Genome-Wide Association Analysis of High-Density Lipoprotein Cholesterol in the Population-Based KORA Study Sheds New Light on Intergenic Regions

被引：84

作者：

Heid, Iris M. ^{[2
,4
]}

Boes, Eva ^{[1
]}

Mueller, Martina ^{[2
,4
]}

Kollerits, Barbara ^{[1
]}

Lamina, Claudia ^{[2
]}

Coassin, Stefan ^{[1
]}

Gieger, Christian ^{[2
]}

Doering, Angela ^{[2
]}

Klopp, Norman ^{[2
,4
]}

Frikke-Schmidt, Ruth ^{[5
]}

Tybjaerg-Hansen, Anne ^{[5
,6
]}

Brandstaetter, Anita ^{[1
]}

Luchner, Andreas ^{[8
]}

Meitinger, Thomas ^{[3
,7
]}

Wichmann, H. -Erich ^{[2
,4
]}

Kronenberg, Florian ^{[1
]}

机构：

[1] Innsbruck Med Univ, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, A-6020 Innsbruck, Austria

[2] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Epidemiol, Neuherberg, Germany

[3] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, Neuherberg, Germany

[4] Univ Munich, Inst Informat Management Biometry & Epidemiol, Munich, Germany

[5] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark

[6] Copenhagen Univ Hosp, Bispebjerg Hosp, Copenhagen City Heart Study, Copenhagen, Denmark

[7] Tech Univ Munich, Inst Human Genet, Munich, Germany

[8] Univ Regensburg, Regensburg, Germany

来源：

CIRCULATION-CARDIOVASCULAR GENETICS | 2008年 / 1卷 / 01期

关键词：

genome; cholesterol; genetics; polymorphism; single nucleotide; genotype; genome-wide association study;

D O I：

10.1161/CIRCGENETICS.108.776708

中图分类号：

R5 [内科学];

学科分类号：

1002 [临床医学]; 100201 [内科学];

摘要：

Background-High-density lipoprotein cholesterol (HDLC) is a strong risk factor for atherosclerosis and is assumed to be under considerable genetic control. We aimed to identify gene regions that influence HDLC levels by a genome-wide association analysis in the population-based KORA (Cooperative Health Research in the Region of Augsburg) study. Methods and Results-In KORA S3/F3 (n=1643), we analyzed 377 865 quality-checked single-nucleotide polymorphisms (SNPs; 500K, Affymetrix, Santa Clara, Calif), complemented by the publicly available genome-wide association results from the Diabetes Genetics Initiative (n=2631) and by replication data from KORA S4 (n=4037) and the Copenhagen City Heart Study (n=9205). Among the 13 SNPs selected from the KORA S3/F3 500K probability value list, 3 showed consistent associations in subsequent replications: 1 SNP 10 kb upstream of CETP (pooled probability value=8.5x10(-27)), 1 SNP approximately 40 kb downstream of LIPG (probability value=4.67x10(-10)), both independent of previously reported SNPs, and 1 from an already reported region of LPL (probability value=2.82x10(-11)). Bioinformatical analyses indicate a potential functional relevance of the respective SNPs. Conclusions-The present genome-wide association study identified 2 interesting HDLC-relevant regions upstream of CETP and downstream of LIPG. This draws attention to the importance of long-range effects of intergenic regions, which have been underestimated so far, and may impact future candidate-gene-association studies toward extending the region analyzed. Furthermore, the present study reinforced CETP and LPL as HDLC genes and thereby underscores the power of this type of genome-wide association approach to pinpoint associations of common polymorphisms with effects explaining as little as 0.5% of the HDLC variance in the general population. (Circ Cardiovasc Genet. 2008;1:10-20.)

引用

页码：10 / U65

页数：49

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