APOE/C1/C4/C2 hepatic control region polymorphism influences plasma apoE and LDL cholesterol levels.
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.
Klos
Kathy
K
Human Genetic Center, University of Texas Health Science Center at Houston, Houston, TX 77225, USA. kathy.klos@uth.tmc.edu
Shimmin
Lawrence
L
Ballantyne
Christie
C
Boerwinkle
Eric
E
Clark
Andrew
A
Coresh
Josef
J
Hanis
Craig
C
Liu
Kiang
K
Sayre
Scott
S
Hixson
James
J
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000818:Animals; D001053:Apolipoproteins / Q000097:blood / Q000235:genetics*; D001057:Apolipoproteins E / Q000097:blood*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D002888:Chromosomes, Human, Pair 19; D005260:Female; D005838:Genotype; D006801:Humans; D006822:Hybrid Cells / Q000502:physiology; D008297:Male; D017058:Mexican Americans / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014481:United States; D044465:White People / Q000235:genetics
D001053:Apolipoproteins; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D002784:Cholesterol