Genome-wide association analysis of high-density lipoprotein cholesterol in the population-based KORA study sheds new light on intergenic regions.
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.


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.
Heid
Iris M
IM
Institute of Epidemiology, Helmholtz Center, Munich, German Research Center for Environmental Health, Neuherberg, Germany.
Boes
Eva
E
Müller
Martina
M
Kollerits
Barbara
B
Lamina
Claudia
C
Coassin
Stefan
S
Gieger
Christian
C
Döring
Angela
A
Klopp
Norman
N
Frikke-Schmidt
Ruth
R
Tybjaerg-Hansen
Anne
A
Brandstätter
Anita
A
Luchner
Andreas
A
Meitinger
Thomas
T
Wichmann
H-Erich
HE
Kronenberg
Florian
F
D008076:Cholesterol, HDL / Q000235:genetics*; D019295:Computational Biology; D003299:Cooperative Behavior; D021901:DNA, Intergenic / Q000235:genetics*; D055106:Genome-Wide Association Study; D005858:Germany; D006302:Health Services Research; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012044:Regression Analysis; D015203:Reproducibility of Results
D008076:Cholesterol, HDL; D021901:DNA, Intergenic