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Mendelian randomization 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 -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.

SUBMITTER: Yaghootkar H

PROVIDER: S-EPMC3781444 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Yaghootkar Hanieh H Lamina Claudia C Scott Robert A RA Dastani Zari Z Hivert Marie-France MF Warren Liling L LL Stancáková Alena A Buxbaum Sarah G SG Lyytikäinen Leo-Pekka LP Henneman Peter P Wu Ying Y Cheung Chloe Y Y CY Pankow James S JS Jackson Anne U AU Gustafsson Stefan S Zhao Jing Hua JH Ballantyne Christie M CM Xie Weijia W Bergman Richard N RN Boehnke Michael M el Bouazzaoui Fatiha F Collins Francis S FS Dunn Sandra H SH Dupuis Josee J Forouhi Nita G NG Gillson Christopher C Hattersley Andrew T AT Hong Jaeyoung J Kähönen Mika M Kuusisto Johanna J Kedenko Lyudmyla L Kronenberg Florian F Doria Alessandro A Assimes Themistocles L TL Ferrannini Ele E Hansen Torben T Hao Ke K Häring Hans H Knowles Joshua W JW Lindgren Cecilia M CM Nolan John J JJ Paananen Jussi J Pedersen Oluf O Quertermous Thomas T Smith Ulf U Lehtimäki Terho T Liu Ching-Ti CT Loos Ruth J F RJ McCarthy Mark I MI Morris Andrew D AD Vasan Ramachandran S RS Spector Tim D TD Teslovich Tanya M TM Tuomilehto Jaakko J van Dijk Ko Willems KW Viikari Jorma S JS Zhu Na N Langenberg Claudia C Ingelsson Erik E Semple Robert K RK Sinaiko Alan R AR Palmer Colin N A CN Walker Mark M Lam Karen S L KS Paulweber Bernhard B Mohlke Karen L KL van Duijn Cornelia C Raitakari Olli T OT Bidulescu Aurelian A Wareham Nick J NJ Laakso Markku M Waterworth Dawn M DM Lawlor Debbie A DA Meigs James B JB Richards J Brent JB Frayling Timothy M TM

Diabetes 20130708 10

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 st ...[more]

PMID: 23835345

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

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

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