Genome-Wide Association Study in a Lebanese Cohort Confirms PHACTR 1 as a Major Determinant of Coronary Artery Stenosis

The manifestation of coronary artery disease (CAD) follows a well-choreographed series of events that includes damage of arterial endothelial cells and deposition of lipids in the sub-endothelial layers. Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are a crucial step in understanding global CAD pathophysiology. In this study, we report a GWAS on the genetic basis of arterial stenosis as measured by cardiac catheterization in a Lebanese population. The locus of the phosphatase and actin regulator 1 gene (PHACTR1) showed association with coronary stenosis in a discovery experiment with genome wide data in 1,949 individuals (rs9349379, OR = 1.37, p = 1.57610). The association was replicated in an additional 2,547 individuals (OR = 1.31, p = 8.85610), leading to genome-wide significant association in a combined analysis (OR = 1.34, p = 8.02610). Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. This association provides a plausible component for understanding molecular mechanisms involved in the formation of stenosis in cardiac vessels and a potential drug target against CAD. Citation: Hager J, Kamatani Y, Cazier J-B, Youhanna S, Ghassibe-Sabbagh M, et al. (2012) Genome-Wide Association Study in a Lebanese Cohort Confirms PHACTR1 as a Major Determinant of Coronary Artery Stenosis. PLoS ONE 7(6): e38663. doi:10.1371/journal.pone. 0038663 Editor: Dan Nebert, University of Cincinnati, United States of America Received November 24, 2011; Accepted May 9, 2012; Published June 20, 2012 Copyright: 2012 Hager et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by a grant from the European Commission (FGENTCARD, LSHG-CT-2006-037683). JBC is supported by the Wellcome Trust core award grant number 075491/Z/04. DG held a Wellcome Trust senior fellowship in basic biomedical science (057733). MF is supported by a BHF Clinical Research Excellence award. MGS and PAZ are partly funded by Qatar National Research Fund (QNRF, NPRP 09-215-3-049), JR is partly funded by QNRF (NPRP 4230-1-047). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: DEP is an employee of Bioinformatics and Pattern Discovery, IBM, FR is an employee of IntegraGenSA, Ulla Grove Sidelmann is an employee of Novo Nordisk and Frank Bonner is an employee of Metabometrix Ltd. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors. * E-mail: pzalloua@lau.edu. lb . These authors contributed equally to this work. "Members of the FGENTCARD Consortium are listed in the Acknowledgments.