厦门地区原发性高血压患者抗高血压药物相关基因多态性分析与基因导向用药的疗效评估

Analysis of Antihypertensive Drug-related Gene Polymorphisms in 1082 Patients with Essential Hypertension and Evaluation the Efficacy of Gene-directed Drug Therapy in Xiamen

目的了解厦门地区原发性高血压患者抗高血压药物相关基因多态性分布情况,评估基因导向使用降压药的疗效。方法选取厦门大学附属心血管病医院住院或门诊确诊的原发性高血压患者1082例,采用实时荧光定量PCR检测CYP2C9*3(c.1075A>C)、AGTR1(c.1166A>C)、CYP2D6*10(c.100C>T)、ADRB1(c.1165G>C)、ACE(I/D)、CYP3A5*3(A6986G)、NPPA(T2238C)7种抗高血压药物相关基因,分析各基因多态性位点的频率,并比较不同性别、高血压等级、是否为H型高血压和不同地区高血压患者等位基因多态性的分布情况。再根据是否在基因检测结果指导下使用降压药,抽取基因导向治疗组90例与传统治疗对照组90例,两组中高血压1级、2级、3级患者各30例,比较两组患者的血压达标情况、平均血压稳定时间、药物不良反应情况和用药6周后的收缩压与舒张压水平。结果在1082例患者中,CYP2C9*3(c.1075A>C)、AGTR1(c.1166A>C)、CYP2D6*10(c.100C>T)、ADRB1(c.1165G>C)、ACE(I/D)、CYP3A5*3(A6986G)、NPPA(T2238C)基因型为突变纯合子的频率分别为0.00%、0.46%、32.53%、57.76%、10.07%、49.35%、0.09%,等位基因发生突变的频率分别为2.73%、4.99%、54.90%、75.28%、31.79%、70.56%、0.74%。比较不同性别、高血压等级、是否为H型高血压的7种抗高血压药物相关基因型和等位基因频率,差异无统计学意义(P>0.05)。不同地区比较,河南CYP2C9*3(c.1075A>C)、贵州AGTR1(c.1166A>C)和潮州CYP2D6*10(c.100C>T)与厦门地区的相应基因型比较,差异有统计学意义(χ^(2)=5.74,P=0.02,χ^(2)=7.54,P=0.01,χ^(2)=5.01,P=0.03),其他基因型各地区间差异无统计学意义(P>0.05)。经6周药物治疗后,基因导向组与对照组患者血压均得到有效控制,都达标,平均血压达标时间分别为(6.5±1.65)d和(7.02±2.04)d,差异无统计学意义(P>0.05);其中基因导向组与对照组的高血压1级、2级患者平均血压达标时间差异无统计学意义,但两组研究对象的高血压3级患者的平均血压达标时间分别为(7.13±1.85)d和(8.33±2.55)d,差异有统计学意义(t=-2.09,P=0.04)。两组药物不良反应分别有2例和4例,差异无统计学意义(P>0.05)。6周后基因导向组收缩压(130.29±6.51)mmHg、舒张压(81.51±6.59)mmHg与对照组收缩压(132.40±7.29)mmHg、舒张压(83.06±5.96)mmHg对比,差异无统计学意义(P>0.05);但两组高血压3级患者的收缩压分别为(132.13±6.46)mmHg与(135.73±6.73)mmHg,差异有统计学意义(t=-2.11,P=0.04)。结论厦门地区原发性高血压患者抗高血压药物相关基因多态性分布与性别、高血压等级、是否为H型高血压无关,但存在一定地域特异性,不同地区原发性高血压患者进行抗高血压药物相关基因的检测对合理安全用药具有临床意义。

Objective To investigate the genetic polymorphism of antihypertensive drug-related gene among patients with essential hypertension and evaluation the efficacy of gene-directed drug therapy in Xiamen area.Methods A total of 1082 patients with essential hypertension who visited the Cardiovascular Hospital of Xiamen University were selected as study subjects.Real-time fluorescence quantitative PCR used to analyze the polymorphism sites of CYP2C9*3(C.1075A>C),AGTR1(C.1166A>C),CYP2D6*10(C.100C>T),ADRB1(C.1165G>C),ACE(I/D),CYP3A5*3(A6986G),NPPA(T2238C),the distributions of genetype frequency and allele frequency of different genders,hypertension grades,whether or not H type hypertension and different regions were compared.And 90 cases in the gene-directed drug therapy group and 90 cases in the control group were selected according to whether the antihypertensive drugs were used under the guidance of the genetic test results.There were 30 cases in each of the two groups of patients with hypertension grade 1,grade 2 and grade 3.The blood pressure standard,average time of blood pressure stability,adverse drug reactions,the SBP and DBP levels after 6 weeks of medication were compared between the two groups.Results The frequencies of CYP2C9*3(C.1075A>C),AGTR1(C.1166A>C),CYP2D6*10(C.100C>T),ADRB1(C.1165G>C),ACE(I/D),CYP3A5*3(A6986G),NPPA(T2238C)homozygous allele were 0.00%,0.46%,32.53%,57.76%,10.07%,49.35%,0.09%,and the frequencies of allele mutation were 2.73%,4.99%,54.90%,75.28%,31.79%,70.56%,0.74%.There was no statistical significance in the genotypes and allele frequencies of this 7 antihypertensive drugs related to different genders,hypertension grades,and whether or not H type hypertension was detected(P>0.05).The CYP2C9*3(C.1075A>C)in Henan,AGTR1(C.1166A>C)in Guizhou and CYP2D6*10(C.100C>T)in Chaozhou was significantly different from these in Xiamen(χ^(2)=5.74 P=0.02,χ^(2)=7.54,P=0.01,χ^(2)=5.01,P=0.03),there was no significant difference in other loci(P>0.05).After 6 weeks of drug treatment,blood pressure in both groups were effectively controlled and reached the standard.The average time to reach the standard of blood pressure was(6.50±1.65)and(7.02±2.04)days,the difference was not statistically significant(P>0.05),there was no significant difference between the two groups of hypertension grade 1 and grade 2 patients,but the hypertension grade 3 patients in the two groups was(7.13±1.85)and(8.33±2.55)days,the difference was statistically significant(t=-2.09,P=0.04).The number of adverse drug reactions in the two groups was 2 and 4,and the difference was not obvious.There was no significant difference in SBP(130.29±6.51)mmHg,DBP(81.51±6.59)mmHg vs SBP(132.40±7.29)mmHg,DBP(83.06±5.96)mmHg between the gene-directed group and the control group.However,the SBP of the two groups of patients with hypertension grade 3 was(132.13±6.46)mmHg and(135.73±6.73)mmHg,the difference was statistically significant(t=-2.11,P=0.04).Conclusion The polymorphism distribution of antihypertensive drug-related genes in essential hypertension patients in Xiamen was not related to different genders,hypertension grades,whether or not H type hypertension,but there was regional specificity.Detection of antihypertensive drug-related genes in essential hypertension patients in different areas has clinical significance for rational and safe drug use.