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DOI: 10.2337/db06-0613
© 2006 by the American Diabetes Association
Common Haplotypes at the Adiponectin Receptor 1 (ADIPOR1) Locus Are Associated With Increased Risk of Coronary Artery Disease in Type 2 Diabetes
1 Research Division, Joslin Diabetes Center, Boston, Massachusetts
2 Department of Medicine, Harvard Medical School, Boston, Massachusetts
3 Endocrine Unit, Scientific Institute "Casa Sollievo della Sofferenza," San Giovanni Rotondo, Italy
4 Department of Hypertension, Warsaw Medical University, Warsaw, Poland
5 Cardiology Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts
6 Division of Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
7 Department of Clinical Sciences, University "La Sapienza," Rome, Italy
Address correspondence and reprint requests to Alessandro Doria, MD, PhD, MPH, Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: alessandro.doria{at}joslin.harvard.edu
Abbreviations:
CAD, coronary artery disease; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; SNP, single nucleotide polymorphism
Adiponectin, an adipokine facilitating insulin action, has antiatherogenic effects. This study investigated whether common polymorphisms in the adiponectin receptor 1 (ADIPOR1) gene mediating these effects influence the risk of coronary artery disease (CAD) in type 2 diabetes. Linkage disequilibrium analysis of 28 single nucleotide polymorphisms (SNPs) spanning the entire ADIPOR1 locus revealed two haplotype blocks that could be tagged by six SNPs. These six markers were typed in two populations of CAD-positive and -negative subjects with type 2 diabetes, one from Boston (n = 411) and the other from Italy (n = 533). In the Boston population, the three tags of the more 3' block were all significantly associated with CAD (P = 0.001–0.01). A similar trend, although not significant, was found in Italian subjects. Haplotype analysis of the combined populations revealed different haplotype distributions in case and control subjects (P = 0.0002), with one common haplotype being associated in homozygotes with a greater than threefold increase in cardiovascular risk (odds ratio 3.6 [95% CI 1.8–7.2]). Some of the genotypes associated with increased cardiovascular risk were associated with 30–40% lower ADIPOR1 mRNA levels in blood mononuclear cells (n = 60) and adipose tissue biopsies (n = 28) (P = 0.001–0.014). Our findings point to genetic variability at the ADIPOR1 locus as a strong determinant of CAD susceptibility in type 2 diabetes.
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