.46</td></tr><tr><td rowspan="1" colspan="1">rs35372009</td><td rowspan="1" colspan="1">14</td><td rowspan="1" colspan="1">38 782 341</td><td rowspan="1" colspan="1">Del</td><td rowspan="1" colspan="1">CLEC14A, LINC00639</td><td rowspan="1" colspan="1">1.1 × 10<sup>−2</sup></td><td rowspan="1" colspan="1">42.5</td><td rowspan="1" colspan="1">−1.78</td><td rowspan="1" colspan="1">9.0 × 10<sup>−6</sup></td><td rowspan="1" colspan="1">39.5</td><td rowspan="1" colspan="1">−3.07</td><td rowspan="1" colspan="1"><bold>3.3 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">41.6</td><td rowspan="1" colspan="1">−3.24</td></tr><tr><td rowspan="1" colspan="1">rs148077446</td><td rowspan="1" colspan="1">16</td><td rowspan="1" colspan="1">77 310 608</td><td rowspan="1" colspan="1">Del</td><td rowspan="1" colspan="1">SYCE1L, ADAMTS18</td><td rowspan="1" colspan="1">1.6 × 10<sup>−4</sup></td><td rowspan="1" colspan="1">28.7</td><td rowspan="1" colspan="1">−2.42</td><td rowspan="1" colspan="1">5.0 × 10<sup>−3</sup></td><td rowspan="1" colspan="1">31.9</td><td rowspan="1" colspan="1">−1.85</td><td rowspan="1" colspan="1"><bold>5.7 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">29.7</td><td rowspan="1" colspan="1">−2.93</td></tr></tbody></table><table frame="hsides" rules="groups"><thead><tr><td colspan="5" rowspan="1">SNPs that are only significantly associated in Celtic profile</td><td colspan="3" rowspan="1">RAF%</td><td colspan="3" rowspan="1">AF%</td><td colspan="3" rowspan="1">AF%</td></tr></thead><tbody><tr><td rowspan="1" colspan="1">rs12743974</td><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">67 708 357</td><td rowspan="1" colspan="1">A</td><td rowspan="1" colspan="1"><bold>IL23R</bold>, C1ORF141, IL12RB2</td><td rowspan="1" colspan="1"><bold>5.3 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">41.9</td><td rowspan="1" colspan="1">−3.18</td><td rowspan="1" colspan="1">3.8 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">41.8</td><td rowspan="1" colspan="1">0.62</td><td rowspan="1" colspan="1">1.2 × 10<sup>−3</sup></td><td rowspan="1" colspan="1">41.8</td><td rowspan="1" colspan="1">−2.25</td></tr><tr><td rowspan="1" colspan="1">rs12736701</td><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">77 815 425</td><td rowspan="1" colspan="1">C</td><td rowspan="1" colspan="1"><bold>AK5</bold>, PIGK, ZZZ3</td><td rowspan="1" colspan="1"><bold>7.6 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">93.4</td><td rowspan="1" colspan="1">−1.57</td><td rowspan="1" colspan="1">8.4 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">93.9</td><td rowspan="1" colspan="1">0.07</td><td rowspan="1" colspan="1">3.2 × 10<sup>−4</sup></td><td rowspan="1" colspan="1">93.6</td><td rowspan="1" colspan="1">−1.24</td></tr><tr><td rowspan="1" colspan="1">rs7412314</td><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">171 287 252</td><td rowspan="1" colspan="1">T</td><td rowspan="1" colspan="1"><bold>FMO4</bold>, FMO1, TOP1P1</td><td rowspan="1" colspan="1"><bold>4.3 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">73.3</td><td rowspan="1" colspan="1">−2.88</td><td rowspan="1" colspan="1">6.5 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">69.8</td><td rowspan="1" colspan="1">−0.30</td><td rowspan="1" colspan="1">6.3 × 10<sup>−5</sup></td><td rowspan="1" colspan="1">72.1</td><td rowspan="1" colspan="1">−2.53</td></tr><tr><td rowspan="1" colspan="1">rs11099942</td><td rowspan="1" colspan="1">4</td><td rowspan="1" colspan="1">155 132 707</td><td rowspan="1" colspan="1">T</td><td rowspan="1" colspan="1">SFRP2, DCHS2</td><td rowspan="1" colspan="1"><bold>4.3 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">6.4</td><td rowspan="1" colspan="1">−1.59</td><td rowspan="1" colspan="1">6.7 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">5.1</td><td rowspan="1" colspan="1">0.13</td><td rowspan="1" colspan="1">1.7 × 10<sup>−4</sup></td><td rowspan="1" colspan="1">5.9</td><td rowspan="1" colspan="1">−1.26</td></tr><tr><td rowspan="1" colspan="1">rs9502478</td><td rowspan="1" colspan="1">6</td><td rowspan="1" colspan="1">6 593 695</td><td rowspan="1" colspan="1">T</td><td rowspan="1" colspan="1"><bold>LY86-AS1</bold>, F13A1</td><td rowspan="1" colspan="1"><bold>4.3 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">17.3</td><td rowspan="1" colspan="1">−2.46</td><td rowspan="1" colspan="1">6.3 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">16.0</td><td rowspan="1" colspan="1">−0.25</td><td rowspan="1" colspan="1">3.2 × 10<sup>−5</sup></td><td rowspan="1" colspan="1">16.9</td><td rowspan="1" colspan="1">−2.20</td></tr><tr><td rowspan="1" colspan="1">rs2107167</td><td rowspan="1" colspan="1">7</td><td rowspan="1" colspan="1">109 590 911</td><td rowspan="1" colspan="1">A</td><td rowspan="1" colspan="1">EIF3IP1</td><td rowspan="1" colspan="1"><bold>8.0 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">13.7</td><td rowspan="1" colspan="1">−2.17</td><td rowspan="1" colspan="1">9.6 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">9.6</td><td rowspan="1" colspan="1">−0.02</td><td rowspan="1" colspan="1">4.1 × 10<sup>−5</sup></td><td rowspan="1" colspan="1">12.4</td><td rowspan="1" colspan="1">−1.91</td></tr><tr><td rowspan="1" colspan="1">rs10973627</td><td rowspan="1" colspan="1">9</td><td rowspan="1" colspan="1">37 971 389</td><td rowspan="1" colspan="1">C</td><td rowspan="1" colspan="1"><bold>SHB</bold>, SLC25A51, ALDH1B1</td><td rowspan="1" colspan="1"><bold>4.1 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">87.7</td><td rowspan="1" colspan="1">−2.14</td><td rowspan="1" colspan="1">6.4 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">89.2</td><td rowspan="1" colspan="1">−0.21</td><td rowspan="1" colspan="1">9.9 × 10<sup>−6</sup></td><td rowspan="1" colspan="1">88.2</td><td rowspan="1" colspan="1">−2.02</td></tr><tr><td rowspan="1" colspan="1">rs113932007</td><td rowspan="1" colspan="1">11</td><td rowspan="1" colspan="1">115 491 436</td><td rowspan="1" colspan="1">Del</td><td rowspan="1" colspan="1">CADM1, LINC00900</td><td rowspan="1" colspan="1"><bold>5.9 × 10</bold><sup><bold>−7</bold></sup></td><td rowspan="1" colspan="1">65.1</td><td rowspan="1" colspan="1">−3.37</td><td rowspan="1" colspan="1">5.1 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">64.5</td><td rowspan="1" colspan="1">−0.45</td><td rowspan="1" colspan="1">8.8 × 10<sup>−6</sup></td><td rowspan="1" colspan="1">64.9</td><td rowspan="1" colspan="1">−3.00</td></tr><tr><td rowspan="1" colspan="1">rs10512488</td><td rowspan="1" colspan="1">17</td><td rowspan="1" colspan="1">40 963 904</td><td rowspan="1" colspan="1">G</td><td rowspan="1" colspan="1"><bold>BECN1</bold>, CNTD1, MIR6781</td><td rowspan="1" colspan="1"><bold>3.1 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">74.0</td><td rowspan="1" colspan="1">−2.90</td><td rowspan="1" colspan="1">2.9 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">72.2</td><td rowspan="1" colspan="1">−0.67</td><td rowspan="1" colspan="1">9.5 × 10<sup>−6</sup></td><td rowspan="1" colspan="1">73.4</td><td rowspan="1" colspan="1">−2.77</td></tr></tbody></table><table frame="hsides" rules="groups"><thead><tr><td colspan="5" rowspan="1">SNPs that are only significantly associated in Slavic profile</td><td colspan="3" rowspan="1">AF%</td><td colspan="3" rowspan="1">RAF%</td><td colspan="3" rowspan="1">AF%</td></tr></thead><tbody><tr><td rowspan="1" colspan="1">rs340841</td><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">214 124 470</td><td rowspan="1" colspan="1">C</td><td rowspan="1" colspan="1"><bold>PROX1-AS1</bold>, LINC00538, PROX1</td><td rowspan="1" colspan="1">7.9 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">45.9</td><td rowspan="1" colspan="1">0.19</td><td rowspan="1" colspan="1"><bold>8.6 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">52.8</td><td rowspan="1" colspan="1">−3.14</td><td rowspan="1" colspan="1">2.5 × 10<sup>2</sup></td><td rowspan="1" colspan="1">48.1</td><td rowspan="1" colspan="1">−1.59</td></tr><tr><td rowspan="1" colspan="1">rs12714314</td><td rowspan="1" colspan="1">2</td><td rowspan="1" colspan="1">1 943 617</td><td rowspan="1" colspan="1">C</td><td rowspan="1" colspan="1"><bold>MYT1L</bold>, PXDN, MYT1L-AS1</td><td rowspan="1" colspan="1">9.3 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">75.8</td><td rowspan="1" colspan="1">0.05</td><td rowspan="1" colspan="1"><bold>3.4 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">72.8</td><td rowspan="1" colspan="1">−2.92</td><td rowspan="1" colspan="1">1.9 × 10<sup>−2</sup></td><td rowspan="1" colspan="1">74.9</td><td rowspan="1" colspan="1">−1.44</td></tr><tr><td rowspan="1" colspan="1">rs58383906</td><td rowspan="1" colspan="1">3</td><td rowspan="1" colspan="1">29 246 181</td><td rowspan="1" colspan="1">C</td><td rowspan="1" colspan="1">LINC00693, RBMS3-AS3</td><td rowspan="1" colspan="1">3.3 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">51.5</td><td rowspan="1" colspan="1">−0.68</td><td rowspan="1" colspan="1"><bold>2.8 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">50.3</td><td rowspan="1" colspan="1">−3.32</td><td rowspan="1" colspan="1">6.9 × 10<sup>−4</sup></td><td rowspan="1" colspan="1">51.1</td><td rowspan="1" colspan="1">−2.40</td></tr><tr><td rowspan="1" colspan="1">rs13166103</td><td rowspan="1" colspan="1">5</td><td rowspan="1" colspan="1">57 742 202</td><td rowspan="1" colspan="1">C</td><td rowspan="1" colspan="1">LOC101928569, PLK2</td><td rowspan="1" colspan="1">3.5 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">81.3</td><td rowspan="1" colspan="1">0.51</td><td rowspan="1" colspan="1"><bold>4.1 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">79.8</td><td rowspan="1" colspan="1">−2.61</td><td rowspan="1" colspan="1">9.4 × 10<sup>−2</sup></td><td rowspan="1" colspan="1">80.8</td><td rowspan="1" colspan="1">−0.93</td></tr><tr><td rowspan="1" colspan="1">rs12188216</td><td rowspan="1" colspan="1">5</td><td rowspan="1" colspan="1">166 425 736</td><td rowspan="1" colspan="1">G</td><td rowspan="1" colspan="1">CTB-7E3.1, TENM2</td><td rowspan="1" colspan="1">2.9 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">10.7</td><td rowspan="1" colspan="1">−0.46</td><td rowspan="1" colspan="1"><bold>9.7 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">9.7</td><td rowspan="1" colspan="1">−1.85</td><td rowspan="1" colspan="1">1.7 × 10<sup>−3</sup></td><td rowspan="1" colspan="1">10.3</td><td rowspan="1" colspan="1">−1.35</td></tr><tr><td rowspan="1" colspan="1">rs9384193</td><td rowspan="1" colspan="1">6</td><td rowspan="1" colspan="1">154 554 249</td><td rowspan="1" colspan="1">C</td><td rowspan="1" colspan="1"><bold>OPRM1</bold>, CNKSR3</td><td rowspan="1" colspan="1">8.7 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">36.3</td><td rowspan="1" colspan="1">0.11</td><td rowspan="1" colspan="1"><bold>8.8 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">36.3</td><td rowspan="1" colspan="1">−3.02</td><td rowspan="1" colspan="1">2.7 × 10<sup>−2</sup></td><td rowspan="1" colspan="1">36.3</td><td rowspan="1" colspan="1">−1.50</td></tr><tr><td rowspan="1" colspan="1">rs11060464</td><td rowspan="1" colspan="1">12</td><td rowspan="1" colspan="1">130 097 850</td><td rowspan="1" colspan="1">G</td><td rowspan="1" colspan="1"><bold>TMEM132D</bold>, LOC101927735, LOC100190940</td><td rowspan="1" colspan="1">5.4 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">70.9</td><td rowspan="1" colspan="1">0.39</td><td rowspan="1" colspan="1"><bold>3.7 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">73.1</td><td rowspan="1" colspan="1">−2.90</td><td rowspan="1" colspan="1">6.0 × 10<sup>−2</sup></td><td rowspan="1" colspan="1">71.6</td><td rowspan="1" colspan="1">−1.20</td></tr><tr><td rowspan="1" colspan="1">rs1754680</td><td rowspan="1" colspan="1">14</td><td rowspan="1" colspan="1">38 848 003</td><td rowspan="1" colspan="1">A</td><td rowspan="1" colspan="1">CLEC14A, LINC00639</td><td rowspan="1" colspan="1">2.3 × 10<sup>−2</sup></td><td rowspan="1" colspan="1">59.4</td><td rowspan="1" colspan="1">−1.54</td><td rowspan="1" colspan="1"><bold>8.3 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">57.4</td><td rowspan="1" colspan="1">−3.17</td><td rowspan="1" colspan="1">4.8 × 10<sup>−5</sup></td><td rowspan="1" colspan="1">58.7</td><td rowspan="1" colspan="1">−2.85</td></tr><tr><td rowspan="1" colspan="1">rs13043901</td><td rowspan="1" colspan="1">20</td><td rowspan="1" colspan="1">52 170 783</td><td rowspan="1" colspan="1">A</td><td rowspan="1" colspan="1"><bold>LOC101927770</bold>, TSHZ2, ZNF217</td><td rowspan="1" colspan="1">3.3 × 10<sup>−1</sup></td><td rowspan="1" colspan="1">75.3</td><td rowspan="1" colspan="1">−0.60</td><td rowspan="1" colspan="1"><bold>5.0 × 10</bold><sup><bold>−6</bold></sup></td><td rowspan="1" colspan="1">76.5</td><td rowspan="1" colspan="1">−2.74</td><td rowspan="1" colspan="1">4.2 × 10<sup>−4</sup></td><td rowspan="1" colspan="1">75.7</td><td rowspan="1" colspan="1">−2.14</td></tr></tbody></table><table-wrap-foot><fn fn-type="other"><p>RA, risk allele; RAF, risk allele frequency; SNP, single-nucleotide polymorphism.</p></fn><fn fn-type="other" id="TF2-1"><p><sup>a</sup>If gene is in bold, SNP lies within the gene.</p></fn><fn fn-type="other" id="TF2-2"><p><sup>b</sup>The effect size (ES) is determined by the β, MAF, and standard error using the equation described in literature [<xref rid="R37" ref-type="bibr">37</xref>].</p></fn><fn fn-type="other" id="TF2-3"><p><sup>c</sup>Association is considered replicated in two independent samples when <italic>P</italic> values are nominally significant for each of Celtic and Slavic samples and are more significant for combined sample.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Australie</li><li>Canada</li><li>France</li></country><region><li>Nouvelle-Galles du Sud</li><li>Victoria (État)</li><li>Île-de-France</li></region><settlement><li>Melbourne</li><li>Paris</li><li>Sydney</li></settlement><orgName><li>Université de Melbourne</li><li>Université de Sydney</li></orgName></list><tree><noCountry><name sortKey="Haloui, Mounsif" sort="Haloui, Mounsif" uniqKey="Haloui M" first="Mounsif" last="Haloui">Mounsif Haloui</name><name sortKey="Hamet, Pavel" sort="Hamet, Pavel" uniqKey="Hamet P" first="Pavel" last="Hamet">Pavel Hamet</name><name sortKey="Harvey, Francois" sort="Harvey, Francois" uniqKey="Harvey F" first="François" last="Harvey">François Harvey</name><name sortKey="Long, Carole" sort="Long, Carole" uniqKey="Long C" first="Carole" last="Long">Carole Long</name><name sortKey="Marois Blanchet, Francois Christophe" sort="Marois Blanchet, Francois Christophe" uniqKey="Marois Blanchet F" first="François-Christophe" last="Marois-Blanchet">François-Christophe Marois-Blanchet</name><name sortKey="Raelson, John" sort="Raelson, John" uniqKey="Raelson J" first="John" last="Raelson">John Raelson</name><name sortKey="Simon, Paul H G" sort="Simon, Paul H G" uniqKey="Simon P" first="Paul H. G." last="Simon">Paul H. G. Simon</name><name sortKey="Sylvestre, Marie Pierre" sort="Sylvestre, Marie Pierre" uniqKey="Sylvestre M" first="Marie-Pierre" last="Sylvestre">Marie-Pierre Sylvestre</name><name sortKey="Tahir, Muhammad Ramzan" sort="Tahir, Muhammad Ramzan" uniqKey="Tahir M" first="Muhammad-Ramzan" last="Tahir">Muhammad-Ramzan Tahir</name><name sortKey="Tremblay, Johanne" sort="Tremblay, Johanne" uniqKey="Tremblay J" first="Johanne" last="Tremblay">Johanne Tremblay</name></noCountry><country name="Canada"><noRegion><name sortKey="Kanzki, Beatriz Sonja" sort="Kanzki, Beatriz Sonja" uniqKey="Kanzki B" first="Beatriz Sonja" last="Kanzki">Beatriz Sonja Kanzki</name></noRegion></country><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Chalmers, John" sort="Chalmers, John" uniqKey="Chalmers J" first="John" last="Chalmers">John Chalmers</name></region><name sortKey="Harrap, Stephen" sort="Harrap, Stephen" uniqKey="Harrap S" first="Stephen" last="Harrap">Stephen Harrap</name><name sortKey="Woodward, Mark" sort="Woodward, Mark" uniqKey="Woodward M" first="Mark" last="Woodward">Mark Woodward</name></country><country name="France"><region name="Île-de-France"><name sortKey="Marre, Michel" sort="Marre, Michel" uniqKey="Marre M" first="Michel" last="Marre">Michel Marre</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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