Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease

被引：25

作者：

Anderson, Jeffrey L. ^{[1
]}

Horne, Benjamin D. ^{[1
,2
]}

Camp, Nicola J. ^{[2
]}

Muhlestein, Joseph B. ^{[1
]}

Hopkins, Paul N.

Cannon-Albright, Lisa A. ^{[2
]}

Mower, Chrissa P. ^{[1
]}

Park, James J. ^{[1
]}

Clarke, Jessica L. ^{[1
]}

Nicholas, Zachary P. ^{[1
]}

McKinney, Jason T. ^{[3
]}

Carlquist, John F. ^{[1
]}

机构：

[1] Intermt Med Ctr, Cardiovasc Dept, Murray, UT 84107 USA

[2] Univ Utah, Sch Med, Genet Epidemiol Div, Salt Lake City, UT USA

[3] Idaho Technol, Salt Lake City, UT USA

来源：

AMERICAN HEART JOURNAL | 2010年 / 160卷 / 02期

关键词：

9P21; LOCUS; GENOMEWIDE ASSOCIATION; MYOCARDIAL-INFARCTION; CARDIOVASCULAR RISK; RECLASSIFICATION; POLYMORPHISMS; CHOLESTEROL; SELECTION; CURVE; WOMEN;

D O I：

10.1016/j.ahj.2010.05.031

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective The aim of this study is to discover common variants in 6 lipid metabolic genes and construct and validate a genetic risk score (GRS) based on the joint effects of genetic variants in multiple genes from lipid and other pathobiologic pathways. Background Explaining the genetic basis of coronary artery disease (CAD) is incomplete. Discovery and aggregation of genetic variants from multiple pathways may advance this objective. Methods Premature CAD cases (n = 1,947) and CAD-free controls (n = 1,036) were selected from our angiographic registry. In a discovery phase, single nucleotide polymorphisms (SNPs) at 56 loci from internal discovery and external reports were tested for associations with biomarkers and CAD: 28 promising SNPs were then tested jointly for CAD associations, and a GRS consisting of SNPs contributing independently was constructed and validated in a replication set of familial cases and population-based controls (n = 1,320). Results Five variants contributed jointly to CAD prediction in a multigenic GRS model: odds ratio 1.24 (95% CI 1.16-1.33) per risk allele, P = 8.2 x 10(-11), adjusted OR 2.03 (1.53-2.70), fourth versus first quartile. 5-SNP genetic risk score had minor impact on area under the receiver operating characteristic curve (P > .05) but resulted in substantial net reclassification improvement: 0.16 overall, 0.28 in intermediate-risk patients (both P < .0001). GRS(5) predicted familial CAD with similar magnitude in the validation set. Conclusions The Intermountain Healthcare's Coronary Genetics study demonstrates the ability of a multigenic, multipathway GRS to improve discrimination of angiographic CAD. Genetic risk scores promise to increase understanding of the genetic basis of CAD and improve identification of individuals at increased CAD risk. (Am Heart J 2010;160:250-256.e3.)

引用

页码：250 / U64

页数：10

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