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 Owen; Beverley 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; Magic 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

doi:10.1093/hmg/ddp522

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, Magic 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

126 Citations (Scopus)

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 = 2 x 10(-5)], 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 language	English
Journal	Human Molecular Genetics
Volume	19
Issue number	3
Pages (from-to)	535-44
Number of pages	9
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddp522
Publication status	Published - 2009

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10.1093/hmg/ddp522

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Perry, J. R. B., Weedon, M. N., Langenberg, C., Jackson, A. U., Lyssenko, V., Sparsø, T., Thorleifsson, G., Grallert, H., Ferrucci, L., Maggio, M., Paolisso, G., Walker, M., Palmer, C. N. A., Payne, F., Young, E., Herder, C., Narisu, N., Morken, M. A., Bonnycastle, L. L., ... 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), 535-44. https://doi.org/10.1093/hmg/ddp522

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, ME, 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, pp. 535-44. https://doi.org/10.1093/hmg/ddp522

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

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 = 2 x 10(-5)], 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.",

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

year = "2009",

doi = "10.1093/hmg/ddp522",

language = "English",

volume = "19",

pages = "535--44",

journal = "Human Molecular Genetics",

issn = "0964-6906",

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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, Magic 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

Y1 - 2009

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 = 2 x 10(-5)], 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 = 2 x 10(-5)], 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.

U2 - 10.1093/hmg/ddp522

DO - 10.1093/hmg/ddp522

M3 - Journal article

C2 - 19933169

SN - 0964-6906

VL - 19

SP - 535

EP - 544

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 3

ER -

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

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