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

Department of Clinical Biochemistry (M.B., M.C.A.S., A.T.-H.), Rigshospitalet, Copenhagen University Hospital; Department of Clinical Biochemistry (B.G.N.), Herlev University Hospital, The Copenhagen City Heart Study (B.G.N., G.B.J., A.T.-H.), Bispebjerg University Hospital, and Department of Medicine B (R.S.), Hillerød Hospital, all Faculty of Health Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Anne Tybjærg-Hansen, M.D., D.M.Sc., Chief Physician, Associate Professor, Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail: at-h{at}rh.regionh.dk.

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.