Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes

Hanieh Yaghootkar; Claudia Lamina; Robert A. Scott; Zari Dastani; Marie France Hivert; Liling L. Warren; Alena Stancáková; Sarah G. Buxbaum; Leo Pekka Lyytikäinen; Peter Henneman; Ying Wu; Chloe Y Y Cheung; James S. Pankow; Anne U. Jackson; Stefan Gustafsson; Jing Hua Zhao; Christie M. Ballantyne; Weijia Xie; Richard N. Bergman; Michael Boehnke; Fatiha El Bouazzaoui; Francis S. Collins; Sandra H. Dunn; Josee Dupuis; Nita G. Forouhi; Christopher Gillson; Andrew T. Hattersley; Jaeyoung Hong; Mika Kähönen; Johanna Kuusisto; Lyudmyla Kedenko; Florian Kronenberg; Alessandro Doria; Themistocles L. Assimes; Ele Ferrannini; Torben Hansen; Ke Hao; Hans Häring; Joshua W. Knowles; Cecilia M. Lindgren; John J. Nolan; Jussi Paananen; Oluf Pedersen; Thomas Quertermous; Ulf Smith; Terho Lehtimäki; Ching Ti Liu; Ruth J F Loos; Mark I. McCarthy; Andrew D. Morris; Ramachandran S. Vasan; Tim D. Spector; Tanya M. Teslovich; Jaakko Tuomilehto; Ko Willems Van Dijk; Jorma S. Viikari; Na Zhu; Claudia Langenberg; Erik Ingelsson; Robert K. Semple; Alan R. Sinaiko; Colin N A Palmer; Mark Walker; Karen S L Lam; Bernhard Paulweber; Karen L. Mohlke; Cornelia Van Duijn; Olli T. Raitakari; Aurelian Bidulescu; Nick J. Wareham; Markku Laakso; Dawn M. Waterworth; Debbie A. Lawlor; James B. Meig; J. Brent Richards; Timothy M. Frayling

doi:10.2337/db13-0128

Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes

Hanieh Yaghootkar, Claudia Lamina, Robert A. Scott, Zari Dastani, Marie France Hivert, Liling L. Warren, Alena Stancáková, Sarah G. Buxbaum, Leo Pekka Lyytikäinen, Peter Henneman, Ying Wu, Chloe Y Y Cheung, James S. Pankow, Anne U. Jackson, Stefan Gustafsson, Jing Hua Zhao, Christie M. Ballantyne, Weijia Xie, Richard N. Bergman, Michael BoehnkeFatiha El Bouazzaoui, Francis S. Collins, Sandra H. Dunn, Josee Dupuis, Nita G. Forouhi, Christopher Gillson, Andrew T. Hattersley, Jaeyoung Hong, Mika Kähönen, Johanna Kuusisto, Lyudmyla Kedenko, Florian Kronenberg, Alessandro Doria, Themistocles L. Assimes, Ele Ferrannini, Torben Hansen, Ke Hao, Hans Häring, Joshua W. Knowles, Cecilia M. Lindgren, John J. Nolan, Jussi Paananen, Oluf Pedersen, Thomas Quertermous, Ulf Smith, Terho Lehtimäki, Ching Ti Liu, Ruth J F Loos, Mark I. McCarthy, Andrew D. Morris, Ramachandran S. Vasan, Tim D. Spector, Tanya M. Teslovich, Jaakko Tuomilehto, Ko Willems Van Dijk, Jorma S. Viikari, Na Zhu, Claudia Langenberg, Erik Ingelsson, Robert K. Semple, Alan R. Sinaiko, Colin N A Palmer, Mark Walker, Karen S L Lam, Bernhard Paulweber, Karen L. Mohlke, Cornelia Van Duijn, Olli T. Raitakari, Aurelian Bidulescu, Nick J. Wareham, Markku Laakso, Dawn M. Waterworth, Debbie A. Lawlor, James B. Meig, J. Brent Richards, Timothy M. Frayling

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Abstract

Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI 20.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (20.20 SD; 95% CI 20.38 to 20.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin- lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: 20.03 SD; 95% CI 20.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

Original language	English (US)
Pages (from-to)	3589-3598
Number of pages	10
Journal	Diabetes
Volume	62
Issue number	10
DOIs	https://doi.org/10.2337/db13-0128
State	Published - Oct 2013

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Yaghootkar, H., Lamina, C., Scott, R. A., Dastani, Z., Hivert, M. F., Warren, L. L., Stancáková, A., Buxbaum, S. G., Lyytikäinen, L. P., Henneman, P., Wu, Y., Cheung, C. Y. Y., Pankow, J. S., Jackson, A. U., Gustafsson, S., Zhao, J. H., Ballantyne, C. M., Xie, W., Bergman, R. N., ... Frayling, T. M. (2013). Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes. Diabetes, 62(10), 3589-3598. https://doi.org/10.2337/db13-0128

Yaghootkar, H, Lamina, C, Scott, RA, Dastani, Z, Hivert, MF, Warren, LL, Stancáková, A, Buxbaum, SG, Lyytikäinen, LP, Henneman, P, Wu, Y, Cheung, CYY, Pankow, JS, Jackson, AU, Gustafsson, S, Zhao, JH, Ballantyne, CM, Xie, W, Bergman, RN, Boehnke, M, El Bouazzaoui, F, Collins, FS, Dunn, SH, Dupuis, J, Forouhi, NG, Gillson, C, Hattersley, AT, Hong, J, Kähönen, M, Kuusisto, J, Kedenko, L, Kronenberg, F, Doria, A, Assimes, TL, Ferrannini, E, Hansen, T, Hao, K, Häring, H, Knowles, JW, Lindgren, CM, Nolan, JJ, Paananen, J, Pedersen, O, Quertermous, T, Smith, U, Lehtimäki, T, Liu, CT, Loos, RJF, McCarthy, MI, Morris, AD, Vasan, RS, Spector, TD, Teslovich, TM, Tuomilehto, J, Van Dijk, KW, Viikari, JS, Zhu, N, Langenberg, C, Ingelsson, E, Semple, RK, Sinaiko, AR, Palmer, CNA, Walker, M, Lam, KSL, Paulweber, B, Mohlke, KL, Van Duijn, C, Raitakari, OT, Bidulescu, A, Wareham, NJ, Laakso, M, Waterworth, DM, Lawlor, DA, Meig, JB, Richards, JB & Frayling, TM 2013, 'Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes', Diabetes, vol. 62, no. 10, pp. 3589-3598. https://doi.org/10.2337/db13-0128

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title = "Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes",

abstract = "Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI 20.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (20.20 SD; 95% CI 20.38 to 20.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin- lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: 20.03 SD; 95% CI 20.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.",

author = "Hanieh Yaghootkar and Claudia Lamina and Scott, {Robert A.} and Zari Dastani and Hivert, {Marie France} and Warren, {Liling L.} and Alena Stanc{\'a}kov{\'a} and Buxbaum, {Sarah G.} and Lyytik{\"a}inen, {Leo Pekka} and Peter Henneman and Ying Wu and Cheung, {Chloe Y Y} and Pankow, {James S.} and Jackson, {Anne U.} and Stefan Gustafsson and Zhao, {Jing Hua} and Ballantyne, {Christie M.} and Weijia Xie and Bergman, {Richard N.} and Michael Boehnke and {El Bouazzaoui}, Fatiha and Collins, {Francis S.} and Dunn, {Sandra H.} and Josee Dupuis and Forouhi, {Nita G.} and Christopher Gillson and Hattersley, {Andrew T.} and Jaeyoung Hong and Mika K{\"a}h{\"o}nen and Johanna Kuusisto and Lyudmyla Kedenko and Florian Kronenberg and Alessandro Doria and Assimes, {Themistocles L.} and Ele Ferrannini and Torben Hansen and Ke Hao and Hans H{\"a}ring and Knowles, {Joshua W.} and Lindgren, {Cecilia M.} and Nolan, {John J.} and Jussi Paananen and Oluf Pedersen and Thomas Quertermous and Ulf Smith and Terho Lehtim{\"a}ki and Liu, {Ching Ti} and Loos, {Ruth J F} and McCarthy, {Mark I.} and Morris, {Andrew D.} and Vasan, {Ramachandran S.} and Spector, {Tim D.} and Teslovich, {Tanya M.} and Jaakko Tuomilehto and {Van Dijk}, {Ko Willems} and Viikari, {Jorma S.} and Na Zhu and Claudia Langenberg and Erik Ingelsson and Semple, {Robert K.} and Sinaiko, {Alan R.} and Palmer, {Colin N A} and Mark Walker and Lam, {Karen S L} and Bernhard Paulweber and Mohlke, {Karen L.} and {Van Duijn}, Cornelia and Raitakari, {Olli T.} and Aurelian Bidulescu and Wareham, {Nick J.} and Markku Laakso and Waterworth, {Dawn M.} and Lawlor, {Debbie A.} and Meig, {James B.} and Richards, {J. Brent} and Frayling, {Timothy M.}",

year = "2013",

month = oct,

doi = "10.2337/db13-0128",

language = "English (US)",

volume = "62",

pages = "3589--3598",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "10",

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TY - JOUR

T1 - Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes

AU - Yaghootkar, Hanieh

AU - Lamina, Claudia

AU - Scott, Robert A.

AU - Dastani, Zari

AU - Hivert, Marie France

AU - Warren, Liling L.

AU - Stancáková, Alena

AU - Buxbaum, Sarah G.

AU - Lyytikäinen, Leo Pekka

AU - Henneman, Peter

AU - Wu, Ying

AU - Cheung, Chloe Y Y

AU - Pankow, James S.

AU - Jackson, Anne U.

AU - Gustafsson, Stefan

AU - Zhao, Jing Hua

AU - Ballantyne, Christie M.

AU - Xie, Weijia

AU - Bergman, Richard N.

AU - Boehnke, Michael

AU - El Bouazzaoui, Fatiha

AU - Collins, Francis S.

AU - Dunn, Sandra H.

AU - Dupuis, Josee

AU - Forouhi, Nita G.

AU - Gillson, Christopher

AU - Hattersley, Andrew T.

AU - Hong, Jaeyoung

AU - Kähönen, Mika

AU - Kuusisto, Johanna

AU - Kedenko, Lyudmyla

AU - Kronenberg, Florian

AU - Doria, Alessandro

AU - Assimes, Themistocles L.

AU - Ferrannini, Ele

AU - Hansen, Torben

AU - Hao, Ke

AU - Häring, Hans

AU - Knowles, Joshua W.

AU - Lindgren, Cecilia M.

AU - Nolan, John J.

AU - Paananen, Jussi

AU - Pedersen, Oluf

AU - Quertermous, Thomas

AU - Smith, Ulf

AU - Lehtimäki, Terho

AU - Liu, Ching Ti

AU - Loos, Ruth J F

AU - McCarthy, Mark I.

AU - Morris, Andrew D.

AU - Vasan, Ramachandran S.

AU - Spector, Tim D.

AU - Teslovich, Tanya M.

AU - Tuomilehto, Jaakko

AU - Van Dijk, Ko Willems

AU - Viikari, Jorma S.

AU - Zhu, Na

AU - Langenberg, Claudia

AU - Ingelsson, Erik

AU - Semple, Robert K.

AU - Sinaiko, Alan R.

AU - Palmer, Colin N A

AU - Walker, Mark

AU - Lam, Karen S L

AU - Paulweber, Bernhard

AU - Mohlke, Karen L.

AU - Van Duijn, Cornelia

AU - Raitakari, Olli T.

AU - Bidulescu, Aurelian

AU - Wareham, Nick J.

AU - Laakso, Markku

AU - Waterworth, Dawn M.

AU - Lawlor, Debbie A.

AU - Meig, James B.

AU - Richards, J. Brent

AU - Frayling, Timothy M.

PY - 2013/10

Y1 - 2013/10

N2 - Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI 20.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (20.20 SD; 95% CI 20.38 to 20.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin- lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: 20.03 SD; 95% CI 20.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

AB - Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI 20.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (20.20 SD; 95% CI 20.38 to 20.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin- lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: 20.03 SD; 95% CI 20.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

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JO - Diabetes

JF - Diabetes

IS - 10

ER -

Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes

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