A common Hpa I RFLP of apolipoprotein C-I increases gene transcription and exhibits an ethnically distinct pattern of linkage disequilibrium with the alleles of apolipoprotein E

Abstract

Apolipoprotein (apo) C-I is a constituent of triglyceride-rich lipoproteins (TGRL) that interferes with their hepatic clearance. Functional polymorphism in the apoC-I gene has not been established. We determined that an Hpa I site variably present at -317 relative to the apoC-I gene is produced by a 4-bp CGTT insertion. The apoC-I Hpa I alleles showed an ethnically distinct pattern of linkage disequilibrium with the alleles of the adjacent apoE gene. The frequency of apoC-I Hpa I-positive (H2) with apoE varepsilon2 was 0. 98, without significant ethnic difference. In contrast, the frequency of H2 with apoE epsilon4 was 0.85 in European-Americans but only 0.55 in African-Americans (P < 0.001). The frequency of H2 with apoE epsilon3 was 0.02 in European-Americans and 0.08 in African-Americans (P < 0.001). African-American apoE epsilon3/epsilon3 carriers of apoC-I H2 had 19% lower fasting triglyceride levels than H1 homozygotes (P = 0.03) along with 18% higher HDL-cholesterol levels (P = 0.02). ApoB levels were 21% lower (P = 0.002). H2-allelic reporter-gene constructions showed 50% higher expression in transient transfection studies. We localized the source of this difference in expression to the CGTT insertion itself. Deletion studies of the H1 allele showed a negative transcriptional effect of the polymorphic region. An H1 oligodeoxynucleotide showed specific binding of a hepatoma-cell nuclear protein not evident with an H2 oligodeoxynucleotide. The H2 sequence may decrease the binding of a negatively acting transcription factor, leading to overexpression of apoC-I. This may produce a functional effect on lipoprotein levels but confirmation is needed in other populations.