Polymorphisms in apolipoprotein B and risk of ischemic stroke

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 vs. K4154K homozygotes. Design: This was a prospective study ( the Copenhagen City Heart Study) with 23-yr, 100% complete follow-up. Setting: The study was conducted with a Danish general population. Participants: A total of 9157 women and men aged 20-80+ yr participated in the study. Main Outcome Measures: Risk of ischemic cerebrovascular disease and ischemic stroke, apolipoprotein B and LDL levels, and LDL fractional catabolic rate were measured. The hypothesis was formulated before genotyping. Results: APOB K4154K homozygotes had an age-adjusted hazard ratio of 0.4 (95% confidence interval 0.2-0.9) for ischemic cerebrovascular disease and 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- to 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.