Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease

被引：1207

作者：

Clarke, Robert ^{[2
,3
]}

Peden, John F.

Hopewell, Jemma C. ^{[2
,3
]}

Kyriakou, Theodosios

Goel, Anuj

Heath, Simon C. ^{[5
]}

Parish, Sarah ^{[2
,3
]}

Barlera, Simona ^{[6
]}

Franzosi, Maria Grazia ^{[6
]}

Rust, Stephan ^{[7
]}

Bennett, Derrick ^{[2
,3
]}

Silveira, Angela ^{[8
]}

Malarstig, Anders ^{[8
]}

Green, Fiona R. ^{[4
]}

Lathrop, Mark ^{[5
]}

Gigante, Bruna ^{[9
]}

Leander, Karin ^{[9
]}

de Faire, Ulf ^{[9
]}

Seedorf, Udo ^{[7
]}

Hamsten, Anders ^{[8
]}

Collins, Rory ^{[2
,3
]}

Watkins, Hugh

Farrall, Martin ^{[1
]}

机构：

[1] Univ Oxford, Dept Cardiovasc Med, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[2] Univ Oxford, Clin Trial Serv Unit, Oxford OX3 7BN, England

[3] Univ Oxford, Epidemiol Studies Unit, Oxford OX3 7BN, England

[4] Univ Surrey, Fac Hlth & Med Sci, Div Biochem Sci, Surrey, England

[5] CEA, Ctr Natl Genotypage, Inst Genom, Evry, France

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

[7] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany

[8] Karolinska Inst, Dept Med, Atherosclerosis Res Unit, Stockholm, Sweden

[9] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2009年 / 361卷 / 26期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; PENTANUCLEOTIDE REPEAT POLYMORPHISM; ARTERY-DISEASE; MYOCARDIAL-INFARCTION; APOLIPOPROTEIN(A) GENE; PLASMA LIPOPROTEIN(A); HEART-DISEASE; RISK; SUSCEPTIBILITY; LOCUS;

D O I：

10.1056/NEJMoa0902604

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.

引用

页码：2518 / 2528

页数：11

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