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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.
Author(s): Yaghootkar H, Lamina C, Scott RA, Dastani Z, Hivert MF, Warren LL, Stancakova A, Buxbaum SG, Lyytikaeinen LP, Henneman P, Wu Y, Cheung CYY, Pankow JS, Jackson AU, Gustafsson S, Zhao JH, Ballantyne CM, Xie WJ, Bergman RN, Boehnke M, el Bouazzaoui F, Collins FS, Dunn SH, Dupuis J, Forouhi NG, Gillson C, Hattersley AT, Hong JY, Kaehoenen M, Kuusisto J, Kedenko L, Kronenberg F, Doria A, Assimes TL, Ferrannini E, Hansen T, Hao K, Haering H, Knowles JW, Lindgren CM, Nolan JJ, Paananen J, Pedersen O, Quertermous T, Smith U, Lehtimaeki 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, Meigs JB, Richards JB, Frayling TM, GENESIS Consortium, RISC Consortium
Publication type: Article
Publication status: Published
Print publication date: 01/10/2013
Online publication date: 08/07/2013
Acceptance date: 25/06/2013
ISSN (print): 0012-1797
ISSN (electronic): 1939-327X
Publisher: American Diabetes Assocation
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