Common Haplotypes at the Adiponectin Receptor 1 (ADIPOR1) Locus Are Associated With Increased Risk of Coronary Artery Disease in Type 2 Diabetes
- Teresa Soccio12,
- Yuan-Yuan Zhang12,
- Simonetta Bacci3,
- Wojciech Mlynarski12,
- Grzegorz Placha124,
- Greer Raggio1,
- Rosa Di Paola3,
- Antonella Marucci3,
- Michael T. Johnstone25,
- Ernest V. Gervino25,
- Nada A. Abumrad6,
- Samuel Klein6,
- Vincenzo Trischitta37 and
- Alessandro Doria12
- 1Research Division, Joslin Diabetes Center, Boston, Massachusetts
- 2Department of Medicine, Harvard Medical School, Boston, Massachusetts
- 3Endocrine Unit, Scientific Institute “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy
- 4Department of Hypertension, Warsaw Medical University, Warsaw, Poland
- 5Cardiology Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- 6Division of Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
- 7Department 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
Abstract
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.
- CAD, coronary artery disease
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- SNP, single nucleotide polymorphism
Footnotes
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T.S. and Y.-Y.Z. contributed equally to this article.
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted July 5, 2006.
- Received May 4, 2006.
- DIABETES
