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 Xu, Lars Berglund, Rajasekhar Ramakrishnan, Richard Mayeux, Colleen Ngai, Steven Holleran, Benjamin Tycko, Todd Leff, Neil S. Shachter

Research output: Contribution to journalArticle

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Abstract

Apolipoprotein (apt) 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 ε2 was 0.98, without significant ethnic difference. In contrast, the frequency of H2 with apoE ε4 was 0.85 in European-Americans but only 0.55 in African- Americans (P < 0.001). The frequency of H2 with apoE ε3 was 0.02 in European-Americans and 0.08 in African-Americans (P < 0.001). African- Americans apoE ε3/ε3 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.

Original languageEnglish (US)
Pages (from-to)50-58
Number of pages9
JournalJournal of Lipid Research
Volume40
Issue number1
StatePublished - Jan 1999
Externally publishedYes

Fingerprint

Apolipoprotein C-I
Apolipoproteins C
Linkage Disequilibrium
Apolipoproteins E
Transcription
Restriction Fragment Length Polymorphisms
Genes
Alleles
African Americans
Oligodeoxyribonucleotides
Lipoproteins
Triglycerides
Homozygote
Apolipoproteins B
Nuclear Proteins
Hypercholesterolemia
Polymorphism
Reporter Genes
HDL Cholesterol
Transfection

Keywords

  • Apolipoproteins B
  • Apolipoproteins C
  • Apolipoproteins E
  • Biochemical genetics
  • Genotype
  • VLDL

ASJC Scopus subject areas

  • Endocrinology

Cite this

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. / Xu, Yan; Berglund, Lars; Ramakrishnan, Rajasekhar; Mayeux, Richard; Ngai, Colleen; Holleran, Steven; Tycko, Benjamin; Leff, Todd; Shachter, Neil S.

In: Journal of Lipid Research, Vol. 40, No. 1, 01.1999, p. 50-58.

Research output: Contribution to journalArticle

Xu, Yan ; Berglund, Lars ; Ramakrishnan, Rajasekhar ; Mayeux, Richard ; Ngai, Colleen ; Holleran, Steven ; Tycko, Benjamin ; Leff, Todd ; Shachter, Neil S. / 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. In: Journal of Lipid Research. 1999 ; Vol. 40, No. 1. pp. 50-58.
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abstract = "Apolipoprotein (apt) 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 ε2 was 0.98, without significant ethnic difference. In contrast, the frequency of H2 with apoE ε4 was 0.85 in European-Americans but only 0.55 in African- Americans (P < 0.001). The frequency of H2 with apoE ε3 was 0.02 in European-Americans and 0.08 in African-Americans (P < 0.001). African- Americans apoE ε3/ε3 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.",
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T1 - 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

AU - Xu, Yan

AU - Berglund, Lars

AU - Ramakrishnan, Rajasekhar

AU - Mayeux, Richard

AU - Ngai, Colleen

AU - Holleran, Steven

AU - Tycko, Benjamin

AU - Leff, Todd

AU - Shachter, Neil S.

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AB - Apolipoprotein (apt) 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 ε2 was 0.98, without significant ethnic difference. In contrast, the frequency of H2 with apoE ε4 was 0.85 in European-Americans but only 0.55 in African- Americans (P < 0.001). The frequency of H2 with apoE ε3 was 0.02 in European-Americans and 0.08 in African-Americans (P < 0.001). African- Americans apoE ε3/ε3 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.

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KW - Biochemical genetics

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KW - VLDL

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