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

作者：Akasaka Tomonori; Hokimoto Seiji; Sueta Daisuke; Tabata Noriaki; Sakamoto Kenji; Yamamoto Eiichiro; Yamamuro Megumi; Tsujita Kenichi; Kojima Sunao; Kaikita Koichi; Kajiwara Ayami; Morita Kazunori; Oniki Kentaro; Saruwatari Junji; Nakagawa Kazuko; Ogata Yasuhiro; Ogawa Hisao

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2016, 310(11): H1494-H1500.

DOI：10.1152/ajpheart.00911.2015

• cytochrome P-450 2C19
• genetic polymorphism
• coronary microvascular disorder
• sex difference
• low-grade inflammation

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 = 81) and in healthy subjects as control (n = 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 < 2.5. CYP2C19 PMs have two loss-of-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 = 0.013; 0.11 +/- 0.06 vs. 0.07 +/- 0.04 mg/dl, P = 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 +/- 0.06 vs. 0.07 +/- 0.03, P = 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 = 0.033; odds ratio 4.1, 95% confidence interval 1.15-14.1, P = 0.038). CYP2C19 PM genotype may be a new candidate risk factor for CMVD via inflammation exclusively in the female population.

• 出版日期2016-6-1