Common and Rare Alleles in Apolipoprotein B Contribute to Plasma Levels of LDL Cholesterol in the General Population.

M Benn; MC Stene; BG Nordestgaard; Gorm Boje Jensen; R Steffensen; A Tybjaerg-Hansen; Anne Tybjærg-Hansen

Common and Rare Alleles in Apolipoprotein B Contribute to Plasma Levels of LDL Cholesterol in the General Population.

M Benn, MC Stene, BG Nordestgaard, Gorm Boje Jensen, R Steffensen, A Tybjaerg-Hansen, Anne Tybjærg-Hansen

27 Citationer (Scopus)

Abstract

CONTEXT: We have previously shown that rare mutations in the apolipoprotein B gene (APOB) may result in not only severe hypercholesterolemia and ischemic heart disease but also hypocholesterolemia. Despite this, common single-nucleotide polymorphisms (SNPs) in APOB have not convincingly been demonstrated to affect low-density lipoprotein (LDL) cholesterol levels. OBJECTIVE: We tested the hypothesis that nonsynonymous SNPs in three important functional domains of APOB and APOB tag SNPs predict levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease. DESIGN: This was a prospective study with 25 yr 100% follow up, The Copenhagen City Heart Study. SETTING: The study was conducted in the Danish general population. PARTICIPANTS: Participants included 9185 women and men aged 20-80+ yr. MAIN OUTCOME MEASURES: Levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease and myocardial infarction were measured. The hypothesis was formulated before genotyping. RESULTS: We genotyped 9185 individuals for APOB T71I (minor allele frequency: 0.33), Ivs4+171c>a (0.14), A591V (0.47), Ivs18+379a>c (0.30), Ivs18+1708g>t (0.45), T2488Tc>t (0.48), P2712L (0.21), R3611Q (0.09), E4154K (0.17), and N4311S (0.21). SNPs were associated with increases (T71I, Ivs181708g>t, T2488Tc>t, R3611) or decreases (Ivs4+171c>a, A591V, Ivs18+379a>c, P2712L, E4154, N4311S) in LDL cholesterol from -4.7 to +8.2% (-0.28 to 0.30 mmol/liter; P<or=0.002), and corresponding effects on cholesterol and apolipoprotein B levels. However, as predicted from the magnitude of the observed LDL cholesterol effects, none of these SNPs predicted risk of ischemic heart disease prospectively in the general population, in a case-control study, or as haplotypes. CONCLUSIONS: Multiple common and rare alleles in APOB contribute to plasma levels of LDL cholesterol in the general population, although the effects of common alleles and haplotypes are modest.
Udgivelsesdato: Dec 26

Originalsprog	Engelsk
Tidsskrift	Journal of Clinical Endocrinology and Metabolism
Vol/bind	93
Udgave nummer	3
Sider (fra-til)	1038-45
ISSN	0021-972X
Status	Udgivet - 2008

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http://jcem.endojournals.org/cgi/rapidpdf/jc.2007-1365v1

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title = "Common and Rare Alleles in Apolipoprotein B Contribute to Plasma Levels of LDL Cholesterol in the General Population.",

abstract = "CONTEXT: We have previously shown that rare mutations in the apolipoprotein B gene (APOB) may result in not only severe hypercholesterolemia and ischemic heart disease but also hypocholesterolemia. Despite this, common single-nucleotide polymorphisms (SNPs) in APOB have not convincingly been demonstrated to affect low-density lipoprotein (LDL) cholesterol levels. OBJECTIVE: We tested the hypothesis that nonsynonymous SNPs in three important functional domains of APOB and APOB tag SNPs predict levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease. DESIGN: This was a prospective study with 25 yr 100% follow up, The Copenhagen City Heart Study. SETTING: The study was conducted in the Danish general population. PARTICIPANTS: Participants included 9185 women and men aged 20-80+ yr. MAIN OUTCOME MEASURES: Levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease and myocardial infarction were measured. The hypothesis was formulated before genotyping. RESULTS: We genotyped 9185 individuals for APOB T71I (minor allele frequency: 0.33), Ivs4+171c>a (0.14), A591V (0.47), Ivs18+379a>c (0.30), Ivs18+1708g>t (0.45), T2488Tc>t (0.48), P2712L (0.21), R3611Q (0.09), E4154K (0.17), and N4311S (0.21). SNPs were associated with increases (T71I, Ivs181708g>t, T2488Tc>t, R3611) or decreases (Ivs4+171c>a, A591V, Ivs18+379a>c, P2712L, E4154, N4311S) in LDL cholesterol from -4.7 to +8.2% (-0.28 to 0.30 mmol/liter; P<or=0.002), and corresponding effects on cholesterol and apolipoprotein B levels. However, as predicted from the magnitude of the observed LDL cholesterol effects, none of these SNPs predicted risk of ischemic heart disease prospectively in the general population, in a case-control study, or as haplotypes. CONCLUSIONS: Multiple common and rare alleles in APOB contribute to plasma levels of LDL cholesterol in the general population, although the effects of common alleles and haplotypes are modest.",

author = "M Benn and MC Stene and BG Nordestgaard and Jensen, {Gorm Boje} and R Steffensen and A Tybjaerg-Hansen and Anne Tybj{\ae}rg-Hansen",

year = "2008",

language = "English",

volume = "93",

pages = "1038--45",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Oxford University Press",

number = "3",

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TY - JOUR

T1 - Common and Rare Alleles in Apolipoprotein B Contribute to Plasma Levels of LDL Cholesterol in the General Population.

AU - Benn, M

AU - Stene, MC

AU - Nordestgaard, BG

AU - Jensen, Gorm Boje

AU - Steffensen, R

AU - Tybjaerg-Hansen, A

AU - Tybjærg-Hansen, Anne

PY - 2008

Y1 - 2008

N2 - CONTEXT: We have previously shown that rare mutations in the apolipoprotein B gene (APOB) may result in not only severe hypercholesterolemia and ischemic heart disease but also hypocholesterolemia. Despite this, common single-nucleotide polymorphisms (SNPs) in APOB have not convincingly been demonstrated to affect low-density lipoprotein (LDL) cholesterol levels. OBJECTIVE: We tested the hypothesis that nonsynonymous SNPs in three important functional domains of APOB and APOB tag SNPs predict levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease. DESIGN: This was a prospective study with 25 yr 100% follow up, The Copenhagen City Heart Study. SETTING: The study was conducted in the Danish general population. PARTICIPANTS: Participants included 9185 women and men aged 20-80+ yr. MAIN OUTCOME MEASURES: Levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease and myocardial infarction were measured. The hypothesis was formulated before genotyping. RESULTS: We genotyped 9185 individuals for APOB T71I (minor allele frequency: 0.33), Ivs4+171c>a (0.14), A591V (0.47), Ivs18+379a>c (0.30), Ivs18+1708g>t (0.45), T2488Tc>t (0.48), P2712L (0.21), R3611Q (0.09), E4154K (0.17), and N4311S (0.21). SNPs were associated with increases (T71I, Ivs181708g>t, T2488Tc>t, R3611) or decreases (Ivs4+171c>a, A591V, Ivs18+379a>c, P2712L, E4154, N4311S) in LDL cholesterol from -4.7 to +8.2% (-0.28 to 0.30 mmol/liter; P<or=0.002), and corresponding effects on cholesterol and apolipoprotein B levels. However, as predicted from the magnitude of the observed LDL cholesterol effects, none of these SNPs predicted risk of ischemic heart disease prospectively in the general population, in a case-control study, or as haplotypes. CONCLUSIONS: Multiple common and rare alleles in APOB contribute to plasma levels of LDL cholesterol in the general population, although the effects of common alleles and haplotypes are modest.

AB - CONTEXT: We have previously shown that rare mutations in the apolipoprotein B gene (APOB) may result in not only severe hypercholesterolemia and ischemic heart disease but also hypocholesterolemia. Despite this, common single-nucleotide polymorphisms (SNPs) in APOB have not convincingly been demonstrated to affect low-density lipoprotein (LDL) cholesterol levels. OBJECTIVE: We tested the hypothesis that nonsynonymous SNPs in three important functional domains of APOB and APOB tag SNPs predict levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease. DESIGN: This was a prospective study with 25 yr 100% follow up, The Copenhagen City Heart Study. SETTING: The study was conducted in the Danish general population. PARTICIPANTS: Participants included 9185 women and men aged 20-80+ yr. MAIN OUTCOME MEASURES: Levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease and myocardial infarction were measured. The hypothesis was formulated before genotyping. RESULTS: We genotyped 9185 individuals for APOB T71I (minor allele frequency: 0.33), Ivs4+171c>a (0.14), A591V (0.47), Ivs18+379a>c (0.30), Ivs18+1708g>t (0.45), T2488Tc>t (0.48), P2712L (0.21), R3611Q (0.09), E4154K (0.17), and N4311S (0.21). SNPs were associated with increases (T71I, Ivs181708g>t, T2488Tc>t, R3611) or decreases (Ivs4+171c>a, A591V, Ivs18+379a>c, P2712L, E4154, N4311S) in LDL cholesterol from -4.7 to +8.2% (-0.28 to 0.30 mmol/liter; P<or=0.002), and corresponding effects on cholesterol and apolipoprotein B levels. However, as predicted from the magnitude of the observed LDL cholesterol effects, none of these SNPs predicted risk of ischemic heart disease prospectively in the general population, in a case-control study, or as haplotypes. CONCLUSIONS: Multiple common and rare alleles in APOB contribute to plasma levels of LDL cholesterol in the general population, although the effects of common alleles and haplotypes are modest.

M3 - Journal article

SN - 0021-972X

VL - 93

SP - 1038

EP - 1045

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 3

ER -

Common and Rare Alleles in Apolipoprotein B Contribute to Plasma Levels of LDL Cholesterol in the General Population.

Abstract

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