Mendelian randomisation 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 YY 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; the GENESIS consortium; the RISC consortium; Terho Lehtimäki; Ching-Ti Liu; Ruth J. F. Loos; Andrew D. Morris; Colin N. A. Palmer

doi:10.2337/db13-0128

Mendelian randomisation 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 YY 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, the GENESIS consortium, the RISC consortium, Terho Lehtimäki, Ching-Ti Liu, Ruth J. F. Loos, Andrew D. Morris, Colin N. A. Palmer

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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 randomisation 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 cases and 64,731 controls). In conventional regression analyses a 1 SD decrease in adiponectin levels was correlated with a 0.31 SD (95%CIs: 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 of 1.75 (95%CIs: 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: -0.07, 0.11, N=29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95%CIs: -0.38, -0.02; N=1,860) and no evidence of a relationship with type 2 diabetes (odds ratio 0.94; 95%CIs: 0.75, 1.19; N= 2,777 cases and 13,011 controls). 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: -0.03 SD, 95%CIs: -0.07, 0.01; N=2,969) or type 2 diabetes (odds ratio per weighted adiponectin lowering allele: 0.99; 95%CIs: 0.95, 1.04; 15,960 cases vs. 64,731 controls). 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
Pages (from-to)	3589-3598
Number of pages	10
Journal	Diabetes
Volume	62
Issue number	10
DOIs	https://doi.org/10.2337/db13-0128
Publication status	Published - Oct 2013

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http://diabetes.diabetesjournals.org/

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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. YY., Pankow, J. S., Jackson, A. U., Gustafsson, S., Zhao, J. H., Ballantyne, C. M., Xie, W., Bergman, R. N., ... Palmer, C. N. A. (2013). Mendelian randomisation 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

@article{a9b60a53b4d54731b0b3adb46d091c2d,

title = "Mendelian randomisation 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 randomisation 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 cases and 64,731 controls). In conventional regression analyses a 1 SD decrease in adiponectin levels was correlated with a 0.31 SD (95%CIs: 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 of 1.75 (95%CIs: 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: -0.07, 0.11, N=29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95%CIs: -0.38, -0.02; N=1,860) and no evidence of a relationship with type 2 diabetes (odds ratio 0.94; 95%CIs: 0.75, 1.19; N= 2,777 cases and 13,011 controls). 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: -0.03 SD, 95%CIs: -0.07, 0.01; N=2,969) or type 2 diabetes (odds ratio per weighted adiponectin lowering allele: 0.99; 95%CIs: 0.95, 1.04; 15,960 cases vs. 64,731 controls). 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 Marie-France Hivert and Warren, {Liling L.} and Alena Stanc{\'a}kov{\'a} and Buxbaum, {Sarah G.} and Leo-Pekka Lyytik{\"a}inen and Peter Henneman and Ying Wu and Cheung, {Chloe YY} 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 {the GENESIS consortium} and {the RISC consortium} and Terho Lehtim{\"a}ki and Ching-Ti Liu and Loos, {Ruth J. F.} and Morris, {Andrew D.} and Palmer, {Colin N. A.}",

year = "2013",

month = oct,

doi = "10.2337/db13-0128",

language = "English",

volume = "62",

pages = "3589--3598",

journal = "Diabetes",

issn = "1939-327X",

publisher = "American Diabetes Association",

number = "10",

}

Yaghootkar, H, Lamina, C, Scott, RA, Dastani, Z, Hivert, M-F, Warren, LL, Stancáková, A, Buxbaum, SG, Lyytikäinen, L-P, 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, the GENESIS consortium, the RISC consortium, Lehtimäki, T, Liu, C-T, Loos, RJF, Morris, AD & Palmer, CNA 2013, 'Mendelian randomisation 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

TY - JOUR

T1 - Mendelian randomisation 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 YY

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 - the GENESIS consortium

AU - the RISC consortium

AU - Lehtimäki, Terho

AU - Liu, Ching-Ti

AU - Loos, Ruth J. F.

AU - Morris, Andrew D.

AU - Palmer, Colin N. A.

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 randomisation 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 cases and 64,731 controls). In conventional regression analyses a 1 SD decrease in adiponectin levels was correlated with a 0.31 SD (95%CIs: 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 of 1.75 (95%CIs: 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: -0.07, 0.11, N=29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95%CIs: -0.38, -0.02; N=1,860) and no evidence of a relationship with type 2 diabetes (odds ratio 0.94; 95%CIs: 0.75, 1.19; N= 2,777 cases and 13,011 controls). 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: -0.03 SD, 95%CIs: -0.07, 0.01; N=2,969) or type 2 diabetes (odds ratio per weighted adiponectin lowering allele: 0.99; 95%CIs: 0.95, 1.04; 15,960 cases vs. 64,731 controls). 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 randomisation 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 cases and 64,731 controls). In conventional regression analyses a 1 SD decrease in adiponectin levels was correlated with a 0.31 SD (95%CIs: 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 of 1.75 (95%CIs: 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: -0.07, 0.11, N=29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95%CIs: -0.38, -0.02; N=1,860) and no evidence of a relationship with type 2 diabetes (odds ratio 0.94; 95%CIs: 0.75, 1.19; N= 2,777 cases and 13,011 controls). 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: -0.03 SD, 95%CIs: -0.07, 0.01; N=2,969) or type 2 diabetes (odds ratio per weighted adiponectin lowering allele: 0.99; 95%CIs: 0.95, 1.04; 15,960 cases vs. 64,731 controls). 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.

U2 - 10.2337/db13-0128

DO - 10.2337/db13-0128

M3 - Article

C2 - 23835345

SN - 1939-327X

VL - 62

SP - 3589

EP - 3598

JO - Diabetes

JF - Diabetes

IS - 10

ER -

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

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