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This version published online on June 26, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-0221
A more recent version of this article appeared on September 1, 2007
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Submitted on January 30, 2007
Accepted on June 14, 2007

Polymorphisms in Apolipoprotein B and risk of ischemic stroke

Marianne Benn MD, PhD, Børge G. Nordestgaard MD, DMSc, Jan Skov Jensen MD, DMSc, and Anne Tybjærg-Hansen MD, DMSc*

Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (M.B., A.T.-H.), Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark (M.B., B.G.N.), The Copenhagen City Heart Study, Bispebjerg University Hospital, Copenhagen, Denmark (A.T.-H., B.G.N., J.S.J.) and Department of Cardiology, Gentofte University Hospital (J.S.J.); University of Copenhagen, Denmark

* To whom correspondence should be addressed. E-mail: at-h{at}rh.dk.

Context: Apolipoprotein B levels associate with risk of ischemic stroke. APOB polymorphisms may influence levels of apolipoprotein B and low density lipoprotein (LDL), but whether they associate with risk of ischemic stroke is unknown.

Objective: We tested the hypothesis that the APOB T71I, A591V, P2712L, R3611Q, E4154K, and N4311S polymorphisms associate with risk of ischemic stroke in the general population, and performed in vivo human LDL turnover studies of E4154K heterozygotes versus K4154K homozygotes.

Design: Prospective study with 23 years 100% complete follow-up, The Copenhagen City Heart Study.

Setting: The Danish general population.

Participants: 9,157 women and men aged 20-80+ years.

Main Outcome Measures: Risk of ischemic cerebrovascular disease and ischemic stroke, apolipoprotein B and LDL levels, and LDL fractional catabolic rate. The hypothesis was formulated before genotyping.

Results: APOB K4154K homozygotes had an age-adjusted hazard ratio of 0.4(95%CI:0.2-0.9) for ischemic cerebrovascular disease and of 0.2(0.1-0.7) for ischemic stroke relative to E4154E homozygotes. Corresponding multifactorially adjusted hazard ratios were 0.5(0.2-1.0) and 0.2(0.1-0.8). Furthermore, E4154K heterozygotes and K4154K homozygotes had lower levels of apolipoprotein B and LDL cholesterol compared with E4154E homozygotes. Finally, E4154K heterozygotes had an increased fractional catabolic rate of LDL relative to E4154E homozygotes. None of the other polymorphisms studied influenced risk of ischemic stroke.

Conclusions: APOB K4154K homozygosity predicts a 3-5 fold reduction in risk of ischemic cerebrovascular disease and ischemic stroke. This may be explained by lower plasma levels of apolipoprotein B and LDL cholesterol, caused by an increased catabolism of LDL particles, although another yet unknown mechanism is also possible.
Key words: Ischemic stroke • Ischemic cerebrovascular disease • Apolipoprotein B • Lipids • Metabolism • Epidemiology






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