• Iris M Heid, Eva Boes, Martina Müller, Barbara Kollerits, Claudia Lamina, Stefan Coassin, Christian Gieger, Angela Döring, Norman Klopp, Ruth Frikke-Schmidt, Anne Tybjaerg-Hansen, Anita Brandstätter, Andre... more as Luchner, Thomas Meitinger, H-Erich Wichmann, and Florian Kronenberg. less
• Institute of Epidemiology, Helmholtz Center, Munich, German Research Center for Environmental Health, Neuherberg, Germany.
• Circ Cardiovasc Genet. 2008 Oct 1; 1 (1): 10-20.

BackgroundHigh-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 ResultsIn 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.ConclusionsThe 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.

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