Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes

H Yaghootkar, C Lamina, RA Scott, Z Dastani, MF Hivert, LL Warren, A Stancakova, SG Buxbaum, LP Lyytikaeinen, Peter Henneman, Fenny Wu, CYY Cheung, JS Pankow, AU Jackson, S Gustafsson, JH Zhao, CM Ballantyne, WJ Xie, RN Bergman, M BoehnkeF el Bouazzaoui, FS Collins, SH Dunn, J Dupuis, NG Forouhi, C Gillson, AT Hattersley, JY Hong, M Kaehoenen, J Kuusisto, L Kedenko, F Kronenberg, A Doria, TL Assimes, E Ferrannini, T Hansen, K Hao, H Haering, JW Knowles, CM Lindgren, JJ Nolan, J Paananen, O Pedersen, T Quertermous, U Smith, T Lehtimaeki, CT Liu, RJF Loos, MI McCarthy, AD Morris, RS Vasan, TD Spector, TM Teslovich, J Tuomilehto, KW van Dijk, JS Viikari, N Zhu, C Langenberg, E Ingelsson, RK Semple, AR Sinaiko, CNA Palmer, M Walker, KSL Lam, B Paulweber, KL Mohlke, Cornelia Duijn, OT Raitakari, A Bidulescu, NJ Wareham, M Laakso, DM Waterworth, DA Lawlor, JB Meigs, JB Richards, TM 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 -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.
Original languageUndefined/Unknown
Pages (from-to)3589-3598
Number of pages10
JournalDiabetes
Volume62
Issue number10
DOIs
Publication statusPublished - 2013

Research programs

  • EMC NIHES-01-64-01

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