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Human Molecular Genetics Advance Access published online on March 31, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn101
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

APOE/C1/C4/C2 hepatic control region polymorphism influences plasma apoE and LDL cholesterol levels

Kathy Klos1,*, Lawrence Shimmin1, Christie Ballantyne2, Eric Boerwinkle1, Andrew Clark3, Josef Coresh4, Craig Hanis1, Kiang Liu5, Scott Sayre1 and James Hixson1

1 Human Genetic Center, University of Texas Health Science Center at Houston, Houston, TX 2 Center for Cardiovascular Disease Prevention, Baylor College of Medicine and the Methodist DeBakey Heart Center, Houston, TX 3 Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 4 Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, Baltimore, MD 5 Department of Preventive Medicine, Northwestern University; Chicago, IL

* University of Texas Health Science Center at Houston School of Public Health Human Genetics Center P.O. Box 20186 Houston, TX 77225 USA Telephone: (713) 500-9914 Fax: (713) 500-0900 Email: kathy.klos{at}uth.tmc.edu

Received October 23, 2007; Revised March 26, 2008; 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 LDL-C level. DNA variants were identified by comparing sequences of 48 haploid hybrid cell lines. We genotyped participants (1,943 Whites and 2,046 African-Americans) of the Coronary Artery Risk Development in Young Adults (CARDIA) study for 115 variants. After controlling for the effects of the APOE {varepsilon}2/3/4 polymorphism, a single nucleotide polymorphism (SNP), 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 (3,679 African-Americans and 10,427 Whites) and in the Genetic Epidemiology Network of Arteriopathy (GENOA) sibships (1,381 African-Americans in 592 sibships, 1,116 Caucasians in 503 sibships and 1,378 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 apolipoprotein (apo) A-I, apoB, LDL-C, HDL-C, 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.


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