Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes
Authors: Yaghootkar Hanieh , Lamina Claudia , Scott Robert A. , Dastani Zari , Hivert Marie-France , Warren Liling L. , Stancáková Alena , Buxbaum Sarah G. , Lyytikäinen Leo-Pekka , Henneman Peter , Wu Ying , Cheung Chloe Y.Y. , Pankow James S. , Jackson Anne U. , Gustafsson Stefan , Zhao Jing Hua , Ballantyne Christie M. , Xie Weijia , Bergman Richard N. , Boehnke Michael , el Bouazzaoui Fatiha , Collins Francis S. , Dunn Sandra H. , Dupuis Josee , Forouhi Nita G. , Gillson Christopher , Hattersley Andrew T. , Hong Jaeyoung , Kähönen Mika , Kuusisto Johanna , Kedenko Lyudmyla , Kronenberg Florian , Doria Alessandro , Assimes Themistocles L. , Ferrannini Ele , Hansen Torben , Hao Ke , Häring Hans , Knowles Joshua W. , Lindgren Cecilia M. , Nolan John J. , Paananen Jussi , Pedersen Oluf , Quertermous Thomas , Smith Ulf ,   the GENESIS Consortium,   the RISC Consortium, Lehtimäki Terho , Liu Ching-Ti , Loos Ruth J.F. , McCarthy Mark I. , Morris Andrew D. , Vasan Ramachandran S. , Spector Tim D. , Teslovich Tanya M. , Tuomilehto Jaakko , van Dijk Ko Willems , Viikari Jorma S. , Zhu Na , Langenberg Claudia , Ingelsson Erik , Semple Robert K. , Sinaiko Alan R. , Palmer Colin N.A. , Walker Mark , Lam Karen S.L. , Paulweber Bernhard , Mohlke Karen L. , van Duijn Cornelia , Raitakari Olli T. , Bidulescu Aurelian , Wareham Nick J. , Laakso Markku , Waterworth Dawn M. , Lawlor Debbie A. , Meigs James B. , Richards J. Brent , Frayling Timothy M. 
Published: July 2013

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 −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; 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: −0.03 SD; 95% CI −0.07 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.