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Because apolipoprotein E (apoE) and lipopoprotein lipase (LPL) polymorphisms interact with each other and with other factors to affect lipid metabolism, we sought to determine their separate and combined effects in association with ischemic vascular disease.We performed a case-control study of 816 subjects: 246 acute ischemic stroke patients, 234 acute myocardial infarction patients, and 336 controls. APOE exon 4 and LPL S447X genotypes were determined.APOE ε2 and ε4 homozygotes were increased in stroke (4.5% vs. 1.0%, p = 0.008), while in myocardial infarction the ε4 allele was increased (12.6% vs. 9.5%, p = 0.006) but ε2 was decreased (3.7% vs. 12.1%, p = 0.000006). For subjects with either APOE ε2 or ε4 alleles, LPL X alleles were increased in vascular disease (OR = 2.2, p = 0.01). LPL Xalleles displayed opposite tendencies toward association with disease when subjects were divided by sex, smoking, or APOE genotype. Meta-analysis and regression analysis of previous studies supported the sex and smoking dichotomies.This is the first report of an association of vascular disease with an interaction of APOE exon 4 and LPL S447X genotypes. Therefore, APOE genotypes and LPL S447X Interactions with apoE, sex, and smoking may affect the risk of myocardial infarction and ischemic stroke.