CYP2C19 gene polymorphisms and levels of factors related to vascular endothelial functions in Guangzhou Hans treated on anti- platelets

Abstract

Objective To investigate the polymorphism of gene cytochrome P450 2C19 (CYP2C19) associated with clopidogrel metabolism in Guangzhou Han population, and to determine the effect of conventional clopidogrel doses on factors related to vascular endothelial functions in patients with cardio/cerebrovascular diseases and various CYP2C19 genotypes. Methods Included in this study were 1 079 unrelated Han subjects who received CYP2C19 polymorphism detection in our hospital. Gene microarray was used to detect the following CYP2C19 gene loci: CYP2C19*1, CYP2C19*2, and CYP2C19*3. The frequencies of genotypes and alleles were analyzed. According to CYP2C19 alleles, the subjects were classified as rapid, intermediate or poor metabolizers. Twenty- eight rapid metabolizers who were suffering from cardio/cerebrovascular diseases and being treated on antiplatelet agent clopidogrel (75 mg/d) for over six consecutively months were randomly selected as the rapid metabolizer group. Likewise, intermediate (n= 26) and poor metabolizer (n=26) groups were set. Another 13 poor metabolizers on combination therapy with clopidogrel (75 mg/d) plus aspirin (100 mg/d) were recruited as the combined treated poor metabolizer group. A control group was set comprising patients with cardio/cerebrovascular diseases but not on any antiplatelets (n=27). For all groups, plasma levels of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule (VCAM-1) were determined. Results CYP2C19 genotypes in Guangzhou Han population were found predominated by wild- type. The frequencies were 41.97% for CYP2C19*1*1, 39.85% for CYP2C19*1*2, 5.65% for CYP2C19*1*3, 9.08% for CYP2C19*2*2, 3.05% for CYP2C19*2* 3, and 0.58% for CYP2C19*3*3. The allele frequencies of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were 64.55% , 30.53% and 4.92% , respectively. CYP2C19 metabolizer phenotypes were chiefly intermediate metabolizers (45.50%) , followed by rapid metabolizers (41.79%) and poor metabolizers (12.71%). The VEGF and VCAM-1 levels showed an increasing trend from rapid, intermediate, poor metabolizer groups to the control group, but the difference was not significant (P>0.05). Poor metabolizers on single clopidogrel therapy and those on combination therapy did not differ statistically in plasma VEGF and VCAM-1 levels (P> 0.05). Conclusion In Guangzhou Han population, intermediate metabolizers account for most of CYP2C19 metabolizer phenotypes, followed by rapid metabolizers and poor metabolizers. Compared with Clopidogrel alone, conventional doses of clopidogrel in combination with aspirin do not lead to additional improvement in vascular endothelium-related factors. Key words: Cytochrome P450 enzyme system; Vascular endothelial growth factors; Polymorphism, single nucleotide; Vascular endothelial related factors