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

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 -