TY - JOUR
T1 - Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes
AU - Perry, John R.B.
AU - Weedon, Michael N.
AU - Langenberg, Claudia
AU - Jackson, Anne U.
AU - Lyssenko, Valeriya
AU - Sparsø, Thomas
AU - Thorleifsson, Gudmar
AU - Grallert, Harald
AU - Ferrucci, Luigi
AU - Maggio, Marcello
AU - Paolisso, Giuseppe
AU - Walker, Mark
AU - Palmer, Colin N.A.
AU - Payne, Felicity
AU - Young, Elizabeth
AU - Herder, Christian
AU - Narisu, Narisu
AU - Morken, Mario A.
AU - Bonnycastle, Lori L.
AU - Owen, Katharine R.
AU - Shields, Beverley
AU - Knight, Beatrice
AU - Bennett, Amanda
AU - Groves, Christopher J.
AU - Ruokonen, Aimo
AU - Jarvelin, Marjo Riitta
AU - Pearson, Ewan
AU - Pascoe, Laura
AU - Ferrannini, Ele
AU - Bornstein, Stefan R.
AU - Stringham, Heather M.
AU - Scott, Laura J.
AU - Kuusisto, Johanna
AU - Nilsson, Peter
AU - Neptin, Malin
AU - Gjesing, Anette P.
AU - Pisinger, Charlotta
AU - Lauritzen, Torsten
AU - Sandbaek, Annelli
AU - Sampson, Mike
AU - Zeggini, Ele
AU - Lindgren, Cecilia M.
AU - Steinthorsdottir, Valgerdur
AU - Thorsteinsdottir, Unnur
AU - Hansen, Torben
AU - Schwarz, Peter
AU - Illig, Thomas
AU - Laakso, Markku
AU - Stefansson, Kari
AU - Morris, Andrew D.
AU - Groop, Leif
AU - Pedersen, Oluf
AU - Boehnke, Michael
AU - Barroso, Inês
AU - Wareham, Nicholas J.
AU - Hattersley, Andrew T.
AU - McCarthy, Mark I.
AU - Frayling, Timothy M.
N1 - Funding Information:
Collection of the UK type 2 diabetes cases was supported by Diabetes UK, BDA Research and the UK Medical Research Council (Biomedical Collections Strategic Grant G0000649). The UK Type 2 Diabetes Genetics Consortium collection was supported by the Wellcome Trust (Biomedical Collections Grant GR072960). The GWA genotyping was supported by the Wellcome Trust (076113) and replication genotyping by the European Commission (EURODIA LSHG-CT-2004-518153), MRC (Project Grant G016121), Wellcome Trust (Project Grant 083270/Z/07/Z), Peninsula Medical School and Diabetes UK. The work on the Cambridgeshire case– control, Ely and EPIC-Norfolk studies was funded by support from the Wellcome Trust and Medical research Council (MRC). ADDITION-Cambridge was supported by the Wellcome Trust, MRC, National Health Service R&D support funding and the National Institute for Health Research. The Norfolk Diabetes study is funded by the MRC with support from NHS Research & Development and the Wellcome Trust. The Danish case – control study was supported by the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LUCAMP) and the Danish Diabetes Association. Inter99 is supported by grants from the Danish Research Counsil, The Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, Ministry of Internal Affaires and Health, The Danish Heart Foundation, The Danish Pharmaceutical Association, The Augustinus Foundation and The Ib Henriksen Foundation, the Becket Foundation. The ADDITION sub-study Denmark was initiated by: Knut Borch-Johnsen (PI), Torsten Lauritzen (PI) and Annelli Sandbaek. The study was supported by the National Health Services in the counties of Copenhagen, Aarhus, Ringkøbing, Ribe and South Jutland, together with the Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, the diabetes fund of the National Board of Health, the Danish Medical Research Council, the Aarhus University Research Foundation and the Novo Nordisk Foundation. The study received unrestricted grants from Novo Nordisk, Novo Nordisk Scandinavia, Astra Denmark, Pfizer Denmark,Glax-oSmithKline Pharma Denmark, Servier Denmark and HemoCue Denmark. The KORA studies were financed by the Helmholtz Zentrum München, Research Center for Environment and Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF), the German National Genome Research Network (NGFN) and the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. Additional funds were provided by the German Diabetes Center (Düsseldorf, Germany), the Federal Ministry of Health (Berlin, Germany) and the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Düsseldorf, Germany). The RISC Study is supported by European Union grant QLG1-CT-2001-01252 and AstraZeneca. Support for FUSION study was provided by the following: American Diabetes Association grant 1-05-RA-140 (R.M.W.) and NIH grants DK069922 (R.M.W.), U54 DA021519 (R.M.W.), DK062370 (M.B.) and DK072193 (K.L.M.). Additional support comes from the National Human Genome Research Institute intramural project number 1 Z01 HG000024 (F.S.C.). DIAGEN study was supported by the Dresden University of Technology funding grant, Med Drive. METSIM: support was provided by grant 124243 from the Academy of Finland. The InCHIANTI study is supported in part by the Intramural Research Program of the NIH, National Institute on Aging and in part by NIH/NIA grant R01 AG24233-01. I.B. is supported by the Wellcome Trust (077016/Z/05/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.
PY - 2009/11/18
Y1 - 2009/11/18
N2 - Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P 5 2 3 1025], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
AB - Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P 5 2 3 1025], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
UR - http://www.scopus.com/inward/record.url?scp=77949911881&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddp522
DO - 10.1093/hmg/ddp522
M3 - Article
C2 - 19933169
AN - SCOPUS:77949911881
SN - 0964-6906
VL - 19
SP - 535
EP - 544
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 3
M1 - ddp522
ER -
