Journal Article

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

Kathy Klos, Lawrence Shimmin, Christie Ballantyne, Eric Boerwinkle, Andrew Clark, Josef Coresh, Craig Hanis, Kiang Liu, Scott Sayre and James Hixson

in Human Molecular Genetics

Volume 17, issue 13, pages 2039-2046
Published in print July 2008 | ISSN: 0964-6906
Published online March 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn101
APOE/C1/C4/C2 hepatic control region polymorphism influences plasma apoE and LDL cholesterol levels

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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 ε2/3/4 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.

Journal Article.  4383 words.  Illustrated.

Subjects: Genetics and Genomics

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