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Title: Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease
Authors: Butterworth, Adam S.
Braund, Peter S.
Farrall, Martin
Hardwick, Robert J.
Saleheen, Danish
Peden, John F.
Soranzo, Nicole
Chambers, John C.
Sivapalaratnam, Suthesh
Kleber, Marcus E.
Keating, Brendan
Ouwehand, Willem H.
Watkins, Hugh
Danesh, John
Samani, Nilesh J.
Qasim, Atif
Klopp, Norman
Erdmann, Jeanette
Assimes, Themistocles L.
Ball, Stephen G.
Balmforth, Anthony J.
Barnes, Timothy A.
Basart, Hanneke
Baumert, Jens
Bezzina, Connie R.
Boerwinkle, Eric
Boehm, Bernhard O.
Brocheton, Jessy
Bugert, Peter
Cambien, Francois
Clarke, Robert
Codd, Veryan
Collins, Rory
Couper, David
Cupples, L. Adrienne
de Jong, Jonas S.
Diemert, Patrick
Ejebe, Kenechi
Elbers, Clara C.
Elliott, Paul
Fornage, Myriam
Franzosi, Maria-Grazia
Frossard, Philippe
Garner, Stephen
Goel, Anuj
Goodall, Alison H.
Hengstenberg, Christian
Hunt, Sarah E.
Kastelein, John J.P.
Klungel, Olaf H.
Klueter, Harald
Koch, Kerstin
Koenig, Inke R.
Kooner, Angad S.
Laaksonen, Reijo
Lathrop, Mark
Li, Mingyao
Liu, Kiang
McPherson, Ruth
Musameh, Muntaser D.
Musani, Solomon
Nelson, Christopher P.
O'Donnell, Christopher J.
Ongen, Halit
Papanicolaou, George
Peters, Annette
Peters, Bas J.M.
Potter, Simon
Psaty, Bruce M.
Qu, Liming
Rader, Daniel J.
Rasheed, Asif
Rice, Catherine
Scott, James
Seedorf, Udo
Sehmi, Joban S.
Sotoodehnia, Nona
Stark, Klaus
Stephens, Jonathan
van der Schoot, C. Ellen
van der Schouw, Yvonne T.
Thorsteinsdottir, Unnur
Tomaszewski, Maciej
van der Harst, Pim
Vasan, Ramachandran S.
Wilde, Arthur A.M.
Willenborg, Christina
Winkelmann, Bernhard R.
Zaidi, Moazzam
Zhang, Weihua
Ziegler, Andreas
de Bakker, Paul I.W.
Koenig, Wolfgang
Maerz, Win fried
Trip, Mieke .D
Reilly, Muredach P.
Kathiresan, Sekar
Schunkert, Heribert
Hamsten, Anders
Hall, Alistair S.
Kooner, Jaspal S.
Thompson, Simon G.
Thompson, John R.
Deloukas, Panos
First Published: 22-Sep-2011
Publisher: Public Library of Science
Citation: PLoS Genetics, 2011, 7 (9), (14), e1002260.
Abstract: 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.
DOI Link: 10.1371/journal.pgen.1002260
ISSN: 1553-7390
eISSN: 1553-7404
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: © 2011 Butterworth 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.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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