Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes

John R B Perry, Michael N. Weedon, Claudia Langenberg, Anne U. Jackson, Valeriya Lyssenko, Thomas Sparsø, Gudmar Thorleifsson, Harald Grallert, Luigi Ferrucci, Marcello Maggio, Giuseppe Paolisso, Mark Walker, Colin N A Palmer, Felicity Payne, Elizabeth Young, Christian Herder, Narisu Narisu, Mario A. Morken, Lori L. Bonnycastle, Katharine R. OwenBeverley Shields, Beatrice Knight, Amanda Bennett, Christopher J. Groves, Aimo Ruokonen, Marjo Riitta Jarvelin, Ewan Pearson, Laura Pascoe, Ele Ferrannini, Stefan R. Bornstein, Heather M. Stringham, Laura J. Scott, Johanna Kuusisto, Peter Nilsson, Malin Neptin, Anette P. Gjesing, Charlotta Pisinger, Torsten Lauritzen, Annelli Sandbaek, Mike Sampson, Ele Zeggini, Cecilia M. Lindgren, Valgerdur Steinthorsdottir, Unnur Thorsteinsdottir, Torben Hansen, Peter Schwarz, Thomas Illig, Markku Laakso, Kari Stefansson, Andrew D. Morris, Leif Groop, Oluf Pedersen, Michael Boehnke, Inês Barroso, Nicholas J. Wareham, Andrew T. Hattersley, Mark I. McCarthy, Timothy M. Frayling

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numberddp522
Pages (from-to)535-544
Number of pages10
JournalHuman Molecular Genetics
Volume19
Issue number3
DOIs
StatePublished - Nov 18 2009
Externally publishedYes

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Sex Hormone-Binding Globulin
Type 2 Diabetes Mellitus
Single Nucleotide Polymorphism
Alleles
Odds Ratio
Gonadal Steroid Hormones
Random Allocation
Insulin Resistance
Epidemiologic Studies

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Perry, J. R. B., Weedon, M. N., Langenberg, C., Jackson, A. U., Lyssenko, V., Sparsø, T., ... Frayling, T. M. (2009). Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Human Molecular Genetics, 19(3), 535-544. [ddp522]. https://doi.org/10.1093/hmg/ddp522

Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. / Perry, John R B; Weedon, Michael N.; Langenberg, Claudia; Jackson, Anne U.; Lyssenko, Valeriya; Sparsø, Thomas; Thorleifsson, Gudmar; Grallert, Harald; Ferrucci, Luigi; Maggio, Marcello; Paolisso, Giuseppe; Walker, Mark; Palmer, Colin N A; Payne, Felicity; Young, Elizabeth; Herder, Christian; Narisu, Narisu; Morken, Mario A.; Bonnycastle, Lori L.; Owen, Katharine R.; Shields, Beverley; Knight, Beatrice; Bennett, Amanda; Groves, Christopher J.; Ruokonen, Aimo; Jarvelin, Marjo Riitta; Pearson, Ewan; Pascoe, Laura; Ferrannini, Ele; Bornstein, Stefan R.; Stringham, Heather M.; Scott, Laura J.; Kuusisto, Johanna; Nilsson, Peter; Neptin, Malin; Gjesing, Anette P.; Pisinger, Charlotta; Lauritzen, Torsten; Sandbaek, Annelli; Sampson, Mike; Zeggini, Ele; Lindgren, Cecilia M.; Steinthorsdottir, Valgerdur; Thorsteinsdottir, Unnur; Hansen, Torben; Schwarz, Peter; Illig, Thomas; Laakso, Markku; Stefansson, Kari; Morris, Andrew D.; Groop, Leif; Pedersen, Oluf; Boehnke, Michael; Barroso, Inês; Wareham, Nicholas J.; Hattersley, Andrew T.; McCarthy, Mark I.; Frayling, Timothy M.

In: Human Molecular Genetics, Vol. 19, No. 3, ddp522, 18.11.2009, p. 535-544.

Research output: Contribution to journalArticle

Perry, JRB, Weedon, MN, Langenberg, C, Jackson, AU, Lyssenko, V, Sparsø, T, Thorleifsson, G, Grallert, H, Ferrucci, L, Maggio, M, Paolisso, G, Walker, M, Palmer, CNA, Payne, F, Young, E, Herder, C, Narisu, N, Morken, MA, Bonnycastle, LL, Owen, KR, Shields, B, Knight, B, Bennett, A, Groves, CJ, Ruokonen, A, Jarvelin, MR, Pearson, E, Pascoe, L, Ferrannini, E, Bornstein, SR, Stringham, HM, Scott, LJ, Kuusisto, J, Nilsson, P, Neptin, M, Gjesing, AP, Pisinger, C, Lauritzen, T, Sandbaek, A, Sampson, M, Zeggini, E, Lindgren, CM, Steinthorsdottir, V, Thorsteinsdottir, U, Hansen, T, Schwarz, P, Illig, T, Laakso, M, Stefansson, K, Morris, AD, Groop, L, Pedersen, O, Boehnke, M, Barroso, I, Wareham, NJ, Hattersley, AT, McCarthy, MI & Frayling, TM 2009, 'Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes', Human Molecular Genetics, vol. 19, no. 3, ddp522, pp. 535-544. https://doi.org/10.1093/hmg/ddp522
Perry JRB, Weedon MN, Langenberg C, Jackson AU, Lyssenko V, Sparsø T et al. Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Human Molecular Genetics. 2009 Nov 18;19(3):535-544. ddp522. https://doi.org/10.1093/hmg/ddp522
Perry, John R B ; Weedon, Michael N. ; Langenberg, Claudia ; Jackson, Anne U. ; Lyssenko, Valeriya ; Sparsø, Thomas ; Thorleifsson, Gudmar ; Grallert, Harald ; Ferrucci, Luigi ; Maggio, Marcello ; Paolisso, Giuseppe ; Walker, Mark ; Palmer, Colin N A ; Payne, Felicity ; Young, Elizabeth ; Herder, Christian ; Narisu, Narisu ; Morken, Mario A. ; Bonnycastle, Lori L. ; Owen, Katharine R. ; Shields, Beverley ; Knight, Beatrice ; Bennett, Amanda ; Groves, Christopher J. ; Ruokonen, Aimo ; Jarvelin, Marjo Riitta ; Pearson, Ewan ; Pascoe, Laura ; Ferrannini, Ele ; Bornstein, Stefan R. ; Stringham, Heather M. ; Scott, Laura J. ; Kuusisto, Johanna ; Nilsson, Peter ; Neptin, Malin ; Gjesing, Anette P. ; Pisinger, Charlotta ; Lauritzen, Torsten ; Sandbaek, Annelli ; Sampson, Mike ; Zeggini, Ele ; Lindgren, Cecilia M. ; Steinthorsdottir, Valgerdur ; Thorsteinsdottir, Unnur ; Hansen, Torben ; Schwarz, Peter ; Illig, Thomas ; Laakso, Markku ; Stefansson, Kari ; Morris, Andrew D. ; Groop, Leif ; Pedersen, Oluf ; Boehnke, Michael ; Barroso, Inês ; Wareham, Nicholas J. ; Hattersley, Andrew T. ; McCarthy, Mark I. ; Frayling, Timothy M. / Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. In: Human Molecular Genetics. 2009 ; Vol. 19, No. 3. pp. 535-544.
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abstract = "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.",
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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.

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.

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