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

Hum Mol Genet. 2008 Jul 1;17(13):2039-46. doi: 10.1093/hmg/ddn101. Epub 2008 Mar 31.


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 epsilon2/3/4 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • African Americans / genetics
  • Aged
  • Animals
  • Apolipoproteins / blood
  • Apolipoproteins / genetics*
  • Apolipoproteins E / blood*
  • Cholesterol / blood
  • Cholesterol, LDL / blood*
  • Chromosomes, Human, Pair 19*
  • Female
  • Genotype
  • Humans
  • Hybrid Cells / physiology
  • Male
  • Mexican Americans / genetics
  • Mice
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • United States
  • Whites / genetics


  • Apolipoproteins
  • Apolipoproteins E
  • Cholesterol, LDL
  • Cholesterol