J. Lipid Res.
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The Journal of Lipid Research, Vol. 40, 50-58, January 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

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

Yan Xua, Lars Berglunda, Rajasekhar Ramakrishnanc, Richard Mayeuxb, Colleen Ngaia, Steven Holleranc, Benjamin Tyckod, Todd Leffe, and Neil S. Shachtera
a 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
b Gertrude H. Sergievsky Center and Department of Neurology, College of Physicians and Surgeons of Columbia University, 630 W. 168th Street, New York, NY 10032
c Department of Pediatrics, College of Physicians and Surgeons of Columbia University, 630 W. 168th Street, New York, NY 10032
d Department of Pathology, College of Physicians and Surgeons of Columbia University, 630 W. 168th Street, New York, NY 10032
e Department of Biological Chemistry, University of Michigan and Department of Cell Biology, Parke-Davis Pharmaceuticals, 2800 Plymouth Road, Ann Arbor, MI 48106

Correspondence to: Neil S. Shachter

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 {varepsilon}2 was 0.98, without significant ethnic difference. In contrast, the frequency of H2 with apoE {varepsilon}4 was 0.85 in European-Americans but only 0.55 in African-Americans (P < 0.001). The frequency of H2 with apoE {varepsilon}3 was 0.02 in European-Americans and 0.08 in African-Americans (P < 0.001). African-American apoE {varepsilon}3/{varepsilon}3 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.—Xu, Y., L. Berglund, R. Ramakrishnan, R. Mayeux, C. Ngai, S. Holleran, B. Tycko, T. Leff, and N. S. Shachter. 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. J. Lipid Res. 1999. 40: 50–58.

Supplementary key words: apolipoproteins C, apolipoproteins E, apolipoproteins B, biochemical genetics, genotype, VLDL


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