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Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.

Identifieur interne : 001738 ( PubMed/Curation ); précédent : 001737; suivant : 001739

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.

Auteurs : Carolina Bonilla [Royaume-Uni] ; Sarah J. Lewis [Royaume-Uni] ; Mari-Anne Rowlands [Royaume-Uni] ; Tom R. Gaunt [Royaume-Uni] ; George Davey Smith [Royaume-Uni] ; David Gunnell [Royaume-Uni] ; Tom Palmer [Royaume-Uni] ; Jenny L. Donovan [Royaume-Uni] ; Freddie C. Hamdy [Royaume-Uni] ; David E. Neal [Royaume-Uni] ; Rosalind Eeles [Royaume-Uni] ; Doug Easton [Royaume-Uni] ; Zsofia Kote-Jarai [Royaume-Uni] ; Ali Amin Al Olama [Royaume-Uni] ; Sara Benlloch [Royaume-Uni] ; Kenneth Muir [Royaume-Uni] ; Graham G. Giles [Australie] ; Fredrik Wiklund [Suède] ; Henrik Grönberg [Suède] ; Christopher A. Haiman [États-Unis] ; Johanna Schleutker [Finlande] ; B Rge G. Nordestgaard [Danemark] ; Ruth C. Travis [Royaume-Uni] ; Nora Pashayan [Royaume-Uni] ; Kay-Tee Khaw [Royaume-Uni] ; Janet L. Stanford [États-Unis] ; William J. Blot [États-Unis] ; Stephen Thibodeau [États-Unis] ; Christiane Maier [Allemagne] ; Adam S. Kibel ; Cezary Cybulski [Pologne] ; Lisa Cannon-Albright [États-Unis] ; Hermann Brenner [Allemagne] ; Jong Park [États-Unis] ; Radka Kaneva [Bulgarie] ; Jyotsna Batra [Australie] ; Manuel R. Teixeira [Portugal] ; Hardev Pandha [Royaume-Uni] ; Mark Lathrop [France] ; Richard M. Martin [Royaume-Uni] ; Jeff M P. Holly [Royaume-Uni]

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RBID : pubmed:27225428

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Abstract

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.

DOI: 10.1002/ijc.30206
PubMed: 27225428

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Adam S. Kibel
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<nlm:affiliation>Brigham and Women's Hospital/Dana-Farber Cancer Institute, 45 Francis Street-ASB II-3, Boston, Massachussets.</nlm:affiliation>
<wicri:noCountry code="subField">Massachussets</wicri:noCountry>
</affiliation>

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<name sortKey="Palmer, Tom" sort="Palmer, Tom" uniqKey="Palmer T" first="Tom" last="Palmer">Tom Palmer</name>
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<name sortKey="Hamdy, Freddie C" sort="Hamdy, Freddie C" uniqKey="Hamdy F" first="Freddie C" last="Hamdy">Freddie C. Hamdy</name>
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<name sortKey="Neal, David E" sort="Neal, David E" uniqKey="Neal D" first="David E" last="Neal">David E. Neal</name>
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<name sortKey="Eeles, Rosalind" sort="Eeles, Rosalind" uniqKey="Eeles R" first="Rosalind" last="Eeles">Rosalind Eeles</name>
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<nlm:affiliation>The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom.</nlm:affiliation>
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<name sortKey="Easton, Doug" sort="Easton, Doug" uniqKey="Easton D" first="Doug" last="Easton">Doug Easton</name>
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<nlm:affiliation>The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom.</nlm:affiliation>
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<name sortKey="Al Olama, Ali Amin" sort="Al Olama, Ali Amin" uniqKey="Al Olama A" first="Ali Amin" last="Al Olama">Ali Amin Al Olama</name>
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<nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge</wicri:regionArea>
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<name sortKey="Benlloch, Sara" sort="Benlloch, Sara" uniqKey="Benlloch S" first="Sara" last="Benlloch">Sara Benlloch</name>
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<nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge</wicri:regionArea>
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<name sortKey="Muir, Kenneth" sort="Muir, Kenneth" uniqKey="Muir K" first="Kenneth" last="Muir">Kenneth Muir</name>
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<nlm:affiliation>University of Warwick, Coventry, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>University of Warwick, Coventry</wicri:regionArea>
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<name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G" last="Giles">Graham G. Giles</name>
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<nlm:affiliation>The Cancer Council Victoria, 615 St. Kilda Road, Melbourne, Victoria, 3004, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
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<name sortKey="Wiklund, Fredrik" sort="Wiklund, Fredrik" uniqKey="Wiklund F" first="Fredrik" last="Wiklund">Fredrik Wiklund</name>
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<nlm:affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation>
<country xml:lang="fr">Suède</country>
<wicri:regionArea>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm</wicri:regionArea>
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<name sortKey="Gronberg, Henrik" sort="Gronberg, Henrik" uniqKey="Gronberg H" first="Henrik" last="Grönberg">Henrik Grönberg</name>
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<nlm:affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation>
<country xml:lang="fr">Suède</country>
<wicri:regionArea>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm</wicri:regionArea>
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<name sortKey="Haiman, Christopher A" sort="Haiman, Christopher A" uniqKey="Haiman C" first="Christopher A" last="Haiman">Christopher A. Haiman</name>
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<nlm:affiliation>Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.</nlm:affiliation>
<country>États-Unis</country>
<placeName>
<region type="state">Californie</region>
</placeName>
<wicri:cityArea>Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles</wicri:cityArea>
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<name sortKey="Schleutker, Johanna" sort="Schleutker, Johanna" uniqKey="Schleutker J" first="Johanna" last="Schleutker">Johanna Schleutker</name>
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<nlm:affiliation>Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.</nlm:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Medical Biochemistry and Genetics, University of Turku, Turku</wicri:regionArea>
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<name sortKey="Nordestgaard, B Rge G" sort="Nordestgaard, B Rge G" uniqKey="Nordestgaard B" first="B Rge G" last="Nordestgaard">B Rge G. Nordestgaard</name>
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<nlm:affiliation>Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev, DK, 2730, Denmark.</nlm:affiliation>
<country xml:lang="fr">Danemark</country>
<wicri:regionArea>Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev, DK, 2730</wicri:regionArea>
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<name sortKey="Travis, Ruth C" sort="Travis, Ruth C" uniqKey="Travis R" first="Ruth C" last="Travis">Ruth C. Travis</name>
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<nlm:affiliation>Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
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<name sortKey="Pashayan, Nora" sort="Pashayan, Nora" uniqKey="Pashayan N" first="Nora" last="Pashayan">Nora Pashayan</name>
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<nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge</wicri:regionArea>
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<name sortKey="Khaw, Kay Tee" sort="Khaw, Kay Tee" uniqKey="Khaw K" first="Kay-Tee" last="Khaw">Kay-Tee Khaw</name>
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<nlm:affiliation>Forvie Site, Cambridge Institute of Public Health, University of Cambridge, Robinson Way, Cambridge, CB2 0SR, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Forvie Site, Cambridge Institute of Public Health, University of Cambridge, Robinson Way, Cambridge, CB2 0SR</wicri:regionArea>
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<name sortKey="Stanford, Janet L" sort="Stanford, Janet L" uniqKey="Stanford J" first="Janet L" last="Stanford">Janet L. Stanford</name>
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<nlm:affiliation>Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<region type="state">Washington (État)</region>
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<wicri:cityArea>Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle</wicri:cityArea>
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<name sortKey="Blot, William J" sort="Blot, William J" uniqKey="Blot W" first="William J" last="Blot">William J. Blot</name>
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<nlm:affiliation>International Epidemiology Institute, 1455 Research Blvd, Suite 550, Rockville, Maryland.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName>
<region type="state">Maryland</region>
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<wicri:cityArea>International Epidemiology Institute, 1455 Research Blvd, Suite 550, Rockville</wicri:cityArea>
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<name sortKey="Thibodeau, Stephen" sort="Thibodeau, Stephen" uniqKey="Thibodeau S" first="Stephen" last="Thibodeau">Stephen Thibodeau</name>
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<nlm:affiliation>Mayo Clinic, Rochester, Minnesota.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName>
<region type="state">Minnesota</region>
</placeName>
<wicri:cityArea>Mayo Clinic, Rochester</wicri:cityArea>
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</author>
<author>
<name sortKey="Maier, Christiane" sort="Maier, Christiane" uniqKey="Maier C" first="Christiane" last="Maier">Christiane Maier</name>
<affiliation wicri:level="1">
<nlm:affiliation>Department of Urology, University Hospital Ulm, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Urology, University Hospital Ulm</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kibel, Adam S" sort="Kibel, Adam S" uniqKey="Kibel A" first="Adam S" last="Kibel">Adam S. Kibel</name>
<affiliation>
<nlm:affiliation>Brigham and Women's Hospital/Dana-Farber Cancer Institute, 45 Francis Street-ASB II-3, Boston, Massachussets.</nlm:affiliation>
<wicri:noCountry code="subField">Massachussets</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Cybulski, Cezary" sort="Cybulski, Cezary" uniqKey="Cybulski C" first="Cezary" last="Cybulski">Cezary Cybulski</name>
<affiliation wicri:level="1">
<nlm:affiliation>International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.</nlm:affiliation>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea>International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin</wicri:regionArea>
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</author>
<author>
<name sortKey="Cannon Albright, Lisa" sort="Cannon Albright, Lisa" uniqKey="Cannon Albright L" first="Lisa" last="Cannon-Albright">Lisa Cannon-Albright</name>
<affiliation wicri:level="2">
<nlm:affiliation>Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName>
<region type="state">Utah</region>
</placeName>
<wicri:cityArea>Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City</wicri:cityArea>
</affiliation>
</author>
<author>
<name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name>
<affiliation wicri:level="1">
<nlm:affiliation>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Park, Jong" sort="Park, Jong" uniqKey="Park J" first="Jong" last="Park">Jong Park</name>
<affiliation wicri:level="2">
<nlm:affiliation>Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, Florida.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName>
<region type="state">Floride</region>
</placeName>
<wicri:cityArea>Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr, Tampa</wicri:cityArea>
</affiliation>
</author>
<author>
<name sortKey="Kaneva, Radka" sort="Kaneva, Radka" uniqKey="Kaneva R" first="Radka" last="Kaneva">Radka Kaneva</name>
<affiliation wicri:level="1">
<nlm:affiliation>Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University - Sofia, 2 Zdrave St, Sofia, 1431, Bulgaria.</nlm:affiliation>
<country xml:lang="fr">Bulgarie</country>
<wicri:regionArea>Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University - Sofia, 2 Zdrave St, Sofia, 1431</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Batra, Jyotsna" sort="Batra, Jyotsna" uniqKey="Batra J" first="Jyotsna" last="Batra">Jyotsna Batra</name>
<affiliation wicri:level="1">
<nlm:affiliation>Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Teixeira, Manuel R" sort="Teixeira, Manuel R" uniqKey="Teixeira M" first="Manuel R" last="Teixeira">Manuel R. Teixeira</name>
<affiliation wicri:level="1">
<nlm:affiliation>Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.</nlm:affiliation>
<country xml:lang="fr">Portugal</country>
<wicri:regionArea>Department of Genetics, Portuguese Oncology Institute, Porto</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Pandha, Hardev" sort="Pandha, Hardev" uniqKey="Pandha H" first="Hardev" last="Pandha">Hardev Pandha</name>
<affiliation wicri:level="1">
<nlm:affiliation>The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>The University of Surrey, Guildford, Surrey, GU2 7XH</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Lathrop, Mark" sort="Lathrop, Mark" uniqKey="Lathrop M" first="Mark" last="Lathrop">Mark Lathrop</name>
<affiliation wicri:level="1">
<nlm:affiliation>Commissariat à L'Energie Atomique, Center National De Génotypage, Evry, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Commissariat à L'Energie Atomique, Center National De Génotypage, Evry</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Martin, Richard M" sort="Martin, Richard M" uniqKey="Martin R" first="Richard M" last="Martin">Richard M. Martin</name>
<affiliation wicri:level="1">
<nlm:affiliation>School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>School of Social and Community Medicine, University of Bristol, Bristol</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Holly, Jeff M P" sort="Holly, Jeff M P" uniqKey="Holly J" first="Jeff M P" last="Holly">Jeff M P. Holly</name>
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<nlm:affiliation>NIHR Bristol Biomedical Research Unit in Nutrition, Bristol, United Kingdom.</nlm:affiliation>
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<title xml:lang="en">Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.</title>
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<name sortKey="Bonilla, Carolina" sort="Bonilla, Carolina" uniqKey="Bonilla C" first="Carolina" last="Bonilla">Carolina Bonilla</name>
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<title level="j">International journal of cancer</title>
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<term>Somatomedins</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Tumeurs de la prostate</term>
</keywords>
<keywords scheme="MESH" qualifier="blood" xml:lang="en">
<term>Prostatic Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="epidemiology" xml:lang="en">
<term>Prostatic Neoplasms</term>
<term>United Kingdom</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>Prostatic Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Protéines de liaison aux IGF</term>
<term>Somatomédines</term>
<term>Tumeurs de la prostate</term>
</keywords>
<keywords scheme="MESH" qualifier="methods" xml:lang="en">
<term>Mendelian Randomization Analysis</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Protéines de liaison aux IGF</term>
<term>Somatomédines</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Prostatic Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="sang" xml:lang="fr">
<term>Tumeurs de la prostate</term>
</keywords>
<keywords scheme="MESH" qualifier="épidémiologie" xml:lang="fr">
<term>Royaume-Uni</term>
<term>Tumeurs de la prostate</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Aged</term>
<term>Case-Control Studies</term>
<term>Genome-Wide Association Study</term>
<term>Humans</term>
<term>Longitudinal Studies</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Neoplasm Grading</term>
<term>Neoplasm Staging</term>
<term>Polymorphism, Single Nucleotide</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Adulte d'âge moyen</term>
<term>Analyse de randomisation mendélienne</term>
<term>Grading des tumeurs</term>
<term>Humains</term>
<term>Mâle</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Stade de la tumeur</term>
<term>Sujet âgé</term>
<term>Étude d'association pangénomique</term>
<term>Études cas-témoins</term>
<term>Études longitudinales</term>
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<front>
<div type="abstract" xml:lang="en">Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.</div>
</front>
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<PMID Version="1">27225428</PMID>
<DateCreated>
<Year>2016</Year>
<Month>07</Month>
<Day>15</Day>
</DateCreated>
<DateCompleted>
<Year>2017</Year>
<Month>06</Month>
<Day>23</Day>
</DateCompleted>
<DateRevised>
<Year>2017</Year>
<Month>09</Month>
<Day>22</Day>
</DateRevised>
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<Journal>
<ISSN IssnType="Electronic">1097-0215</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>139</Volume>
<Issue>7</Issue>
<PubDate>
<Year>2016</Year>
<Month>Oct</Month>
<Day>01</Day>
</PubDate>
</JournalIssue>
<Title>International journal of cancer</Title>
<ISOAbbreviation>Int. J. Cancer</ISOAbbreviation>
</Journal>
<ArticleTitle>Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.</ArticleTitle>
<Pagination>
<MedlinePgn>1520-33</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1002/ijc.30206</ELocationID>
<Abstract>
<AbstractText>Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.</AbstractText>
<CopyrightInformation>© 2016 UICC.</CopyrightInformation>
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<Affiliation>School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.</Affiliation>
</AffiliationInfo>
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<LastName>Lewis</LastName>
<ForeName>Sarah J</ForeName>
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</AffiliationInfo>
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<Affiliation>MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.</Affiliation>
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<ForeName>Rosalind</ForeName>
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<Grant>
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