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Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease

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posted on 2013-06-17, 13:19 authored by Adam S. Butterworth, Peter S. Braund, Martin Farrall, Robert J. Hardwick, Danish Saleheen, John F. Peden, Nicole Soranzo, John C. Chambers, Suthesh Sivapalaratnam, Marcus E. Kleber, Brendan Keating, Willem H. Ouwehand, Hugh Watkins, John Danesh, Nilesh J. Samani, Atif Qasim, Norman Klopp, Jeanette Erdmann, Themistocles L. Assimes, Stephen G. Ball, Anthony J. Balmforth, Timothy A. Barnes, Hanneke Basart, Jens Baumert, Connie R. Bezzina, Eric Boerwinkle, Bernhard O. Boehm, Jessy Brocheton, Peter Bugert, Francois Cambien, Robert Clarke, Veryan Codd, Rory Collins, David Couper, L. Adrienne Cupples, Jonas S. de Jong, Patrick Diemert, Kenechi Ejebe, Clara C. Elbers, Paul Elliott, Myriam Fornage, Maria-Grazia Franzosi, Philippe Frossard, Stephen Garner, Anuj Goel, Alison H. Goodall, Christian Hengstenberg, Sarah E. Hunt, John J.P. Kastelein, Olaf H. Klungel, Harald Klueter, Kerstin Koch, Inke R. Koenig, Angad S. Kooner, Reijo Laaksonen, Mark Lathrop, Mingyao Li, Kiang Liu, Ruth McPherson, Muntaser D. Musameh, Solomon Musani, Christopher P. Nelson, Christopher J. O'Donnell, Halit Ongen, George Papanicolaou, Annette Peters, Bas J.M. Peters, Simon Potter, Bruce M. Psaty, Liming Qu, Daniel J. Rader, Asif Rasheed, Catherine Rice, James Scott, Udo Seedorf, Joban S. Sehmi, Nona Sotoodehnia, Klaus Stark, Jonathan Stephens, C. Ellen van der Schoot, Yvonne T. van der Schouw, Unnur Thorsteinsdottir, Maciej Tomaszewski, Pim van der Harst, Ramachandran S. Vasan, Arthur A.M. Wilde, Christina Willenborg, Bernhard R. Winkelmann, Moazzam Zaidi, Weihua Zhang, Andreas Ziegler, Paul I.W. de Bakker, Wolfgang Koenig, Win fried Maerz, Mieke .D Trip, Muredach P. Reilly, Sekar Kathiresan, Heribert Schunkert, Anders Hamsten, Alistair S. Hall, Jaspal S. Kooner, Simon G. Thompson, John R. Thompson, Panos Deloukas
Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ~2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10−33; LPA:p<10−19; 1p13.3:p<10−17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10−7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ~4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.



PLoS Genetics, 2011, 7 (9), (14), e1002260.

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/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences


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