Sex differences in the impact of CYP2C19 polymorphisms and low-grade inflammation on coronary microvascular disorder

Abstract

Categorization as a cytochrome P-450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. It is correlated with an increase in the circulating levels of high-sense C-reactive protein (hs-CRP) in women only, although its role in coronary microcirculation is unclear. We examined sex differences in the impact of the CYP2C19 genotype and low-grade inflammation on coronary microvascular disorder (CMVD). We examined CYP2C19 genotypes in patients with CMVD (n ϭ 81) and in healthy subjects as control (n ϭ 81). CMVD was defined as the absence of coronary artery stenosis and epicardial spasms, the presence of inverted lactic acid levels between the intracoronary and coronary sinuses, or an adenosine triphosphate-induced coronary flow reserve ratio Ͻ 2.5. CYP2C19 PMs have two loss-of-function (LOF) alleles (*2, *3). Extensive metabolizers have no LOF alleles, and intermediate metabolizers have one LOF allele. The ratio of CYP2C19 PM and hs-CRP levels in CMVD was significantly higher than that of controls, especially in women (40.9 vs. 13.8%, P ϭ 0.013; 0.11 Ϯ 0.06 vs. 0.07 Ϯ 0.04 mg/dl, P ϭ 0.001). Moreover, in each CYP2C19 genotype, hs-CRP levels in CMVD in CYP2C19 PMs were significantly higher than those of the controls, especially in women (0.15 Ϯ 0.06 vs. 0.07 Ϯ 0.03, P ϭ 0.004). Multivariate analysis for CMVD indicated that the female sex, current smoking, and hypertension were predictive factors, and that high levels of hs-CRP and CYP2C19 PM were predictive factors in women only (odds ratio 3.5, 95% confidence interval 1.26 -9.93, P ϭ 0.033; odds ratio 4.1, 95% confidence interval 1.15-14.1, P ϭ 0.038). CYP2C19 PM genotype may be a new candidate risk factor for CMVD via inflammation exclusively in the female population.

Inflammation is a potential risk factor of voriconazole overdose in hematological patients

“…In addition, we investigated the possible link between CRP levels and the CYP2C19 phenotype by additional statistical analyses (see Table S2 and Figure S1 in Data S1). Although there was no association between CRP and pharmacogenetic parameters (both CYP2C19 phenotype and class of combined genetic score), the absence of a link cannot be completely ruled out as CRP and IL‐6 levels have been reported to be elevated in poor CYP2C19 metabolizers . These findings suggest that an association between loss‐of‐function SNPs of CYP2C19 and elevated VRC C min could result in reduced VRC metabolism due to diminished CYP2C19 activity (direct effect), as well as an increase in IL‐6 levels, and hence down‐regulation of CYP2C19 and CYP3A4 activities (indirect effect).…”

“…We investigated a possible link between CRP levels and pharmacogenetic parameters by comparing CRP levels (considered as continuous variables or CRP classes) according to CYP2C19 phenotype and combined genetic score class. There was no difference in CRP levels depending on either CYP2C19 phenotype or combined genetic score class (Figure S1 and Table S2).…”

“…We investigated a possible link between CRP levels and pharmacogenetic parameters [17][18][19] score class. There was no difference in CRP levels depending on either CYP2C19 phenotype or combined genetic score class ( Figure S1 and Table S2).…”

Genetic Polymorphisms and Ischemic Heart Disease

“…Microvascular angina has been also associated with CYP2C19 variants that may affect coronary microvascular dysfunction [64]. Moreover, recent data in the female population showed that the specific CYP2C19 poor metabolizer genotype can lead to coronary microvascular disorders via inflammation [65].…”

“…Moreover, the specific CYP2C19 poor metabolizer has been described as a risk factor for coronary microvascular disorders via inflammation exclusively in the female population [65]. Usually, in fertile female exhibits a protection in ischemic injury compared to age-related men, a phenomenon designated as sex-specific cardioprotection.…”