Heid Iris M, Boes Eva, Müller Martina, Kollerits Barbara, Lamina Claudia, Coassin Stefan, Gieger Christian, Döring Angela, Klopp Norman, Frikke-Schmidt Ruth, Tybjaerg-Hansen Anne, Brandstätter Anita, Luchner Andreas, Meitinger Thomas, Wichmann H-Erich, Kronenberg Florian
Institute of Epidemiology, Helmholtz Center, Munich, German Research Center for Environmental Health, Neuherberg, Germany.
Circ Cardiovasc Genet. 2008 Oct;1(1):10-20. doi: 10.1161/CIRCGENETICS.108.776708.
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.
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.
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.
高密度脂蛋白胆固醇（HDLC）是动脉粥样硬化的一个重要危险因素，且被认为受相当程度的基因控制。我们旨在通过基于人群的KORA（奥格斯堡地区合作健康研究）研究中的全基因组关联分析，确定影响HDLC水平的基因区域。
在KORA S3/F3（n = 1643）中，我们分析了377865个经过质量检验的单核苷酸多态性（SNP；500K，Affymetrix，加利福尼亚州圣克拉拉），并补充了糖尿病遗传计划的公开全基因组关联结果（n = 2631）以及KORA S4（n = 4037）和哥本哈根市心脏研究（n = 9205）的复制数据。从KORA S3/F3 500K概率值列表中选出的13个SNP中，3个在后续复制中显示出一致的关联：1个在CETP上游10 kb处的SNP（合并概率值 = 8.5×10⁻²⁷），1个在LIPG下游约40 kb处的SNP（概率值 = 4.67×10⁻¹⁰），二者均独立于先前报道的SNP，还有1个来自已报道的LPL区域（概率值 = 2.82×10⁻¹¹）。生物信息学分析表明各个SNP具有潜在的功能相关性。
目前的全基因组关联研究确定了CETP上游和LIPG下游2个与HDLC相关的有趣区域。这凸显了基因间区域远距离效应的重要性，而这种效应迄今一直被低估，并且可能会影响未来旨在扩大分析区域的候选基因关联研究。此外，本研究强化了CETP和LPL作为HDLC相关基因的地位，从而强调了这种全基因组关联方法在确定常见多态性与效应之间关联方面的能力，这些效应在普通人群中对HDLC变异的解释力低至0.5%。
