【作者】 樊晓寒；

【导师】 惠汝太；

【作者基本信息】 中国协和医科大学 ， 内科学， 2007， 博士

【摘要】 目的“基于药物基因组学在未治疗高血压患者中探讨抗高血压药物治疗反应研究”是一个社区基础临床药物基因组学试验。本研究是该试验的分支研究，探讨了四种常用抗高血压药物在中国农民未治疗原发性高血压患者中短期治疗4周后的降压疗效及不良反应。方法设计为社区为基础的随机、双盲临床试验。在信阳平桥区7个乡镇经3次筛查40—75岁农民入选了未治疗高血压患者3408例，按1：1.5：1.5：1.5的比例随机分到4个药物治疗组：阿替洛尔组(25mg／day)584例，双氢克尿噻组(25mg／day)891例，硝苯地平缓释剂组(20mg／day)947例，卡托普利组(50mg／day)976例。比较药物干预4周后降压反应、降压达标率和不良反应的差异。结果治疗4周后收缩压下降18.0±21.5mmHg，舒张压下降8.73±11.2mmHg，收缩压达标率44.5％，舒张压56.2％。收缩压达标率在四种药物组间男、女均有显著差异(all P＜0.001)：阿替洛尔组男32.7％，女43.3％；双氢克尿噻组男51.9％，女51.7％；硝苯地平缓释剂组男52.2％，女51.8％；卡托普利组37.4％，女32.7％。舒张压达标率有相似的趋势。收缩压降压反应在调整年龄、血糖、药物剂量、治疗前血压等因素后，男、女性在四种药物间均有显著差异(P＜0.001)：阿替洛尔组男-11.2±1.5mmHg，女-16.6±1.0mmHg，双氢克尿噻组男-18.7±1.2mmHg，女-21.5±1.9mmHg，硝苯地平缓释剂组男-20.9±1.3mmHg，女-23.1±1.7mmHg，卡托普利组男-15.7±1.1mmHg，女-14.9±1.6mmHg。卡托普利组舒张压降压反应显著低于其它治疗组(P＜0.001)。四种药物治疗组间不良反应有显著差异(P＜0.001)：双氢克尿噻4.62％；阿替洛尔11.1％；硝苯地平缓释剂8.03％；卡托普利7.52％。结论小剂量双氢克尿噻的收缩压达标率相对较高，收缩压降压反应与硝苯地平缓释片相似，显著优于阿替洛尔和卡托普利，且不良反应发生率较低，价格便宜，适合我国农村高血压患者的一线治疗。背景与目的肾素—血管紧张素—醛固酮系统(RAS)是体内血压水平主要调节因素并参与了高血压的发病机制。RAS中许多基因多态血压调节相关及抗高血压治疗的降压反应相关。ACE2是RAS的新成员。ACE2和血管紧张素转换酶(AcE)在RAS中合成生物活性肽，其生物功能相互拮抗，参与心血管及血压的调节。本研究假设ACE和ACE2基因的单核苷酸多态性可能相互作用增加高血压发病易感性，并可影响抗高血压药物血管紧张素转换酶抑制剂(ACEI)的降压治疗反应。方法进行了2个病例对照试验验证ACE2和ACE基因多态与高血压的相关性。第一个病例对照：信阳入选高血压病人973例，年龄、性别匹配的对照969例。第二个病例对照：山东日照入选高血压病人286例和匹配的对照316例。进行了一个社区—基础的随机临床试验验证ACE2和ACE基因多态对抗高血压药物降压反应的影响。入选了3408例未治疗高血压病人，随机分配到双氢克尿噻组、阿替洛尔组、倪福达组和卡托普利组单药治疗4周，测量治疗前和治疗后血压差值。依据国际人类基因组单体型图计划(HapMap)中国人ACE2基因SNP资料运用Haploview软件的Tagger程序挑选了3个标签SNP(TagSNP：rs2106809，rs4646155 and rs879922)；依据NCBI—SNP数据库和先前的研究资料选择另外2个标签SNP(rs4646112，rs2285666)。选择ACE基因I／D多态检测基因相互作用。采用标准的PCR-RFLP技术进行基因分型，抽取部分进行测序验证。结果第一个病例对照研究中，ACE2基因rs2106809的TT±CT基因型在女性高血压病人中显著高于女性血压正常对照(59％vs 48.9％，OR，1.21，95％CI 1.09 to1.34，P＜0.001)，男性中没有发现这种差异。经过多元logistic回归分析，排除年龄、体重指数、总胆固醇、高密度和低密度脂蛋白胆固醇、及空腹血糖的影响，女性T等位基因携带者高血压易感性增加了1.6倍(OR，1.59，95％CI，1.13 to 2.06，P＜0.001)。女性高血压病人中，ACE DD基因型+ACE2 rs2106809TT／TC基因型频率显著高于对照组(11.7％vs 6.0％，P＜0.001)。Logistic回归模型调整了其它危险因素后联合ACE DD和ACE2 rs2106809TT／TC基因型高血压危险(OR 2.34，95％CI 1.75 to 4.85，P=0.002)较单个ACE2 rs2106809T等位基因危险增加。上述结果在第二个病例对照样本中得到验证。在临床试验中发现，ACE2 rs2106809基因型与女性高血压病人对卡托普利的舒张压降压反应相关(P=0.003)。多元回归分析调整了治疗前血压水平、年龄，体重指数，空腹血糖及ACE基因I／D多态后，携带ACE2 rs2106809 TT+CT基因型的女性未治疗高血压病人应用卡托普利治疗后舒张压下降程度比携带ACE2 rs2106809 CC基因型者显著减少3.3mmHg(P=0.019)。运用协方差分析ACE2 rs2106809基因型对卡托普利组降压反应的影响是否与“其它”(阿替洛尔组+双氢克尿噻组+硝苯地平缓释剂组)药物组有差异，发现ACE2 rs2106809 CC和CT+TT基因型间舒张压降压反应的差异在卡托普利组显著大于“其它”药物组(P=0.009)。结论ACE2 T等位基因独立于其它的心血管危险因素，增加女性高血压易感性。且可以预测女性对卡托普利治疗的舒张压降压反应。更多还原

【Abstract】 Background Few studies compared the relative efficacy and tolerability of antihypertensive drug classes as initial treatment for hypertensive patients in rural area in developing countries. The study "An antihypertensive intervention trial to lower blood pressure in untreated hypertensive patients based on the gene polymorphisms in the pathway of the drug-metabolism and biological effects" was a randomized, double-blind, active-controlled, community based clinical trial in rural area in China aiming to determine antihypertensive effects and side effects of Atenolol, Captopril, Nifidipine sustained release (SR) and Hydrochlorothiazide relative to the gene polymorphisms in untreated hypertensive patients in countryside. The present study is the prelementary results of the study to compare the efficacy and tolerability of monotherapy with different classes drugs as initial treatment in untreated patients after 4-week’s treatment.Methods At baseline, unrelated patients never receiving antihypertensive therapy aged 40 to 75 years of either sex were recruited from 7 communities in XinYang County from March to May in 2005. A total of 3408 untreated patients (66% women) enrolled with mean systolic blood pressure, 160.5±19.2mmHg; mean diastolic blood pressure, 95.9±11.0mmHg. Patients were randomized to 1 of 4 treatments—Atenolol (25mg/d) group of 594, or Hydrochlorothiazide (25mg/d) of 891, or Nifedipine SR (20mg/d) of 947, or Captopril (50mg/d) of 976,—in a ratio of 1:1.5:1.5:1.5, respectively. The antihypertensive goals were that systolic blood pressure was reduced to less than 140mmHg, or diastolic blood pressure, less than 90mmHg, and the goal-achieving rate from baseline to week 4. Tolerability was assessed by recording adverse events and physical examination.Results On week 4, the goal-achieving rates were 44.5% for systolic pressure and 56.2% for diastolic pressure, respectively. The mean reductions in systolic and diastolic blood pressure were 18.0±21.5mmHg and 8.73±11.2mmHg, respectively. The goal- achieving rates for systolic blood pressure were significantly different among four treatment groups in male (32.7% in Atenolol, 51.9% in Hydrochlorothiazide, 52.2% in Nifedipine SR, and 37.4% in Captopril, respectively, P＜0.001) as well as in female patients (43.3%, 51.7%, 51.8%, and 32.7%, respectively, P＜0.001). After adjustment for the age, blood glucose, drug doses and pretreatment blood pressure, the mean reduction in systolic pressure showed significant difference among 4 treatment groups either in male (11.2±1.5mmHg for Atenolol, 18.7±1.2mmHg for Hydrochlorothiazide, 20.9±1.3mmHg for Nifedipine SR, and 15.7±1.1mmHg for Captopril, respectively, P＜0.001) or in female patients. The mean diastolic pressure showed the similar pattern as systolic pressure with the lowest reduction and goal-achivement rate in Captopril group either in meles or in females. Total adverse event was significantly lower in Hydrochlorothiazide treatment (4.62%) than other treatments (11.1% in Atenolol, 8.03% in Nifedipine SR, and 7.52% in Captopril, respectively; P＜0.001). Discontinuation rate due to adverse events was 2.0% for Hydrochlorothiazide, 6.9% for Atenolol, 5.4% for Nifedipine SR, and 2.8% for Captopril (P＜0.001).Conclusions Our results support that hydrochlorothiazide is suitable as the first line antihypertensive drug in developing countries due to its significantly higher efficacy, better tolerability, and lower cost. Its long-term metabolic side effects and cardiovascular events are under investigation. Background ACE2 is a newer member of renin-angiotensin system. Both ACE2 and ACE are involved in the production of biologically active peptides and appear to have complementary functions in the regulation of blood pressure. We hypothesized ACE2 genetic variations could confer high risk of hypertension and predict blood pressure response to ACE inhibitors.Methods Two case control studies were performed to test the association of single nucleotide polymorphisms of ACE2 and ACE I/D with hypertension (first, 973 cases vs 969 controls; second, 286 cases vs 316 controls). A total of 3,408 untreated hypertensive patients were randomized to captopril, atenolol, hydrochlorothiazide, or nifedipine sustained release treatments for 4 weeks to determine the association of blood pressure response with polymorphisms of ACE2. Five single nucleotide polymorphisms of ACE2 and ACE insert/delete were selected.Results We found an independent association of ACE2 rs2106809 T allele with an increased risk of hypertension in women (OR, 1.59, 95%CI, 1.13 to 2.06, P＜0.001). The genotypes of ACE DD and ACE2 CT/TT had much higher risk of hypertension than did ACE2 CT/TT genotype alone(OR 2.34, 95%CI 1.75 to 4.85, P=0.002). The results were confirmed in the second sample. ACE2 T allele female carriers had 3.3mmHg lower reduction in diastolic blood pressure response to captopril than did CC genotype female carriers after adjusting for pretreatment blood pressure, age, body mass index, and ACE I/D polymorphism (P=0.019). The difference between CC and CT+TT genotype groups was larger in captopril group than other drugs aggregated group in women.Conclusions ACE2 T allele confers high risk of hypertension and can predict blood pressure responses to ACE inhibitors in women.更多还原