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

TY - JOUR

T1 - Novel mutations in leukotriene C4 synthase and risk of cardiovascular disease based on genotypes from 50,000 individuals

AU - Freiberg, J J

AU - Tybjærg-Hansen, Anne

AU - Nordestgaard, B G

N1 - © 2010 International Society on Thrombosis and Haemostasis.

PY - 2010/8/1

Y1 - 2010/8/1

N2 - 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 C4 synthase, is associated with risk of venous thromboembolism, ischemic stroke and myocardial infarction. Methods and Results: Resequencing the gene coding for leukotriene C4 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 C4 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.

AB - 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 C4 synthase, is associated with risk of venous thromboembolism, ischemic stroke and myocardial infarction. Methods and Results: Resequencing the gene coding for leukotriene C4 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 C4 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.

U2 - 10.1111/j.1538-7836.2010.03903.x

DO - 10.1111/j.1538-7836.2010.03903.x

M3 - Journal article

SN - 1538-7933

VL - 8

SP - 1694

EP - 1701

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

IS - 8

ER -