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

被引：147

作者：

Butterworth, Adam S. ^{[1
]}

Braund, Peter S. ^{[2
,3
]}

Farrall, Martin ^{[4
,5
]}

Hardwick, Robert J. ^{[2
,3
,6
]}

Saleheen, Danish ^{[1
,7
]}

Peden, John F. ^{[4
,5
]}

Soranzo, Nicole ^{[8
]}

Chambers, John C. ^{[9
]}

Sivapalaratnam, Suthesh ^{[10
]}

Kleber, Marcus E. ^{[11
]}

Keating, Brendan ^{[12
]}

Qasim, Atif ^{[13
]}

Klopp, Norman ^{[14
]}

Erdmann, Jeanette ^{[15
]}

Assimes, Themistocles L. ^{[16
]}

Ball, Stephen G. ^{[17
]}

Balmforth, Anthony J. ^{[18
]}

Barnes, Timothy A. ^{[2
,3
]}

Basart, Hanneke ^{[10
]}

Baumert, Jens ^{[14
]}

Bezzina, Connie R. ^{[19
]}

Boerwinkle, Eric ^{[20
,21
]}

Boehm, Bernhard O. ^{[22
]}

Brocheton, Jessy ^{[23
,24
]}

Bugert, Peter ^{[25
]}

Cambien, Francois ^{[23
,24
]}

Clarke, Robert ^{[26
,27
]}

Codd, Veryan ^{[2
,3
]}

Collins, Rory ^{[26
,27
]}

Couper, David ^{[28
]}

Cupples, L. Adrienne ^{[29
,30
]}

de Jong, Jonas S. ^{[19
]}

Diemert, Patrick ^{[15
]}

Ejebe, Kenechi ^{[31
,32
,33
]}

Elbers, Clara C. ^{[34
,35
]}

Elliott, Paul ^{[36
]}

Fornage, Myriam ^{[37
]}

Franzosi, Maria-Grazia ^{[38
]}

Frossard, Philippe ^{[7
]}

Garner, Stephen ^{[39
,40
]}

Goel, Anuj ^{[4
,5
]}

Goodall, Alison H. ^{[2
,3
]}

Hengstenberg, Christian ^{[41
]}

Hunt, Sarah E. ^{[8
]}

Kastelein, John J. P. ^{[10
]}

Klungel, Olaf H. ^{[42
]}

Klueter, Harald ^{[25
]}

Koch, Kerstin ^{[39
,40
]}

Koenig, Inke R. ^{[43
]}

Kooner, Angad S. ^{[44
]}

机构：

[1] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[2] Univ Leicester, Dept Cardiovas Sci, Glenfield Gen Hosp, Leicester, Leics, England

[3] Glenfield Gen Hosp, Leicester Natl Inst Hlth Res Biomed Res Unit Card, Leicester LE3 9QP, Leics, England

[4] Univ Oxford, Dept Cardiovasc Med, Oxford, England

[5] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[6] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

[7] Ctr Noncommunicable Dis, Karachi, Pakistan

[8] Wellcome Trust Sanger Inst, Hinxton, England

[9] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England

[10] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands

[11] LURIC Non Profit LLC, Freiburg, Germany

[12] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[13] Univ Penn, Med Ctr, Cardiovasc Inst, Philadelphia, PA 19104 USA

[14] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany

[15] Univ Lubeck, Med Klin 2, Lubeck, Germany

[16] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[17] Univ Leeds, Fac Med & Hlth, LIGHT Res Inst, Leeds, W Yorkshire, England

[18] Univ Leeds, Div Cardiovasc & Diabet Res, Multidisciplinary Cardiovasc Res Ctr, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England

[19] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, Dept Clin & Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands

[20] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA

[21] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA

[22] Univ Ulm, Div Endocrinol & Diabet, Ctr Excellence Metab Dis, Dept Internal Med, Ulm, Germany

[23] Univ Paris 06, INSERM, UMRS 937, Paris, France

[24] Sch Med, Paris, France

[25] Heidelberg Univ, Inst Transfus Med & Immunol, Germany Red Cross Blood Serv, Baden Wurttemberg Hessen gGmbH,Med Fac Mannheim, D-6800 Mannheim, Germany

[26] Univ Oxford, Clin Trial Serv Unit, Oxford, England

[27] Univ Oxford, Epidemiol Studies Unit, Oxford, England

[28] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA

[29] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[30] NHLBI, Framingham Heart Study, Framingham, MA USA

[31] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[32] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[33] Harvard Univ, Sch Med, Boston, MA USA

[34] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[35] Univ Med Ctr Utrecht, Div Biomed Genet, Dept Med Genet, Utrecht, Netherlands

[36] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, London, England

[37] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA

[38] Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy

[39] Univ Cambridge, Dept Haematol, Cambridge, England

[40] NHS Blood & Transplant, Cambridge, England

[41] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany

[42] Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands

[43] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany

[44] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England

[45] Tampere Univ Hosp, Ctr Sci, Tampere, Finland

[46] CEA, Inst Genom, Ctr Natl Genotypage, F-91057 Evry, France

[47] Fdn Jean Dausset CEPH, F-75010 Paris, France

[48] Univ Penn, Med Ctr, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[49] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA

[50] Univ Ottawa, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada

来源：

PLOS GENETICS | 2011年 / 7卷 / 09期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; MYOCARDIAL-INFARCTION; SUSCEPTIBILITY LOCI; RISK; METAANALYSIS; LIPOPROTEIN;

D O I：

10.1371/journal.pgen.1002260

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：14

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