title: 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.
authors.affiliation: Division of Preventive Medicine and Nutrition, Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 W. 168th Street, New York, NY 10032, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: L
authors.initials: L
authors.lastname: Berglund
authors.forename: R
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: R
authors.initials: R
authors.lastname: Mayeux
authors.forename: C
authors.initials: C
authors.lastname: Ngai
authors.forename: S
authors.initials: S
authors.lastname: Holleran
authors.forename: B
authors.initials: B
authors.lastname: Tycko
authors.forename: T
authors.initials: T
authors.lastname: Leff
authors.forename: N S
authors.initials: NS
authors.lastname: Shachter
mesh_terms: D000483:Alleles; D053302:Apolipoprotein C-I; D001056:Apolipoproteins C / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015252:Deoxyribonucleases, Type II Site-Specific; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D008074:Lipoproteins / Q000097:blood; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014162:Transfection; D044465:White People / Q000235:genetics; D001741:Black or African American
chemical_list: D053302:Apolipoprotein C-I; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D017931:DNA Primers; D008074:Lipoproteins; D009687:Nuclear Proteins; D004247:DNA; C024406:endodeoxyribonuclease HpaI; D015252:Deoxyribonucleases, Type II Site-Specific