A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol

Rudy Guerra, Jinping Wang, Scott M Grundy, Jonathan C Cohen

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Abstract

Genetic factors strongly influence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 165 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction (≃25%) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5' flanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 ± 11 vs. 37 ± 10 mg/dl, P < 0.05) and apolipoprotein AI in men (131 ± 23 vs. 122 ± 21 mg/dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 ± 3 mg/dl) and apolipoprotein AI (153 ± 9 mg/dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels.

Original languageEnglish (US)
Pages (from-to)4532-4537
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number9
DOIs
StatePublished - Apr 29 1997

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Lipase
HDL Cholesterol
Alleles
Liver
Apolipoprotein A-I
Genes
5' Flanking Region
Linkage Disequilibrium
Genetic Polymorphisms
Nuclear Family
DNA Sequence Analysis

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol",
abstract = "Genetic factors strongly influence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 165 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction (≃25{\%}) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5' flanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 ± 11 vs. 37 ± 10 mg/dl, P < 0.05) and apolipoprotein AI in men (131 ± 23 vs. 122 ± 21 mg/dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 ± 3 mg/dl) and apolipoprotein AI (153 ± 9 mg/dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels.",
author = "Rudy Guerra and Jinping Wang and Grundy, {Scott M} and Cohen, {Jonathan C}",
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T1 - A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol

AU - Guerra, Rudy

AU - Wang, Jinping

AU - Grundy, Scott M

AU - Cohen, Jonathan C

PY - 1997/4/29

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N2 - Genetic factors strongly influence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 165 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction (≃25%) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5' flanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 ± 11 vs. 37 ± 10 mg/dl, P < 0.05) and apolipoprotein AI in men (131 ± 23 vs. 122 ± 21 mg/dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 ± 3 mg/dl) and apolipoprotein AI (153 ± 9 mg/dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels.

AB - Genetic factors strongly influence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 165 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction (≃25%) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5' flanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 ± 11 vs. 37 ± 10 mg/dl, P < 0.05) and apolipoprotein AI in men (131 ± 23 vs. 122 ± 21 mg/dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 ± 3 mg/dl) and apolipoprotein AI (153 ± 9 mg/dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels.

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