依那普利叶酸片、辛伐他汀药物疗效个体差异的易感基因研究
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摘要
心脑血管疾病是全球范围重大公共健康问题之一,学术界普遍认为高血压病人体内同型半胱氨酸(Homocysteine, Hey)水平升高,会引发心脑血管疾病,并且同型半胱氨酸作为独立危险因素已被列入中国及欧美脑血管疾病防治指南中。编码同型半胱氨酸代谢的各种酶的多态性以及营养因素都会引起血浆同型半胱氨酸的代谢紊乱,导致血浆中同型半胱氨酸水平升高；叶酸干预以及降脂降压药物治疗也可能会影响血浆Hcy水平。
目的验证中国高血压人群NOX4(rs9299894)和DPEP1(rs1126464)基因位点与基线Hcy,的相关性,并进一步探讨它们对患者基线收缩压和舒张压的影响;调查高血压病人服用不同剂量的依那普利叶酸片与DPEP1、NOX4基因的多态性相关性,并进一步深入研究服用药物4周和8周后对血浆Hcy水平、血清叶酸水平以及血压水平变化的影响。调查高血脂人群服用降脂药辛伐他汀对血浆Hcy,水平的影响以及亚甲基四氢叶酸还原酶C677T基因型多态性、吸烟和饮酒对辛伐他汀治疗后Hcy疗效的影响。
方法本研究从沈阳、北京、上海、西安、哈尔滨、南京六大城市收集原发性高血压患者480例,随机分成3组分别服用不同剂量的依那普利叶酸片(依那普利10mg／依那普利叶酸片10.4mg/依那普利叶酸片10.8mg),药物服用疗程为8周；以及从安徽安庆地区收集高血脂患者339例,每天服用剂量为20mg辛伐他汀共8周。NOX4(rs9299894)和DPEP1(rs1126464)基因位点采用PCR-RFLP法测定基因型,采用高效液相色谱方法测定了血浆中Hcy水平,采用化学发光免疫测定方法测定血清中叶酸水平,亚甲基四氢叶酸还原酶C677T基因型多态性出高通量Taqman探针技术测定.
结果中国高血压人群患有高同型半胱氨酸血症(HHcy≥10umol/L)占74.8%,其中男性高达90.9%。血浆Hcy水平与叶酸水平呈显著负相关(r=-0.27, P<0.001); DPEP1rs1126464基因多态性与基线Hcy有显著性相关,与GG基因型相比,DPEP1基因位点CC基因型具有显著更低基线Hcy水平(多因素校正β士SE：-0.13+0.07,P=0.04)：而NOX4基因rs9299894多态性位点与基线Hcy没有显著性相关；NOX4和DPEP1基因与基线收缩压和舒张压均无关。不同剂量的依那普利叶酸片服用4周和8周后,,基因型的多态性对血浆Hcy、血清叶酸和血压水平的相关性没有显著性修饰作用。辛伐他汀能显著降低患者体内血浆Hcy水平(P=0.003)。将基线Hcy水平分层后,Hcy≥10μmol/L患者治疗后血浆中Hcy显著降低(P<0.001),而Hcy<10μmol/L患者治疗后血浆中Hcy水平没有显著性变化(P=0.93)；多元线性回归校正混杂变量后显示：基线高水平的患者(≥10μmol/L) Hey降低水平更显著(P<0.001)。MTHFR677TT基因型携带者不仅具有显著的基线Hcy水平,而且辛伐他汀治疗后Hcy水平显著升高；进一步BMl分层后发现：BMI≥25kg/m2肥胖患者TT基因型携带者治疗后血浆Hcy水平显著升高(P-0.002)。此外,我们还发现：不吸烟或不饮酒的患者,辛伐他汀治疗能显著降低Hcy水平,但是在吸烟饮酒患者中不显者。
结论DPEP1基因是影响基线血浆Hcy水平的重要遗传因子,而NOX4基因与血浆Hcy水平没有相关性,且两个基因多态性位点与基线血压水平无关；不同剂量依那普利叶酸片与DPEP1和NOX4基因多态性交互作用对血浆Hcy、血清叶酸和血压疗效没有显著性修饰作用。辛伐他汀能显著降低高血脂病人体内血浆Hcy水平,且这种影响受到遗传因子(MTHFR)和环境因子(吸烟和饮酒)的修饰作用。
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.
目的验证中国高血压人群NOX4(rs9299894)和DPEP1(rs1126464)基因位点与基线Hcy,的相关性,并进一步探讨它们对患者基线收缩压和舒张压的影响;调查高血压病人服用不同剂量的依那普利叶酸片与DPEP1、NOX4基因的多态性相关性,并进一步深入研究服用药物4周和8周后对血浆Hcy水平、血清叶酸水平以及血压水平变化的影响。调查高血脂人群服用降脂药辛伐他汀对血浆Hcy,水平的影响以及亚甲基四氢叶酸还原酶C677T基因型多态性、吸烟和饮酒对辛伐他汀治疗后Hcy疗效的影响。
方法本研究从沈阳、北京、上海、西安、哈尔滨、南京六大城市收集原发性高血压患者480例,随机分成3组分别服用不同剂量的依那普利叶酸片(依那普利10mg／依那普利叶酸片10.4mg/依那普利叶酸片10.8mg),药物服用疗程为8周；以及从安徽安庆地区收集高血脂患者339例,每天服用剂量为20mg辛伐他汀共8周。NOX4(rs9299894)和DPEP1(rs1126464)基因位点采用PCR-RFLP法测定基因型,采用高效液相色谱方法测定了血浆中Hcy水平,采用化学发光免疫测定方法测定血清中叶酸水平,亚甲基四氢叶酸还原酶C677T基因型多态性出高通量Taqman探针技术测定.
结果中国高血压人群患有高同型半胱氨酸血症(HHcy≥10umol/L)占74.8%,其中男性高达90.9%。血浆Hcy水平与叶酸水平呈显著负相关(r=-0.27, P<0.001); DPEP1rs1126464基因多态性与基线Hcy有显著性相关,与GG基因型相比,DPEP1基因位点CC基因型具有显著更低基线Hcy水平(多因素校正β士SE：-0.13+0.07,P=0.04)：而NOX4基因rs9299894多态性位点与基线Hcy没有显著性相关；NOX4和DPEP1基因与基线收缩压和舒张压均无关。不同剂量的依那普利叶酸片服用4周和8周后,,基因型的多态性对血浆Hcy、血清叶酸和血压水平的相关性没有显著性修饰作用。辛伐他汀能显著降低患者体内血浆Hcy水平(P=0.003)。将基线Hcy水平分层后,Hcy≥10μmol/L患者治疗后血浆中Hcy显著降低(P<0.001),而Hcy<10μmol/L患者治疗后血浆中Hcy水平没有显著性变化(P=0.93)；多元线性回归校正混杂变量后显示：基线高水平的患者(≥10μmol/L) Hey降低水平更显著(P<0.001)。MTHFR677TT基因型携带者不仅具有显著的基线Hcy水平,而且辛伐他汀治疗后Hcy水平显著升高；进一步BMl分层后发现：BMI≥25kg/m2肥胖患者TT基因型携带者治疗后血浆Hcy水平显著升高(P-0.002)。此外,我们还发现：不吸烟或不饮酒的患者,辛伐他汀治疗能显著降低Hcy水平,但是在吸烟饮酒患者中不显者。
结论DPEP1基因是影响基线血浆Hcy水平的重要遗传因子,而NOX4基因与血浆Hcy水平没有相关性,且两个基因多态性位点与基线血压水平无关；不同剂量依那普利叶酸片与DPEP1和NOX4基因多态性交互作用对血浆Hcy、血清叶酸和血压疗效没有显著性修饰作用。辛伐他汀能显著降低高血脂病人体内血浆Hcy水平,且这种影响受到遗传因子(MTHFR)和环境因子(吸烟和饮酒)的修饰作用。
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.
引文
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