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

Arterioscler Thromb Vasc Biol. 2008 May;28(5):990-6. doi: 10.1161/ATVBAHA.107.158873. Epub 2008 Feb 14.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carotid Artery Diseases / genetics
  • Carotid Artery Diseases / physiopathology
  • Case-Control Studies
  • Cerebrovascular Disorders / genetics*
  • Cerebrovascular Disorders / physiopathology
  • Cross-Sectional Studies
  • Cysteine / physiology
  • Female
  • Follow-Up Studies
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics
  • Glutathione Transferase / genetics*
  • Glutathione Transferase / physiology
  • Humans
  • Leukotrienes / physiology
  • Linkage Disequilibrium / genetics
  • Male
  • Middle Aged
  • Polymorphism, Genetic / genetics*
  • Predictive Value of Tests
  • Prospective Studies
  • Risk Factors
  • Stroke / genetics*
  • Stroke / physiopathology
  • Venous Thrombosis / genetics
  • Venous Thrombosis / physiopathology

Substances

  • Leukotrienes
  • cysteinyl-leukotriene
  • Glutathione Transferase
  • leukotriene-C4 synthase
  • Cysteine