Variations in adiponectin receptor genes and susceptibility to type 2 diabetes in women: A tagging-SNP haplotype analysis

Adiponectin has been associated with low diabetes risk. The metabolic effects of adiponectin are mediated by adiponectin receptor 1 (ADIPOR1) and receptor 2 (ADIPOR2). We conducted a prospective, nested case-control study of 714 cases of type 2 diabetes and 1,120 control subjects. Six polymorphisms in ADIPOR1 and sixteen polymorphisms in ADIPOR2 were determined. Haplotypes inferred from ADIPOR1 polymorphisms were significantly associated with diabetes risk (overall test, -2loglikelihood=15.1 on 5 DF, P=0.0098). A single copy of haplotype 001100 (‘0’, common allele; and ‘1’, minor allele) was associated with 24% (OR=0.76, 95%CI 0.61-0.96, and P=0.02) decreased risk compared with the most common haplotype 110000, adjusting for age, BMI, and other covariates. A 3’ UTR polymorphism, rs1139646, showed the strongest and nominally significant association with greater diabetic risk (unadjusted OR=1.26, 95%CI 1.03-1.53; and adjusted OR=1.36, 95%CI 1.10-1.70). However, such an association became marginal after controlling for multiple comparisons by permutation test (P=0.08, on the basis of 10,000 permutation). There were not significant associations between ADIPOR2 polymorphisms, individually or in haplotypes, and the risk of type 2 diabetes. In conclusion, our data indicate significant associations between ADIPOR1 haplotypes and diabetes risk but do not support a relation between ADIPOR2 variability and the disease.