The Genetic Susceptibility To Individualized Different Efficacy Of Enalapril-folic Acid Tablets And Simvastatin Treatment

Cardio-cerebrovascular disease is a major cause of morbidity and mortality worldwide. Hyperhomocysteinemia, an increased level of plasma homocysteine (Hey), has been demonstrated to be an independent risk factor for vascular diseases, which has been included in Chinese, European and American guidelines on cardiovascular disease prevention. Polymorphisms of gene encoding Hey metabolism-related enzyme, nutritional factors and their interactions influence plasma Hcy levels, Drugs such as folic acid and lipid-lowering simvastatin may also affect the level of plasma Hcy.Objective1) To verify the association of NOX4(rs9299894) and DPEP1(rs1126464) gene polymorphisms with plasma Hey levels in Chinese hypertensive patients, further identify their impacts on baseline systolic and diastolic blood pressure levels.2) To further investigate the modification effects of the changes in plasma Hey levels, serum folic acid levels and blood pressure levels at4and8weeks by DPEP1and NOX4gene polymorphisms in hypertensive patients randomizedly treated by different doses of enalapril-folic acid tablets.3) To investigate the effect of Simvastatin on plasma Hey levels and the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with the changes of Hey levels in response to Simvastatin among patients with hyperlipidemia.Method480patients with mild-to-moderate hypertension were recruited from six larger hospitals in different Chinese regions (Shenyang, Beijing, Shanghai, Xi’an, Ha’rbin, and Nanjing), which were randomizedly assigned into three groups taking different doses of enalapril-folic acid tablets (control/low FA/high FA) for8weeks; A total of339patients with hyperlipidemia were enrolled and Simvastatin was orally administered at a dose of20mg/d for8weeks. Hey in plasma was determined by high-performance liquid chromatography in duplicate. Folic acid in serum was determined in duplicate by chemiluminescent immunoassay using a Beckman Coulter ACCESS Immunoassay System. NOX4(rs9299894) and DPEP1(rs1126464) gene polymorphism were genotyped by PCR-RFLP. Genotyping of MTHFR C677T polymorphism was performed by TaqMan probe technique. Results The subject with hyperhomocysteinemia (HHcy≥10μmol/L) accounted for74.8%, among the males up to90.9%. Plasma Hey levels was inversely correlated with folic acid levels (r=-0.27, P<0.001). DPEP1rs1126464gene polymorphism was significantly associated with baseline Hey, compared with CC genotype, the subject with GG genotype had significantly lower baseline Hey levels (adjusted beta±SE:-0.13±0.07, P=0.04); NOX4gene rs9299894polymorphism wasn’t significantly correlated with baseline Hey levels. Neither NOX4nor DPEP1gene was also associated with baseline systolic and diastolic blood pressure. Moreover, the correlations of the genotypes to plasma Hey and blood pressure levels weren’t significantly modified by folic acid levels. The genetic factors made no difference of the changes in Hey levels and serum folate levels and blood pressure levels at4and8weeks in response to different doses of enalapril-folic acid tablets among subjects with hypertension. Simvastatin treatment can significantly reduce plasma Hey levels after eight weeks (P=0.003). Stratified by baseline Hey levels, a significant decrease in plasma Hey levels (P<0.001) among those with Hey>10pmol/L was observed, in contrast to no significant changes in plasma Hey levels (P=0.93) among those with Hey<10μmol/L. multiple linear regression model with adjustment for multi-variates was identified that relative to a group of Hey<10μmol/L, Hey>10μmol/L group had significantly greater reduction of Hey in response to Simvastatin (beta±SE:-1.124±0.256; P<0.001). The individuals with677TT genotype had a significantly higher baseline Hey level. Moreover, the greater changes in Hey levels in response to Simvastatin were observed in non-smoker, non-drinker, and MTHFR677TT genotype. After stratification by body mass index (BMI), we observed a more significant increase of Hey levels among the TT genotype group in adjusted model (beta±SE:2.64±0.84μmol/L; P=0.002) among patients with BMI≥25(kg/m2).Conclusion The DPEP1gene, but not NOX4gene, was a major genetic determinant of the plasma Hey levels, the two genes weren’t involved in the regulation of baseline blood pressure levels; The interaction of different doses of enazepril-folic acid tablets and DPEP1and NOX4gene polymorphism did not significantly affect the changes of plasma Hey values and serum folate values and blood pressure values; Simvastatin may cause a markedly decrease in plasma Hey levels. Both environmental factors (drinking and smoking) and genetic factor (MTHFR), made a difference to the changes in Hcy levels in response to Simvastatin among subjects with hyperlipidemia.