Novel mutations in leukotriene C4 synthase and risk of cardiovascular disease based on genotypes from 50 000 individuals

Background: Atherosclerosis is an inflammatory condition where cysteinyl leukotrienes have been identified to play an important role. Furthermore, cysteinyl leukotrienes may also affect thrombus formation. Using prospective, cross-sectional and case-control designs, we tested the hypothesis that hitherto unknown genetic variation, likely to affect the function of leukotriene C-4 synthase, is associated with risk of venous thromboembolism, ischemic stroke and myocardial infarction. Methods and Results: Resequencing the gene coding for leukotriene C-4 synthase in an extreme risk population with more than 1500 individuals revealed 17 new mutations, of which four are likely to change protein function (211G > A (minor allele frequency, 0.0001), IVS3 + 1G > A (0.002), 374G > A (0.0006) and 451_453+10del (0.0007)). Based on genotyping 50 000 individuals, age and sex adjusted odds ratios for venous thromboembolism were 2.0 (95% CI, 1.3-3.5) for IVS3+1G > A heterozygotes vs. wild type, and 1.9 (1.5-2.7) for any mutation heterozygote vs. wild type. Corresponding values were 2.0 (1.3-3.2) and 1.5 (1.1-2.1) for ischemic stroke, and 1.0 (0.8-1.3) and 1.2 (1.0-1.4) for myocardial infarction. Conclusions: Four novel mutations that are likely to change the function of leukotriene C-4 synthase were associated with increased risk of venous thromboembolism and ischemic stroke. These findings need confirmation in other independent studies. In addition, the mechanism behind these findings deserves further investigation.