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Large-scale gene-centric analysis identifies novel variants for coronary Artery disease

Title: Large-scale gene-centric analysis identifies novel variants for coronary Artery disease
Authors: Butterworth, AS
Braund, PS
Farrall, M
Hardwick, RJ
Saleheen, D
Peden, JF
Soranzo, N
Chambers, JC
Sivapalaratnam, S
Kleber, ME
Keating, B
Qasim, A
Klopp, N
Erdmann, J
Assimes, TL
Ball, SG
Balmforth, AJ
Barnes, TA
Basart, H
Baumert, J
Bezzina, CR
Boerwinkle, E
Boehm, BO
Brocheton, J
Bugert, P
Cambien, F
Clarke, R
Codd, V
Collins, R
Couper, D
Cupples, LA
De Jong, JS
Diemert, P
Ejebe, K
Elbers, CC
Elliott, P
Fornage, M
Franzosi, M-G
Frossard, P
Garner, S
Goel, A
Goodall, AH
Hengstenberg, C
Hunt, SE
Kastelein, JJP
Klungel, OH
Klueter, H
Koch, K
Koenig, IR
Kooner, AS
Laaksonen, R
Lathrop, M
Li, M
Liu, K
McPherson, R
Musameh, MD
Musani, S
Nelson, CP
O'Donnell, CJ
Ongen, H
Papanicolaou, G
Peters, A
Peters, BJM
Potter, S
Psaty, BM
Qu, L
Rader, DJ
Rasheed, A
Rice, C
Scott, J
Seedorf, U
Sehmi, JS
Sotoodehnia, N
Stark, K
Stephens, J
Van der Schoot, CE
Van der Schouw, YT
Thorsteinsdottir, U
Tomaszewski, M
Van der Harst, P
Vasan, RS
Wilde, AAM
Willenborg, C
Winkelmann, BR
Zaidi, M
Zhang, W
Ziegler, A
De Bakker, PIW
Koenig, W
Maerz, W
Trip, MD
Reilly, MP
Kathiresan, S
Schunkert, H
Hamsten, A
Hall, AS
Kooner, JS
Thompson, SG
Thompson, JR
Deloukas, P
Ouwehand, WH
Watkins, H
Danesh, J
Samani, NJ
Item Type: Journal Article
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.
Issue Date: 1-Sep-2011
Date of Acceptance: 29-Jun-2011
URI: http://hdl.handle.net/10044/1/53986
DOI: https://dx.doi.org/10.1371/journal.pgen.1002260
ISSN: 1553-7390
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS Genetics
Volume: 7
Issue: 9
Copyright Statement: © 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.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: G0700931
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Asian Continental Ancestry Group
Case-Control Studies
Coronary Artery Disease
European Continental Ancestry Group
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Middle Aged
Polymorphism, Single Nucleotide
IBC 50K CAD Consortium
0604 Genetics
Developmental Biology
Publication Status: Published
Article Number: ARTN e1002260
Appears in Collections:National Heart and Lung Institute
National Heart and Lung Institute

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