TY - JOUR
T1 - Large-scale gene-centric analysis identifies novel variants for coronary artery disease
AU - AUTHOR GROUP
AU - Butterworth, Adam S.
AU - Braund, Peter S.
AU - Farrall, Martin
AU - Hardwick, Robert J.
AU - Saleheen, Danish
AU - Peden, John F.
AU - Soranzo, Nicole
AU - Chambers, John C.
AU - Sivapalaratnam, Suthesh
AU - Kleber, Marcus E.
AU - Keating, Brendan
AU - Qasim, Atif
AU - Klopp, Norman
AU - Erdmann, Jeanette
AU - Assimes, Themistocles L.
AU - Ball, Stephen G.
AU - Balmforth, Anthony J.
AU - Barnes, Timothy A.
AU - Basart, Hanneke
AU - Baumert, Jens
AU - Bezzina, Connie R.
AU - Boerwinkle, Eric
AU - Boehm, Bernhard O.
AU - Brocheton, Jessy
AU - Bugert, Peter
AU - Cambien, Francois
AU - Clarke, Robert
AU - Codd, Veryan
AU - Collins, Rory
AU - Couper, David
AU - Cupples, L. Adrienne
AU - de Jong, Jonas S.
AU - Diemert, Patrick
AU - Ejebe, Kenechi
AU - Elbers, Clara C.
AU - Elliott, Paul
AU - Fornage, Myriam
AU - Franzosi, Maria-Grazia
AU - Frossard, Philippe
AU - Garner, Stephen
AU - Goel, Anuj
AU - Kastelein, John J. P.
AU - Wilde, Arthur A. M.
AU - Trip, Mieke D.
AU - Dekker, Lukas R.
AU - Henriques, José P.
AU - Koch, Karel T.
AU - de Winter, Robbert J.
AU - Boekholdt, S. Matthijs
AU - Maitland-van der Zee, Anke-Hilse
PY - 2011
Y1 - 2011
N2 - 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
AB - 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
U2 - https://doi.org/10.1371/journal.pgen.1002260
DO - https://doi.org/10.1371/journal.pgen.1002260
M3 - Article
C2 - 21966275
SN - 1553-7390
VL - 7
SP - e1002260
JO - PLoS genetics
JF - PLoS genetics
IS - 9
ER -