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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.

TitleMendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes.
Publication TypeJournal Article
Year of Publication2013
AuthorsYaghootkar H, Lamina C, Scott RA, Dastani Z, Hivert M-F, Warren LL, Stancáková A, Buxbaum SG, Lyytikäinen L-P, Henneman P, Wu Y, Y Y Cheung C, Pankow JS, Jackson AU, Gustafsson S, Zhao JHua, Ballantyne CM, Xie W, Bergman RN, Boehnke M, Bouazzaoui Fel, Collins FS, Dunn SH, Dupuis J, Forouhi NG, Gillson C, Hattersley AT, Hong J, Kähönen M, Kuusisto J, Kedenko L, Kronenberg F, Doria A, Assimes TL, Ferrannini E, Hansen T, Hao K, Häring H, Knowles JW, Lindgren CM, Nolan JJ, Paananen J, Pedersen O, Quertermous T, Smith U, Lehtimäki T, Liu C-T, Loos RJF, McCarthy MI, Morris AD, Vasan RS, Spector TD, Teslovich TM, Tuomilehto J, van Dijk KWillems, 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, J Richards B
Secondary AuthorsFrayling TM
Corporate AuthorsGENESIS Consortium, RISC Consortium
JournalDiabetes
Volume62
Issue10
Pagination3589-98
Date Published2013 Oct
ISSN1939-327X
KeywordsAdiponectin, Blood Glucose, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Insulin Resistance, Male, Mendelian Randomization Analysis, Odds Ratio, Polymorphism, Single Nucleotide, Regression Analysis
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.

DOI10.2337/db13-0128
Alternate JournalDiabetes
PubMed ID23835345
PubMed Central IDPMC3781444
Grant ListR01 DK093757 / DK / NIDDK NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
DK078150 / DK / NIDDK NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
G0500070 / / Medical Research Council / United Kingdom
MC_UP_A100_1003 / / Medical Research Council / United Kingdom
R01HL59367 / HL / NHLBI NIH HHS / United States
12/0004470 / / Diabetes UK / United Kingdom
G20234 / / Biotechnology and Biological Sciences Research Council / United Kingdom
RC2 HL102419 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
T32 NR009759 / NR / NINR NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
1Z01 HG000024 / HG / NHGRI NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
MO1-RR-00400 / RR / NCRR NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
ES10126 / ES / NIEHS NIH HHS / United States
TW05596 / TW / FIC NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
DK072193 / DK / NIDDK NIH HHS / United States
DK56350 / DK / NIDDK NIH HHS / United States
RR20649 / RR / NCRR NIH HHS / United States
/ / Intramural NIH HHS / United States
098498 / / Wellcome Trust / United Kingdom
N01-HC-55019 / HC / NHLBI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
P20 MD006899 / MD / NIMHD NIH HHS / United States
HL085144 / HL / NHLBI NIH HHS / United States
UH1 HL073461 / HL / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
HL52851 / HL / NHLBI NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
UL1 TR000454 / TR / NCATS NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01-HC-95171 / HC / NHLBI NIH HHS / United States
G0600717 / / Medical Research Council / United Kingdom
100574 / / Wellcome Trust / United Kingdom
DK062370 / DK / NIDDK NIH HHS / United States
N01-HC-95172 / HC / NHLBI NIH HHS / United States
MC_U106179471 / / Medical Research Council / United Kingdom
P30 DK020572 / DK / NIDDK NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
UL1 RR025008 / RR / NCRR NIH HHS / United States
MC_U106188470 / / Medical Research Council / United Kingdom
R01DK056918 / DK / NIDDK NIH HHS / United States
MC_UU_12013/5 / / Medical Research Council / United Kingdom
N01-HC-95170 / HC / NHLBI NIH HHS / United States
G0600705 / / Medical Research Council / United Kingdom
R01HL086694 / HL / NHLBI NIH HHS / United States
DK36836-25 / DK / NIDDK NIH HHS / United States
N01-HG-65403 / HG / NHGRI NIH HHS / United States