Context: We have previously shown that rare mutations in the apolipoprotein B gene (APOB) may result not only in severe hypercholesterolemia and ischemic heart disease, but also in hypocholesterolemia. Despite this, common SNPs in APOB have not convincingly been demonstrated to affect LDL cholesterol levels.

Objective: We tested the hypothesis that non-synonymous 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: Prospective study with 25 years 100% follow-up, The Copenhagen City Heart Study.

Setting: The Danish general population.

Participants: 9,185 women and men aged 20–80+ years.

Main Outcome Measures: Levels of LDL cholesterol and apolipoprotein B, and risk of ischemic heart disease and myocardial infarction. The hypothesis was formulated before genotyping.

Results: We genotyped 9,185 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/L; P-values0.002), and with 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 IHD 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.