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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:990.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Promotor Polymorphisms in Leukotriene C₄ Synthase and Risk of Ischemic Cerebrovascular Disease

Jacob J. Freiberg; Anne Tybjærg-Hansen; Henrik Sillesen; Gorm B. Jensen; Børge G. Nordestgaard

From the Department of Clinical Biochemistry (J.J.F., B.G.N.), Herlev Hospital, Copenhagen University Hospital; the Copenhagen City Heart Study (A.T.-H., G.B.J., B.G.N.), Bispebjerg Hospital, Copenhagen University Hospital; the Department of Clinical Biochemistry (A.T.-H.), and the Department of Vascular Surgery (H.S.), Rigshospitalet, Copenhagen University Hospital; Faculty of Health Sciences, University of Copenhagen, Denmark.

Correspondence to Børge G. Nordestgaard, Professor, Chief Physician, MD, DMSc, Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail brno{at}heh.regionh.dk

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 C₄ 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 C₄ synthase –1072 AA genotype predict increased risk, whereas –444 CC genotype predict decreased risk of ischemic cerebrovascular disease.

Leukotrienes are involved in innate immunity and inflammation. We tested the hypothesis that the –1072 G/A and –444 A/C polymorphisms of the leukotriene C₄ synthase associate with risk of ischemic cerebrovascular disease. These leukotriene C₄ synthase genotypes predicted 3-fold increased and 40% reduced risk of ischemic cerebrovascular disease.

Key Words: 5-lipoxygenase pathway • cysteinyl leukotrienes • LTC₄ synthase • ischemic cerebrovascular disease • atherosclerosis

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Cysteinyl-Leukotrienes in Cerebrovascular Disease: Angels and Demons?

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