Promotor polymorphisms in leukotriene C4 synthase and risk of ischemic cerebrovascular disease.
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.


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.
Freiberg
Jacob J
JJ
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
Tybjaerg-Hansen
Anne
A
Sillesen
Henrik
H
Jensen
Gorm B
GB
Nordestgaard
Børge G
BG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002340:Carotid Artery Diseases / Q000235:genetics / Q000503:physiopathology; D016022:Case-Control Studies; D002561:Cerebrovascular Disorders / Q000235:genetics* / Q000503:physiopathology; D003430:Cross-Sectional Studies; D003545:Cysteine / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics* / Q000502:physiology; D006801:Humans; D015289:Leukotrienes / Q000502:physiology; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D020521:Stroke / Q000235:genetics* / Q000503:physiopathology; D020246:Venous Thrombosis / Q000235:genetics / Q000503:physiopathology
D015289:Leukotrienes; C112381:cysteinyl-leukotriene; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D003545:Cysteine