Published Online
on August 5, 2002

A more recent version of this article appeared on August 13, 2002

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Submitted on May 1, 2002
Revised on June 17, 2002
Accepted on June 18, 2002

Frequent Mutation in the ABCC6 Gene (R1141X) Is Associated With a Strong Increase in the Prevalence of Coronary Artery Disease

Mieke D. Trip MD^*, Yvo M. Smulders MD, PhD, Jurgen J. Wegman MD, Xiaofeng Hu MD, Jolanda M.A. Boer PhD, Jacoline B. ten Brink Ing, Aeilko H. Zwinderman PhD, John J.P. Kastelein MD, PhD, Edith J.M. Feskens PhD, and Arthur A.B. Bergen PhD

From the Departments of Cardiology (M.D.T.), Clinical Epidemiology and Biostatistics (A.H.Z.), and Vascular Medicine (Y.MS, J.J.W., J.J.P.K.), Clinical Genetics (A.A.B.B.), Academic Medical Centre, University of Amsterdam, Amsterdam; Department of Chronic Diseases Epidemiology, National Institute of Public Health and the Environment (J.B., E.J.M.F.), Bilthoven; and The Netherlands Ophthalmic Research Institute (J.B.t.B., X.H., A.A.B.B.), Amsterdam, the Netherlands.

^* To whom correspondence should be addressed. E-mail: M.D.Trip{at}AMC.UVA.NL.

Background—Pseudoxanthoma elasticum (PXE) is an inborn disorder of the connective tissue with specific skin, ocular, and cardiovascular disease (CVD) manifestations. Recently, we and others have identified mutations in the gene coding for the ABCC6 transporter in PXE patients with ocular and skin involvement. In the Netherlands, as in the rest of Europe, a particular premature truncation variant ABCC6 (R1141X) was found in a large cohort of PXE patients. Given the association between CVD and PXE, we hypothesized that heterozygosity of this ABCC6 mutation could also confer an increased risk for CVD.

Methods and Results—To assess the relationship between the frequent R1141X mutation in the ABCC6 gene and the prevalence of premature coronary artery disease (CAD), we conducted a case-control study of 441 patients under the age of 50 years who had definite CAD and 1057 age- and sex-matched population-based controls who were free of coronary disease. Strikingly, the prevalence of the R1141X mutation was 4.2 times higher among patients than among controls (3.2% versus 0.8%; P<0.001). Consequently, among subjects with the R1141X mutation, the odds ratio for a coronary event was 4.23 (95% CI: 1.76 to 10.20, P=0.001).

Conclusion—The presence of the R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature CAD.

Key words: cardiovascular diseases • coronary disease • atherosclerosis • genes

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