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Variations in Adiponectin Receptor Genes and Susceptibility to Type 2 Diabetes in Women

A Tagging–Single Nucleotide Polymorphism Haplotype Analysis

¹ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
² Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
³ Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts
⁴ Department of Mathematics and Statistics, University of Massachusetts, Amherst, Massachusetts
⁵ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts

Address correspondence and reprint requests to Dr. Lu Qi, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. E-mail: nhlqi{at}channing.harvard.edu

Abbreviations: LD, linkage disequilibrium; MAF, minor allele frequency; SNP, single nucleotide polymorphism; UTR, untranslated region

Adiponectin has been associated with low diabetes risk. The metabolic effects of adiponectin are mediated by adiponectin receptors 1 (ADIPOR1) and 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 16 polymorphisms in ADIPOR2 were determined. Haplotypes inferred from ADIPOR1 polymorphisms were significantly associated with diabetes risk (overall test, –2log-likelihood = 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% decreased risk (odds ratio [OR] 0.76 [95% CI 0.61–0.96], P = 0.02) compared with the most common haplotype, 110000, adjusting for age, BMI, and other covariates. A 3' untranslated region (UTR) polymorphism, rs1139646, showed the strongest and nominally significant association with greater diabetes risk (unadjusted OR 1.26 [1.03–1.53] and adjusted OR 1.36 [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 permutations). 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.

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