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Original Articles

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

Iris M. Heid, PhD; Eva Boes, MSc; Martina Müller, MSc; Barbara Kollerits, MSc; Claudia Lamina, MSc; Stefan Coassin, MSc; Christian Gieger, PhD; Angela Döring, MD; Norman Klopp, PhD; Ruth Frikke-Schmidt, MD, PhD; Anne Tybjærg-Hansen, MD; Anita Brandstätter, PhD; Andreas Luchner, MD; Thomas Meitinger, MD; H.-Erich Wichmann, MD, PhD and Florian Kronenberg, MD

From the Institute of Epidemiology (I.M.H., M.M., C.L., C.G., A.D., N.K., H.-E.W.) and Institute of Human Genetics (T.M.), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Information Management, Biometry and Epidemiology (I.M.H., M.M., N.K., H.-E.W.), Ludwig Maximilians University of Munich, Munich, Germany; Division of Genetic Epidemiology (E.B., B.K., S.C., A.B., F.K.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria; Department of Clinical Biochemistry (R.F.-S., A.T.-H.), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen City Heart Study (A.T.-H.), Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Internal Medicine II (A.L.), University of Regensburg, Regensburg, Germany; and Institute of Human Genetics (T.M.), Technical University Munich, Munich, Germany.

Correspondence to Florian Kronenberg, MD, Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstraße 41, A-6020 Innsbruck, Austria. E-mail Florian.Kronenberg{at}i-med.ac.at

Received February 29, 2008; accepted June 13, 2008.

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.

Key Words: genome • cholesterol • genetics • polymorphism, single nucleotide • genotype • genome-wide association study

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CLINICAL PERSPECTIVE

The online-only Data Supplement is available with this article at http://circgenetics.ahajournals.org/cgi/content/full/1/1/10/DC1.

The authors wish to dedicate this work to Professor Gerd Utermann. We consider him one of the pioneers in the investigation of genetic variability in lipoprotein metabolism since he described the apolipoprotein E polymorphism as well as the kringle-IV repeat polymorphism of the apolipoprotein (a) gene.

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