Common and rare alleles in apolipoprotein B contribute to plasma levels of low-density lipoprotein cholesterol in the general population

M. Benn; Maria Charlotte Aslaug Stene; Børge Nordestgaard; Gorm Boje Jensen; R. Steffensen; Anne Tybjærg-Hansen

doi:10.1210/jc.2007-1365

Common and rare alleles in apolipoprotein B contribute to plasma levels of low-density lipoprotein cholesterol in the general population

M. Benn, Maria Charlotte Aslaug Stene, Børge Nordestgaard, Gorm Boje Jensen, R. Steffensen, Anne Tybjærg-Hansen

27 Citations (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 <= 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: 2008/3

Original language	English
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	93
Issue number	3
Pages (from-to)	1038-1045
Number of pages	8
ISSN	0021-972X
DOIs	https://doi.org/10.1210/jc.2007-1365
Publication status	Published - 2008

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Common and rare alleles in apolipoprotein B contribute to plasma levels of low-density lipoprotein cholesterol in the general population. / Benn, M.; Stene, Maria Charlotte Aslaug; Nordestgaard, Børge et al.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 3, 2008, p. 1038-1045.

Research output: Contribution to journal › Journal article › Research › peer-review

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title = "Common and rare alleles in apolipoprotein B contribute to plasma levels of low-density lipoprotein 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 <= 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: 2008/3",

author = "M. Benn and Stene, {Maria Charlotte Aslaug} and B{\o}rge Nordestgaard and Jensen, {Gorm Boje} and R. Steffensen and Anne Tybj{\ae}rg-Hansen",

note = "Times Cited: 0ArticleEnglishTybjaerg-Hansen, AUniv Copenhagen Hosp, Rigshosp, Mol Genet Sect, Dept Clin Biochem KB3011, Blegdamsvej 9, DK-2100 Copenhagen O, DenmarkCited References Count: 25271XTENDOCRINE SOC8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USACHEVY CHASE",

year = "2008",

doi = "10.1210/jc.2007-1365",

language = "English",

volume = "93",

pages = "1038--1045",

journal = "Journal of Clinical Endocrinology and Metabolism",

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TY - JOUR

T1 - Common and rare alleles in apolipoprotein B contribute to plasma levels of low-density lipoprotein cholesterol in the general population

AU - Benn, M.

AU - Stene, Maria Charlotte Aslaug

AU - Nordestgaard, Børge

AU - Jensen, Gorm Boje

AU - Steffensen, R.

AU - Tybjærg-Hansen, Anne

N1 - Times Cited: 0ArticleEnglishTybjaerg-Hansen, AUniv Copenhagen Hosp, Rigshosp, Mol Genet Sect, Dept Clin Biochem KB3011, Blegdamsvej 9, DK-2100 Copenhagen O, DenmarkCited References Count: 25271XTENDOCRINE SOC8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USACHEVY CHASE

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 <= 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: 2008/3

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 <= 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: 2008/3

U2 - 10.1210/jc.2007-1365

DO - 10.1210/jc.2007-1365

M3 - Journal article

C2 - 18160469

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 -