Mendelian Randomisation Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes
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Mendelian Randomisation Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes. / 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 Yy; 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; Lehtimäki, Terho; Liu, Ching-Ti; Loos, Ruth Jf; McCarthy, Mark I; Morris, Andrew D; the GENESIS consortium.
In: Diabetes, Vol. 62, No. 10, 08.07.2013, p. 3589.Research output: Contribution to journal › Journal article › Research › peer-review
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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 - 2013/7/8
Y1 - 2013/7/8
N2 - Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes but its causal role remains controversial. We used a Mendelian randomisation 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 cases and 64,731 controls). In conventional regression analyses a 1 SD decrease in adiponectin levels was correlated with a 0.31 SD (95%CIs: 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 of 1.75 (95%CIs: 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, 0.11, N=29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95%CIs: -0.38, -0.02; N=1,860) and no evidence of a relationship with type 2 diabetes (odds ratio 0.94; 95%CIs: 0.75, 1.19; N= 2,777 cases and 13,011 controls). 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%CIs: -0.07, 0.01; N=2,969) or type 2 diabetes (odds ratio per weighted adiponectin lowering allele: 0.99; 95%CIs: 0.95, 1.04; 15,960 cases vs. 64,731 controls). 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 randomisation 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 cases and 64,731 controls). In conventional regression analyses a 1 SD decrease in adiponectin levels was correlated with a 0.31 SD (95%CIs: 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 of 1.75 (95%CIs: 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, 0.11, N=29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95%CIs: -0.38, -0.02; N=1,860) and no evidence of a relationship with type 2 diabetes (odds ratio 0.94; 95%CIs: 0.75, 1.19; N= 2,777 cases and 13,011 controls). 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%CIs: -0.07, 0.01; N=2,969) or type 2 diabetes (odds ratio per weighted adiponectin lowering allele: 0.99; 95%CIs: 0.95, 1.04; 15,960 cases vs. 64,731 controls). 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
VL - 62
SP - 3589
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 10
ER -
ID: 48873443