Role of CYP2C9 and CYP2C19 polymorphisms in patients with atherosclerosis

Abstract

The arachidonic acid metabolizing CYP enzymes with prominent roles in vascular regulation are epoxygenases of the two gene family which generate epoxyeicosatrienoic acids. Carriers of CYP2C9 mutant alleles exhibit a diminished CYP2C9 metabolic capacity leading to decreased endothelium-derived hyperpolarizing factors (EDHF) synthesis and an increased risk for atherosclerosis. We investigated whether the polymorphisms of CYP2C9/19 are related with atherosclerosis. We examined 108 patients having angioraphically > or =70 coronary artery narrowing and 90 healthy controls. CYPC2C9/19*2 and CYP2C9/19*3 alleles were investigated in both patients and controls by a real time PCR instrument. There was no significant difference in the distribution of the CYP2C9*2/*3 alleles between cases and the controls. We found that smoker patients having CYP2C9*2 heterozygote genotype have 3.7-fold risk of developing atherosclerosis. CYP2C19*3 heterozygote alleles are more frequent in patients than in controls (10.2%, 5.6% respectively) and it is related with a three-fold risk of atherosclerosis (odds ratio (OR) = 3.75, confidence interval (CI) = 0.75-18.65). It becomes clear that cigarette smoking can cause almost all major diseases prevalent today, such as cancer or heart disease. This inter-subject variability in cigarette-induced pathologies is partly mediated by genetic variants of genes that may participate in detoxification processes, e.g., cytochrome P450 (CYP), cellular susceptibility to toxins, such as p53, or disease development such as atherosclerosis.

Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52 000 individuals

“…P-values derived from likelihood ratio from z-statistics of the Cox regression model. CYP2C9*2 and CYP2C9*3 and risk of atherosclerosis D Kaur-Knudsen et al polymorphisms and ischemic vascular disease, [21][22][23][24] in accordance with this study. Erroneous genotyping could explain a failure to detect a true association, but we consider this highly unlikely in our study as we included positive controls in all genotype reactions, and also because genotypes were confirmed by sequencing.…”

“…8 Our findings contrast some, 19,20 but not all, studies. [21][22][23][24] A Swedish study published in 2003 reported a modest increased risk of MI among women carrying CYP2C9 polymorphisms (172 MI cases/1503 controls). 20 Another case-control study, however, found that CYP2C9 polymorphisms in men were associated with decreased risk for MI (403 MI cases/431 controls), but found no risk association in women.…”

Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

“…No association between CYP2C9*2 and CYP2C9*3 polymorphisms and risk of subclinical atherosclerosis, ischemic vascular disease (ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease and ischemic stroke) or cardiovascular death was found in a very large Danish study [61]. Similarly, an association with coronary atherosclerosis, detected by angiography, was found in a small study performed in Turky [62]. In a mixed population from the USA, mostly of Caucasian ethnicity, no association with myocardial infarction and stroke was observed in a haplotype analysis using 8 and 7 tag SNPs for the CYP2C8 and CYP2C9, respectively [63].…”

Association of CYP2C19*3 gene polymorphism with breast cancer in Chinese women

“…The CYP2C19*3 mutant A allele changes the tryptophan codon to the termination codon which results in protein synthesis stopping earlier and consequently a truncated protein with a defective heme-binding region (Ercan et al, 2008). Cytochrome P450 epoxygenases metabolize arachidonic acid to EETs.…”

“…CYP2C19 is one of the human cytochrome P450 enzymes, and it is abundantly expressed in endothelial and smooth muscle cells (Imig et al, 2000;Ercan et al, 2008). CYP2C19 is the key enzyme of EET synthesis.…”