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Can Fishing for New Genes Catch Patients at Risk of Coronary Artery Disease?

¹ INSERM, Paris, France,² Université Paris Descartes, Faculté des Sciences Biologiques et Pharmaceutiques, Paris, France,³ Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

^aAddress correspondence to this author at:, INSERM U765, Faculté des Sciences Biologiques et Pharmaceutiques, 4 avenue de l’Observatoire, 75006 Paris, Fax 33-1-44-07-17-72, E-mail joseph.emmerich@egp.aphp.fr

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With rapid and dramatic success, the Genome-Wide Association Study (GWAS) has proven to be an effective tool for the discovery of unsuspected genetic determinants of common disorders and has opened a new armamentarium for the pathophysiologic exploration of numerous diseases. The best illustration of the feasibility and strength of the GWAS approach was demonstrated in June of 2007 by a consortium of more than 50 British research groups participating in the Wellcome Trust Case-Control Consortium (WTCCC). Working collaboratively, the WTCCC investigators studied 14 000 cases of 7 common diseases and 3000 shared controls and identified 24 independent association signals, 1 in bipolar disease, 1 in coronary disease, 9 in Crohn disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes, and 3 in type 2 diabetes, each with a statistical effect approaching or exceeding genome–wide levels of significance (1). Remarkably, the key finding in this study for coronary heart disease—a clear association between vascular risk and common variation in the region of chromosome 9p21.3—was rapidly validated in a series of similar GWAS studies, including the Cardiogenics Consortium; the Ottawa, Dallas, and Framingham Heart Studies; and the DeCode Genetics program in Iceland (2)(3)(4)(5). The chromosome 9p21.3 region contains the coding sequences of genes for 2 cyclin-dependent kinase inhibitors known to play roles in tumor suppression, cell proliferation, and apoptosis. Thus, these validated GWAS findings for coronary disease not only raise the concept of a novel genetic determinant of disease, but also provide strong pathophysiologic support for prior work linking each of these processes directly to atherogenesis and . . . [Full Text of this Article]