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; Terho Lehtimäki; Ching-Ti Liu; Ruth Jf Loos; Mark I McCarthy; Andrew D Morris; the GENESIS consortium

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, Terho Lehtimäki, Ching-Ti Liu, Ruth Jf Loos, Mark I McCarthy, Andrew D Morris, the GENESIS consortium

85 Citations (Scopus)

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
Journal	Diabetes
Volume	62
Issue number	10
Pages (from-to)	3589
Number of pages	3,598
ISSN	0046-0192
DOIs	https://doi.org/10.2337/db13-0128
Publication status	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., Pankow, J. S., Jackson, A. U., Gustafsson, S., Zhao, J. H., Ballantyne, C. M., Xie, W., Bergman, R. N., ... the GENESIS consortium (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. https://doi.org/10.2337/db13-0128

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, CY, 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, C-T, Loos, RJ, McCarthy, MI, Morris, AD & the GENESIS consortium 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. https://doi.org/10.2337/db13-0128

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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 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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year = "2013",

month = oct,

doi = "10.2337/db13-0128",

language = "English",

volume = "62",

pages = "3589",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "10",

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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 - Lehtimäki, Terho

AU - Liu, Ching-Ti

AU - Loos, Ruth Jf

AU - McCarthy, Mark I

AU - Morris, Andrew D

AU - the GENESIS consortium

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.

U2 - 10.2337/db13-0128

DO - 10.2337/db13-0128

M3 - Journal article

C2 - 23835345

SN - 0012-1797

VL - 62

SP - 3589

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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