Polymorphisms of the Renin-Angiotensin System Genes Predict Progression of Subclinical Coronary Atherosclerosis

  1. Adam Kretowski12,
  2. Kim McFann1,
  3. John E. Hokanson3,
  4. David Maahs1,
  5. Gregory Kinney1,
  6. Janet K. Snell-Bergeon1,
  7. R. Paul Wadwa1,
  8. Robert H. Eckel4,
  9. Lorraine Ogden3,
  10. Satish Garg1,
  11. Jia Li5,
  12. Suzanne Cheng5,
  13. Henry A. Erlich5 and
  14. Marian Rewers13
  1. 1Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado
  2. 2Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
  3. 3Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
  4. 4Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
  5. 5Human Genetics Department, Roche Molecular Systems, Alameda, California
  1. Address correspondence and reprint requests to Adam Kretowski, MD, PhD, Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Mail Stop A140, P.O. Box 6511, Aurora, CO 80045-6511. E-mail: adam.kretowski{at}UCHSC.edu

Abstract

Premature coronary artery disease (CAD) in subjects with type 1 diabetes dramatically affects quality of life and morbidity and leads to premature death, but there is still little known about the mechanisms and predictors of this complication. In the present study, we explored the role of genetic variants of angiotensinogen (AGT, M235T), ACE (I/D), and angiotensin type 1 receptor (ATR1, A1166C) as predictors of rapid progression of subclinical coronary atherosclerosis. Five-hundred eighty-five type 1 diabetic patients and 592 similar age and sex control subjects were evaluated for progression of coronary artery calcification (CAC), a marker of subclinical CAD, before and after a 2.5-year follow-up. In logistic regression analysis, CAC progression was dramatically more likely in type 1 diabetic subjects not treated with ACE inhibitor/angiotensin receptor blocker who had the TT-ID-AA/AC genotype combination than in those with other genotypes (odds ratio 11.6 [95%CI 4.5–29.6], P < 0.0001) and was even stronger when adjusted for cardiovascular disease risk factors and the mean A1C (37.5 [3.6–388], P = 0.002). In conclusion, a combination of genotype variants of the renin-angiotensin system genes is a powerful determinant of subclinical progression of coronary artery atherosclerosis in type 1 diabetic patients and may partially explain accelerated CAD in type 1 diabetes.

Footnotes

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1321.

    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.

    • Accepted November 21, 2006.
    • Received September 18, 2006.
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  1. doi: 10.2337/db06-1321 Diabetes March 2007 vol. 56 no. 3 863-871
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