TY - JOUR
T1 - APOE/C1/C4/C2 hepatic control region polymorphism influences plasma apoE and LDL cholesterol levels
AU - Klos, Kathy
AU - Shimmin, Lawrence
AU - Ballantyne, Christie
AU - Boerwinkle, Eric
AU - Clark, Andrew
AU - Coresh, Josef
AU - Hanis, Craig
AU - Liu, Kiang
AU - Sayre, Scott
AU - Hixson, James
PY - 2008/7
Y1 - 2008/7
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddn101
DO - 10.1093/hmg/ddn101
M3 - Article
C2 - 18378515
AN - SCOPUS:45749108646
VL - 17
SP - 2039
EP - 2046
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 13
ER -