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

Abstract

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.

Figure 1.

Pairwise linkage disequilibrium (LD) reported as r² for 115 SNPs on chromosome 19 in (A) African-Americans and (B) Caucasians of CARDIA. The colour gradient indicates relative level of LD from black = complete LD (r² = 1) to white = no LD (r² = 0). Black boxes indicate the locations of rs429358 and rs7412, in the APOE gene, and of rs35136575.

Figure 2.

Results of the tests of association between plasma LDL-C level and 115 SNPs [reported as –log₁₀(false discovery rate (FDR)-adjusted P-value)] in CARDIA African-Americans and Whites. A P-value = 0.05 corresponds to a –log₁₀(P-value) = 1.30. Consecutive SNPs within the genes of this region are noted below the X-axis.

Figure 3.

Results of the tests of association between plasma LDL-C level adjusted for APOE ε2/3/4 genotype and 115 SNPs [reported as –log₁₀(FDR-adjusted P-value] in CARDIA African-Americans and Whites. P = 0.05 corresponds to a –log₁₀(P-value) = 1.30. Consecutive SNPs within the genes of this region are noted below the X-axis.

Figure 4.

The strength of association between rs35136575 genotype and plasma levels of total cholesterol (TC), LDL cholesterol (LDL-C), apolipoprotein (Apo) B, log-transformed ApoE, HDL cholesterol (HDL-C), ApoA-I and log-transformed triglycerides (TG) after linear adjustment for age, age², age³, BMI, gender and APOE genotype.