Genetic variance in CYP2C8 and increased risk of myocardial infarction.
BACKGROUND
Epoxyeicosatrienoic acids (EETs) are important mediators in vasodilatation, acting as endothelium-derived hyperpolarizing factors. CYP2C enzymes catalyze the metabolism of arachidonic acid to EETs. Genetic variation within the genes encoding for these enzymes may result in differences in vascular response, among others in myocardial tissue, and may therefore increase the risk of myocardial infarction (MI). CYP2C8 and CYP2C9 are encoded by the genes of the same name. CYP2C9 polymorphisms have been associated with an increased risk of MI. As CYP2C8 is genetically linked to CYP2C9 and on account of its role in EET production, we hypothesized that CYP2C8 polymorphisms are associated with the risk of MI.


METHODS
This study was embedded within the Rotterdam study, a prospective population-based cohort study. The study population included all participants with successful genotyping and without prevalent MI (n=5199). Twenty-five tagging single nucleotide polymorphisms within and around the gene-coding areas of CYP2C8 and CYP2C9 were tested for an association with incident MI using survival analysis techniques with multivariable adjustment for potential confounders.


RESULTS
During follow-up, 290 persons developed an incident MI. One tag-SNP in the CYP2C8 gene was associated with incident MI after Bonferroni correction, rs1058932C>T (variant genotype hazard ratio 1.54; 95% CI: 1.22-1.95). There was a significant gene-sex interaction with a relative excess risk of 1.40 (95% CI: 0.33-2.47) for men.


CONCLUSIONS
SNP rs1058932C>T within the CYP2C8 gene is associated with an increased risk of MI, which is, possibly because of a vascular effect of sex steroids, highest in males.
Rodenburg
Eline M
EM
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Visser
Loes E
LE
Danser
A H Jan
AH
Hofman
Albert
A
van Noord
Charlotte
C
Witteman
Jacqueline C M
JC
Uitterlinden
André G
AG
Stricker
Bruno H Ch
BH
D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016016:Proportional Hazards Models; D012727:Sex Characteristics
C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8