Genetic variation in members of the leukotriene biosynthesis pathway confer an increased risk of ischemic stroke - A replication study in two independent populations

Background and Purpose - The recent finding that genetic variants in 5-lipoxygenase activating protein and leukotriene A4 hydrolase may confer an increased risk of ischemic stroke has implicated the leukotriene family as potential mediators of cardiovascular disease. Using a case control replication methodology, all members of the leukotriene synthesis pathway and their receptors were examined for genetic variants, which may act as risk factors for all ischemic stroke and stroke subtypes. Methods - A case control methodology using a UK stroke cohort (872 cases, 933 controls) was adopted, with additional 5-lipoxygenase activating protein genotyping and replication of positive findings undertaken in an independent stroke population from Germany (601 cases, 736 controls). Results - Association was identified with variants in 5-lipoxygenase activating protein, leukotriene C4 synthase (leukotriene A4 hydrolase), and the leukotriene B4 receptor complex. Differing risks were identified for ischemic stroke subtypes. A variant in leukotriene C4 synthase was found to confer a 1.5-fold increase in risk of small vessel disease (RR, 1.515; 1.041 to 2.262; P = 0.043) with replication in an independent cohort showing a similar risk (RR, 1.687; 1.065 to 2.675; P = 0.026). A haplotype in the leukotriene B4 receptor complex was found to confer a 2.3-fold increase in risk of cardioembolic stroke (RR, 2.118; 1.194 to 3.760; P = 0.01) and replication in a German cohort revealed a similar risk with a second distinct haplotype (RR, 2.060; 1.162 to 3.665; P = 0.013). Conclusions - Genetic variation in leukotriene pathway members and their receptors confer an increased risk of ischemic stroke in 2 independent populations. These risks show different magnitudes depending on ischemic stroke subtype.