Influence of cytochrome P450 2C9*2 and 2C9*3 variants on the risk of ischemic stroke: a cross-sectional case-control study

Ischemic stroke is a multifactorial disease and a major cause of death and disability throughout the world. Acquired risk factors (e.g., hypertension, cigarette smoking, and diabetes mellitus) account only for ∼69% of the population-attributable risk. Thus, it is likely that other, as yet unidentified, factors contribute to the development of stroke (1). Both epidemiologic and animal-based studies suggest that alterations in a variety of candidate genes, including hemostatic genes, genes controlling homocysteine metabolism, the gene that encodes angiotensin-converting enzyme, and the gene that encodes endothelial nitric oxide synthase, are important in the pathogenesis of ischemic stroke (2)(3). Apparently the genetic influences are polygenic. In addition, ischemic stroke comprises many different phenotypes. According to previous studies, genetic factors seem to have different effects depending on stroke etiology [e.g., lacunar stroke and polymorphisms in the gene encoding interleukin-6 (4)]. In combination with acquired risk factors such as smoking, the presence of one or a combination of several predisposing genes may favor the occurrence of stroke. Cytochrome P-450 (CYP) 2C9 belongs to a large family of heme-containing enzymes that catalyze the oxidation of various drugs and endogenous substrates. CYP2C9 is produced in the liver, is responsible for 50% of the epoxygenase activity in the human liver, and metabolizes a wide variety of clinically important drugs (5). Interestingly, CYP2C isoforms also seem to play a role in the regulation of vascular tone. CYP2C9 is expressed in the endothelium and, via production of endothelium-derived hyperpolarizing factor (EDHF), may cause vasorelaxation as a result of hyperpolarization of vascular smooth muscle cells by activation of Ca2+-activated K+ channels (6). EDHF production seems to be inhibited by NO and/or prostacyclin and has been described as an important regulator of vascular tone under certain pathologic conditions and in certain vascular beds, such as …