【作者】 韩运峰；

【导师】 惠汝太；

【作者基本信息】 中国协和医科大学 ， 内科学， 2008， 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”是一个以社区人群为研究对象的临床药物基因组学试验,主要研究双氢克尿噻、阿替洛尔、硝苯地平缓释片、卡托普利在中国农村社区人群未治疗原发性高血压患者中的降压疗效、副作用及药物基因组学。本研究是该试验的分支研究,探讨了这四种常用抗高血压药物在中国农民未治疗单纯收缩期高血压、单纯舒张期高血压和收缩期舒张期高血玉患者中治疗4周后的降压疗效。材料与方法本研究是以社区为基础的随机、双盲临床试验。在河南省信阳市平桥区的7个乡镇,从年龄为40—75岁范围内的未治疗高血压农民患者中,经过3次筛查,我们挑选了442例单纯收缩期高血压患者、104例单纯舒张期高血压患者和1352例收缩期舒张期高血压患者,将这些患者随机分配到4个药物治疗组:(1)双氢克尿噻组(12.5-25 mg/天),包括113例单纯收缩期高血压患者、37例单纯舒张期高血压患者和313例收缩期舒张期高血压患者;(2)阿替洛尔组(12.5-25mg/天):包括66例单纯收缩期高血压患者、19例单纯舒张期高血压患者和220例收缩期舒张期高血压患者:(3)硝苯地平缓释片组(20-40mg/天):包括130例单纯收缩期高血压患者、27例单纯舒张期高血压患者和439例收缩期舒张期高血压患者;(4)卡托普利组(25-50mg/天):包括133例单纯收缩期高血压患者、21例单纯舒张期高血压患者和380例收缩期舒张期高血压患者。比较药物干预4周后降压疗效的差异。结果药物治疗4周后收缩压、舒张压在各组中均明显下降(P＜0.001)。四组药物中,双氢克尿噻组不良反应发生率最低,阿替洛尔组不良反应发生率最高,并且各组间有显著性差异(P＜0.001)。在药物价格上,双氢克尿噻是目前市场上最为便宜的降压药物。在校正年龄、性别、体重指数、腰围、腰臀比、治疗前相应的血压值、血脂、血糖、吸烟、饮酒等传统危险因素后:在单纯收缩期高血压患者中:阿替洛尔降低收缩压作用明显低于双氢克尿噻(P=0.033)和硝苯地平缓释片(P=0.005):双氢克尿噻降低舒张压作用明显低于硝苯地平缓释片(P=0.015);双氢克尿噻降低脉压作用明显大于阿替洛尔(P=0.006)和卡托普利(P=0.019)。在单纯舒张期高血压患者中:双氢克尿噻降低收缩压作用明显高于阿替洛尔(P=0.040)和卡托普利(P=0.016);在降低舒张压作用上,四组间无明显差异;双氢克尿噻增加脉压作用明显低于阿替洛尔(P=0.029)和卡托普利(P=0.031)。在收缩期舒张期高血压患者中:在降低收缩压作用上,硝苯地平缓释片＞双氢克尿噻＞阿替洛尔=卡托普利(P＜0.001);在降低舒张压作用上,硝苯地平缓释片＞双氢克尿噻＞阿替洛尔=卡托普利(P＜0.001);在降低脉压作用上,硝苯地平缓释片和双氢克尿噻均明显大于阿替洛尔(P＜0.001)和卡托普利(P＜0.001)。结论因而,从降压疗效、药物不良反应及经济学上来说,双氢克尿噻是适合中国农民治疗单纯收缩期高血压和收缩期舒张期高血压的首选一线药物。从降低血压各组分来说,在单纯舒张期高血压患者中,阿替洛尔和卡托普利优于双氢克尿噻及硝苯地平缓释片;而在收缩期舒张期高血压患者中,钙离子拮抗剂降压疗效也较好。背景与目的约95%的双氢克尿噻以原型通过OAT1由血中分泌到肾小管中,然后到达远曲小管抑制TSC,从而起到利尿及降压作用。WNK1蛋白可抑制WNK4蛋白的作用,而WNK4则可以抑制TSC。TSG基因突变可导致Gentleman’s综合症,表现为低血压,与此相反,WNK1和WNK4基因突变则可导致家族性高血压即Ⅱ型假性低醛固酮血症。然而,这些基因常见多态性与原发性高血压及双氢克尿噻的降压疗效的关系仍不十分清楚。本研究是探讨这些基因的常见多态性是否与原发性高血压及双氢克尿噻的降压疗效有关。材料与方法为研究OAT1、TSC、WNK1和WNK4基因多态与原发性高血压的相关性,我们采用2个独立的病例对照人群:第一个人群从河南省信阳市的农村入选原发性高血压病人820例,正常对照772例。第二个人群从山东省日照市农村入选原发性高血压病人286例,正常对照316例。以这两个社区为基础,我们同时完成了随机临床试验,检测OAT1、TSC、WNK1、和WNK4基因多态性对双氢克尿噻降压疗效的影响。在信阳人群中入选原发性高血压病人545例,给予双氢克尿噻治疗4周;在日照人群中入选原发性高血压病人245例,给予双氢克尿噻治疗8周,均测量治疗前和治疗后血压,考察降压疗效。根据人类基因组单体型图计划(HapMap)的中国人数据库挑选SNP,采用标准的PCR-RFLP技术进行基因分型。结果经过多元logistic回归分析,排除年龄、性别、体重指数、腰围、腰臀比的影响,我们发现在第一个病例对照人群中WNK1 rs1468326(OR1.55,95%CI 1.22-1.95,P＜0.001)和WNK4 rs9916754(OR 1.88,95%CI1.32-2.66,P＜0.001)可增加原发性高血压的易感性;第二个人群与此一致,:WNK1 rs1468326的OR值为1.55(95%CI 1.10-2.19),WNK4 rs9916754的OR值为1.82(95%CI 1.08-3.05)。同样住排除传统危险因素及相应基线血压值的影响后,我们发现在第一个临床试验中,在给予双氢克尿噻治疗4周后,OAT1 rs10792367 C等位基因携带者比GG型者的平均压多下降2.6 mmHg(P=0.010)及收缩压多下降4.1mmHg(P=0.014);这一结果在第二个人群的临床实验中也得到了验证:在给予双氢克尿噻治疗8周后,C等位基因携带者比GG型者的平均压多下降3.5 mmHg(P=0.010)及收缩压多下降5.9mmHg(P=0.002)。结论WNK1和WNK4基因多态性增加原发性高血压的易感性,而OAT1基因多态性可以预测高血压病患者对双氢克尿噻的降压反应。更多还原

【Abstract】 Objective 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 and hydrochlorothiazide relative to the gene polymorphisms in untreated hypertensive patients in countryside.The present study is the preliminary results of the study to investigate the different efficacy of mono-therapy with different antihypertensive drugs in Chinese patients with isolated systolic hypertension,isolated diastolic hypertension,and combined systolic and diastolic hypertension after 4-week’ s treatment.Design and methods We recruited 442 patients with isolated systolic hypertension,104 patients with isolated diastolic hypertension and 1352 patients with combined systolic and diastolic hypertension patients aged 40 to 75 years from 7 communities in XinYang county,HeNan province.They were randomly divided into four groups:One hundred and thirty-three patients with isolated systolic hypertension,37 patients with isolated diastolic hypertension and 313 patients with combined systolic and diastolic hypertension received hydrochlorothiazide(12.5mg/d or 25mg/d);Sixty-six patients with isolated systolic hypertension,19 patients with isolated diastolic hypertension and 220 patients with combined systolic and diastolic hypertension received atenolol(12.5mg/d or 25mg/d);One hundred and thirty patients with isolated systolic hypertension,27 patients with isolated diastolic hypertension and 439 with combined systolic and diastolic hypertension patients received nifedipine sustained release(20mg/d or 40mg/d);One hundred and thirty-three patients with isolated systolic hypertension,21 patients with isolated diastolic hypertension and 380 patients with combined systolic and diastolic hypertension received captopril(25mg/d or 50mg/d) respectively for 4 weeks.The systolic and diastolic blood pressures were measured before and after treatment to determine the efficacy of drugs.Results:Both mean systolic and diastolic blood pressure were reduced significantly after the treatment of antihypertensive drugs(P＜0.001). The incidence of side effect was the lowest in hydrochlorothiazide group, and the highest in atenolol group.Up to now,hydrochlorothiazide was the cheapest in all anti-hypertensive drugs.After adjustment for age,sex,pretreatment corresponding blood pressure, body mass index,waist -hip ratio,waist,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,total cholesterol, triglyceride,fasting blood glucose,creatinine,smoking,and drinking:In patients with isolated systolic hypertension,the reduction in systolic blood pressure was significantly lower in atenolol group than in hydrochlorothiazide(P=0.0339) and nifedipine sustained release(P=0.005) groups;The reduction in diastolic blood pressure was lower significantly in hydrochlorothiazide group than in nifedipine sustained release group(P=0.015);The reduction in pulse pressure was significant]y greater in hydrochlorothiazide group than in atenolol(P=0.006) and captopril(P=0.019) groups.In patients with isolated diastolic hypertension,the reduction in systolic blood pressure was significantly greater in hydrochlorothiazide group than in atenolol(P=0.040) and captopril(P=0.016) groups;The reduction in diastolic blood pressure had no significant difference in four groups;The increase in pulse pressure was lower in hydrochlorothiazide group than in atenolol(P=0.029) and captopril(P=0.031)groups.In patients with combined systolic and diastolic hypertension,the reduction in systolic blood pressure was significantly greater in nifedipine sustained release group than in hydrochlorothiazide group(P=0.001),that in hydrochlorothiazide group than that in atenolol(P＜0.001) and captopril (P＜0.001) groups;Nifedipine sustained release decreased diastolic blood pressure to a greater extent than hydrochlorothiazide and atenolol groups(P＜0.001),and hydroehlorothiazide decreased diastolic blood pressure to a greater extent than captopril(P＜0.001).The reduction in pulse pressure was significantly greater in hydrochlorothiazide and nifedipine sustained release groups than that in atenolol and captopril groups (P＜0.001).Conclusions In patients with isolated systolic hypertension or combined systolic and diastolic hypertension,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.In reducing blood pressure,Atenolol and captopril seem to be more effective antihypertensive drug for patients with isolated diastolic hypertension compared with hydrochlorothiazide and nifedipine sustained release;Nifedipine sustained release seems to be more effective antihypertensive drugs for patients with combined systolic and diastolic hypertension compared with atenolol and captopril. Background and Objectives A total of 95%of hydrochlorothiazide is excreted unchanged by organic anion transporter 1 from the blood into the tubular lumen by inhibiting thiazide-sensitive Na,Cl-cotransporter of the distal tubule.Both WNK1 and WNK4 proteins are localized to distal nephrons,WNK1 under physiological condition inactivates WNK4 and WNK4 is an inactivator for thiazide-sensitive Na,Cl-cotransporter.It has been reported that the mutations in TSC cause Gentleman’s syndrome characterized by hypotension.On the contrary,the mutations in WNK1 or WNK4 cause familial hypertension known as pseudohypoaldosteronism typeⅡ.However,the association of common polymorphisms in these genes with hypertension and antihypertensive effects of hydrochlorothiazide remains unclear. This study investigated whether the common polymorphisms in OAT1, TSC,WNK1,and WNK4 were associated with risk of essential hypertension and antihypertensive response to hydrochlorothiazide.Methods We selected 8 single-nucleotide polymorphisms in these 4 genes.The association of these polymorphisms with risk of essential hypertension was determined in 2 independent studies with 820 hypertensive patients and 772 controls recruited from HeNan province,and 286 patients and 316 controls from ShanDong province.We then conducted 2 clinical trials to confirm the association of these polymorphisms with the effect of hydrochlorothiazide in patients treated with hydrochlorothiazide(12.5-25mg/day) for 4 weeks(545 patients from HeNan province) and for 8 weeks(245 patients from ShanDong province),respectively.Results The polymorphisms of WKN1 rs1468326 conferred high risk of essential hypertension(OR 1.55,95%CI 1.22-1.95,P＜0.001) and so did WNK4 rs9916754(OR 1.88,95%CI 1.32-2.66,P＜0.001) in first study after adjustment for conventional risk factors. These results were replicated in the second population(OR 1.55 for WKN1 rs1468326 and OR 1.82 for WNK4 rs9916754).The carrier of OAT1 rs10792367 C allele had 2.6mmHg(P=0.010) lower reduction in mean blood pressure and 4.1mmHg(P=0.014) lower in systolic blood pressure response to hydrochlorothiazide than did the carriers of GG genotype in the first clinical trial.The results were replicated in the second clinical trial:The mean blood pressure was 3.5 mmHg(P=0.010) lower and systolic blood pressure response to hydrochlorothiazide was 5.9mmHg(P=0.002) lower in C allele carriers than in carriers of GG genotype.Conclusions The polymorphisms in WNK1 and WNK4 may increase susceptibility to essential hypertension.The OAT1 polymorphisms predict the antihypertensive effect to hydrochlorothiazide in Chinese hypertensive patients.更多还原