Common and Rare Alleles in Apolipoprotein B Contribute to Plasma Levels of Low-Density Lipoprotein Cholesterol in the General Population

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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.


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.


This was a prospective study with 25 yr 100% follow up, The Copenhagen City Heart Study.


The study was conducted in the Danish general population.


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.


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.


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.

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