Promotor polymorphisms in leukotriene C4 synthase and risk of ischemic cerebrovascular disease

Objective-Cysteinyl leukotrienes are involved in inflammation and possibly in early carotid atherosclerosis. We tested the hypothesis that the -444 A/C and -1072 G/A polymorphisms of the leukotriene C-4 synthase associate with risk of ischemic cerebrovascular disease. Methods and Results-We genotyped 10 592 individuals from the Danish general population, the Copenhagen City Heart Study. During 24 years of follow-up, 557 individuals developed ischemic cerebrovascular disease. The allele frequency was 0.07 for -1072 A and 0.29 for -444 C. Cumulative incidence for ischemic cerebrovascular disease was higher for -1072 AA versus GG genotype (log-rank: P = 0.002), and lower for -444 CC versus AA genotype (log-rank: P = 0.008). Combined genotypes showed corresponding cumulative incidence differences (log-rank: P = 0.003). Multifactorially adjusted hazard ratios for ischemic cerebrovascular disease were 2.8(1.4 to 5.7) for -1072 AA versus GG genotype, 0.6(0.4 to 0.9) for -444 CC versus AA genotype, 2.5(1.2 to 5.4) for combined AA-AA versus GG-AA genotype, and 0.6(0.4 to 0.9) for combined GG-CC versus GG-AA genotype. Genotype did not associate with risk of deep venous thrombosis or severe carotid atherosclerosis, or with levels of platelets and coagulation factors. Conclusions-Leukotriene C-4 synthase -1072 AA genotype predict increased risk, whereas -444 CC genotype predict decreased risk of ischemic cerebrovascular disease.