Human Molecular Genetics Advance Access originally published online on March 31, 2008
Human Molecular Genetics 2008 17(13):2039-2046; doi:10.1093/hmg/ddn101
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APOE/C1/C4/C2 hepatic control region polymorphism influences plasma apoE and LDL cholesterol levels
1 Human Genetic Center, University of Texas Health Science Center at Houston, Houston, TX, USA 2 Center for Cardiovascular Disease Prevention, Baylor College of Medicine and the Methodist DeBakey Heart Center, Houston, TX, USA 3 Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA 4 Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, Baltimore, MD, USA 5 Department of Preventive Medicine, Northwestern University, Chicago, IL, USA
* To whom correspondence should be addressed at: University of Texas Health Science Center at Houston School of Public Health Human Genetics Center, PO Box 20186, Houston, TX 77225, USA. Tel: +1 7135009914; Fax: +1 7135000900; Email: kathy.klos{at}uth.tmc.edu
Received October 23, 2007; Accepted March 26, 2008
We characterized 102 kb of chromosome 19 containing the apolipoprotein (APO) E/C1/C4/C2 cluster and two flanking genes for common DNA variants associated with plasma low-density lipoprotein cholesterol (LDL-C) level. DNA variants were identified by comparing sequences of 48 haploid hybrid cell lines. We genotyped participants (1943 Whites and 2046 African-Americans) of the Coronary Artery Risk Development in Young Adults study for 115 variants. After controlling for the effects of the APOE 
2/3/4 polymorphism, a single nucleotide polymorphism, rs35136575, in the downstream hepatic control region 2 (HCR-2) was associated with LDL-C in Caucasians (P = 0.0004), accounting for 1% of variation. We genotyped rs35136575 in the Atherosclerosis Risk in Communities (ARIC) cohort (3679 African-Americans and 10 427 Whites) and in the Genetic Epidemiology Network of Arteriopathy (GENOA) sibships (1381 African-Americans in 592 sibships, 1116 Caucasians in 503 sibships and 1378 Mexican-Americans in 416 sibships), finding association with LDL-C level in ARIC Caucasians (P = 0.0064). Lower plasma LDL-C was observed with the rare allele. Plasma apoE level was strongly associated with HCR-2 variant genotype in all three GENOA samples (P 
0.002), indicating an effect on apoE concentration. Patterns of association for plasma apo A-I, apoB, LDL-C, high-density lipoprotein cholesterol, total cholesterol and triglyceride levels with rs35136575 in the population-based samples evaluated in this study suggest a pleiotropic effect that may be context-dependent.