Butterworth, Adam S. and Braund, Peter S. and Farrall, Martin and Hardwick, Robert J. and Saleheen, Danish and Peden, John F. and Soranzo, Nicole and Chambers, John C. and Sivapalaratnam, Suthesh and Kleber, Marcus E. and Keating, Brendan and Qasim, Atif and Klopp, Norman and Erdmann, Jeanette and Assimes, Themistocles L. and Ball, Stephen G. and Balmforth, Anthony J. and Barnes, Timothy A. and Basart, Hanneke and Baumert, Jens and Bezzina, Connie R. and Boerwinkle, Eric and Boehm, Bernhard O. and Brocheton, Jessy and Bugert, Peter and Cambien, Francois and Clarke, Robert and Codd, Veryan and Collins, Rory and Couper, David and Cupples, L. Adrienne and de Jong, Jonas S. and Diemert, Patrick and Ejebe, Kenechi and Elbers, Clara C. and Elliott, Paul and Fornage, Myriam and Franzosi, Maria-Grazia and Frossard, Philippe and Garner, Stephen and Goel, Anuj and Goodall, Alison H. and Hengstenberg, Christian and Hunt, Sarah E. and Kastelein, John J. P. and Klungel, Olaf H. and Klueter, Harald and Koch, Kerstin and Koenig, Inke R. and Kooner, Angad S. and Laaksonen, Reijo and Lathrop, Mark and Li, Mingyao and Liu, Kiang and McPherson, Ruth and Musameh, Muntaser D. and Musani, Solomon and Nelson, Christopher P. and O'Donnell, Christopher J. and Ongen, Halit and Papanicolaou, George and Peters, Annette and Peters, Bas J. M. and Potter, Simon and Psaty, Bruce M. and Qu, Liming and Rader, Daniel J. and Rasheed, Asif and Rice, Catherine and Scott, James and Seedorf, Udo and Sehmi, Joban S. and Sotoodehnia, Nona and Stark, Klaus and Stephens, Jonathan and van der Schoot, C. Ellen and van der Schouw, Yvonne T. and Thorsteinsdottir, Unnur and Tomaszewski, Maciej and van der Harst, Pim and Vasan, Ramachandran S. and Wilde, Arthur A. M. and Willenborg, Christina and Winkelmann, Bernhard R. and Zaidi, Moazzam and Zhang, Weihua and Ziegler, Andreas and de Bakker, Paul I. W. and Koenig, Wolfgang and Maerz, Winfried and Trip, Mieke D. and Reilly, Muredach P. and Kathiresan, Sekar and Schunkert, Heribert and Hamsten, Anders and Hall, Alistair S. and Kooner, Jaspal S. and Thompson, Simon G. and Thompson, John R. and Deloukas, Panos and Ouwehand, Willem H. and Watkins, Hugh and Danesh, John and Samani, Nilesh J. (2011) Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease. PLOS GENETICS, 7 (9): e1002260. ISSN 1553-7390,
Full text not available from this repository. (Request a copy)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 similar to 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<5x10(-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 similar to 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GENOME-WIDE ASSOCIATION; MYOCARDIAL-INFARCTION; SUSCEPTIBILITY LOCI; RISK; ATHEROSCLEROSIS; METAANALYSIS; LIPOPROTEIN; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Jun 2020 08:32 |
| Last Modified: | 02 Jun 2020 08:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/20236 |
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