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Common variants in the adiponectin gene (ADIPOQ) associated with plasma adiponectin levels, type 2 diabetes, and diabetes-related quantitative traits: the Framingham Offspring Study.

¹General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts
²Department of Medicine, Harvard Medical School, Boston, Massachusetts
³Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
⁴Center for Human Genetic Research and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
⁵Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
⁶Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and
⁷the National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts

Objective: Variants in ADIPOQ have been inconsistently associated with adiponectin levels or diabetes. Using comprehensive linkage disequilibrium (LD) mapping, we genotyped single nucleotide polymorphisms (SNPs) in ADIPOQ to evaluate the association of common variants with adiponectin levels and risk of diabetes.

Research Design and Methods: Participants in the Framingham Offspring Study (n=2543, 53% women) were measured for glycemic phenotypes and incident diabetes over 28 years of follow up; adiponectin levels were quantified at exam 7. We genotyped 22 tag SNPs that captured common (minor allele frequency >0.05) variation at r²>0.8 across ADIPOQ plus 20 kb 5' and 10 kb 3' of the gene. We used linear mixed effects models to test additive associations of each SNP with adiponectin levels and glycemic phenotypes. Hazard ratios for incident diabetes were estimated using an adjusted Cox proportional hazards models.

Results: Two promoter SNPs in strong LD with each other (r²=0.80) were associated with adiponectin levels (rs17300539; P_nominal=2.6x10^–8; P_empiric=0.0005 and rs822387; P_n=3.8x10^–5; P_e=0.001). A 3'UTR SNP (rs6773957) was associated with adiponectin levels (P_n=4.4x10^–4; P_e=0.005). A non-synonymous coding SNP (rs17366743, Y111H) was confirmed to be associated with diabetes incidence (HR=1.94 [CI=1.16–3.25] for the minor C allele; P_n=0.01), and with higher mean fasting glucose over 28 years of follow up (P_n=0.0004; P_e=0.004). No other significant associations were found with other adiposity and metabolic phenotypes.

Conclusions: Adiponectin levels are associated with SNPs in two different regulatory regions (5'promoter and 3'UTR), while diabetes incidence and time-averaged fasting glucose are associated with a missense SNP of ADIPOQ.

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