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。
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.
引文
1.He J,Klag MJ,Wu Z,Whelton PK.Stroke in the People's Republic of China.I.Geographic variations in incidence and risk factors.Stroke.1995;26(12):2222-2227.
2.Kearney PM,Whelton M,Reynolds K,et al.Global burden of hypertension:analysis of worldwide data.Lancet.2005;365(9455):217-223.
3.卫生部 科技部国家统计局.中国居民营养与健康现状.2004年10月12日.
4.Collins R,Peto R,MacMahon S,et al.Blood pressure,stroke,and coronary disease Short-term reductions in blood pressure:overview of randomized drug trials in their epidemiological context.Lancet 1990;335:827-838.
5.Psaty BM,Smith NL,Siscovick DS,et al.Health outcomes associated with antihypertensive therapies used as first-line agents:a systematic review and meta-analysis.JAVA.1997;277:739-745.
6.Materson BJ,Reda DJ,Cushman WC,etal.Single-drug therapy for hypertension in men:a comparison of six antihypertensive agents with placebo.N Engl J Med.1993;328:914-21.[Erratum,N Engl J Med.1994;330:1689.]
7.Wu X,Duan X,Gu D,Hao J,Tao S,Fan D.Prevalence of hypertension and its trends in Chinese populations.Int J Cardiol.1995;52:39-44.
8.Reynolds K,Gu D,Muntner P,et al.Geographic variations in the prevalence,awareness,treatment and control of hypertension in China.J Hypertens.2003;21:1273 -1281.
9.Guidelines Committee.2003 European Society of Hypertension European Society of Cardiology guidelines for the management of arterial hypertension.J Hypertens.2003;21:1011-1053.
10.Duan Xiufang,Wu Xigui,Gu Dongfeng.The distribution of systolic and diastolic hypertension in Chinese adults.Chin J Hypertension.2005;13(8):500 -503.
11.全国1991年高血压抽样调查数据册.全同1991年高血压抽样调查领导小组业务技术指导组.1993年10月.
12.Guidelines Committee.2003 European Society of Hypertension European Society of Cardiology guidelines for the management of arterial hypertension.J Hypertens.2003;21:1011-1053.
13.Black HR.The paradigm has shifted,to systolic blood pressure.Hypertension.1999;34(3):386-387.
14.Izzo JL Jr,Levy D,Black HR.Clinical Advisory Statement.Importance of systolic blood pressure in older Americans.Hypertension.2000;35(5):1021-1024.
15.Cushman WC,Basile J.Achieving blood pressure goals:why aren't we? J Clin Hypertens(Greenwich).2006;8(12):865-872.
16.European Society of Hypertension-European Society of Cardiology Guidelines Committee.2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension.J Hypertens.2003;21(6):1011-1053.
17.中国高血压防治指南修仃委员会.2004年中国高血压防治指南(使用本). 中华心血管病杂志. 2004; 32 (12): 1060-1064.
18. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham heart study. Circulation. 1999; 100 (4): 354-360.
19. Geeganage C, Sare G, Bath PM. Pulse pressure as a predictor of stroke. Expert Rev Neurother. 2008; 8 (2): 165-167.
20. Amar J, Chamontin B. Cardiovascular risk factors, atherosclerosis and pulse pressure. Adv Cardiol. 2007; 44: 212-222.
21. Blacher J, Staessen JA, Girerd X, et al. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med. 2000; 160 (8): 1085-1089.
22. Benetos A, Rudnichi A, Safar M, Guize L. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension. 1998; 32 (3): 560-564.
23. Duan Xiufang , Wu Xigui , Gu Dongfeng. The distribution of systolic and diastolic hypertension in Chinese adults. Chin J Hypertension. 2005; 13 (8): 500 -503.
24. Sciarrone MT, et al. ACE and α -adducin polymorphism as markers of individual response to diuretic therapy. Hypertension. 2003; 41: 398-403.
25. Cadman PE, O' Connor DT. Pharmacogenomics of hypertension. Curr Opin Nephrol Hypertens. 2003; 12: 61-70.
26. Marteau JB, Zaiou M, Siest G, Visvikis-Siest S. Genetic determinants of blood pressure regulation. J. Hypertens. 2005. 23; 2127-2143.
27. Gifford RW Jr, Borazanian RA.Traditional first-line therapy. Overview of medical benefits and side effects. Hypertension. 1989; 13 (5 Suppl): 1119-1124.
28. Cutler JA, MacMahon SW, Furberg CD. Controlled clinical trials of drug treatment for hypertension. A review. Hypertension. 1989; 13 (5 Suppl): 136-144.
29. Wilson MD, Weart CW. Hypertension: are beta-blockers and diuretics appropriate first-line therapies? Ann Pharmacother.1994; 28 (5): 617-625.
30. Dahlof B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet. 1991; 338(8778): 1281-1285.
31. Lever AF, Brennan PJ. MRC trial of treatment in elderly hypertensives. Clin Exp Hypertens. 1993; 15 (6): 941-952.
32. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991; 265 (24): 3255-3264.
33. Liebson PR, Grandits GA, Dianzumba S, et al. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation. 1995; 91 (3): 698-706.
34. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288 (23): 2981-2997.
35. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA. 1997; 277 (9): 739-745.
36. Freis ED, Reda DJ, Materson BJ. Volume (weight) loss and blood pressure response following thiazide diuretics. Hypertension. 1988; 12 (3): 244-250.
37. Black HR, Elliott WJ, Grandits G, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003; 289: 2073-2082.
38. DahlofB, Devereux RB, KjeldsenSE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE) : A randomized trial against atenolol. Lancet. 2002; 359: 995-1003.
39. Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003; 348: 583-592.
40. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet. 1999; 353: 611 -616.
41. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity:the Swedish Trial in Old Patients with Hypertension-2 study.Lancet.1999;354:1751 -1756.
42.Hansson L,Hedner T,Lund-Johansen P,et al.Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension:the Nordic Diltiazem(NORDIL) study.Lancet.2000;356:359-365.
43.Brown MJ,Palmer CR,Castaigne A,et al.Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study:Intervention as a Goal in Hypertension Treatment(INSIGHT).Lancet.2000;356:366-372.
44.Staessen JA,Wang.JG,Thijs L.Cardiovascular prevention and blood pressure reduction:a meta-analysis,Lancet.2001;358:1305-1315.
45.Staessen JA,Wang JG,Thijs L.Calcium-channel blockade and cardiovascular prognosis:recent evidence from clinical outcome trials.Am J Hypertens.2002;15:85S-93S.
46.Turnbull F;Blood Pressure Lowering Treatment Trialists'Collaboration.Effects of different blood-pressure-lowering regimens on major cardiovascular events:results of prospectively-designed overviews of randomised trials.Lancet.2003;362(9395):1527-1535.
47.Lewington S,Clarke R,Qizilbash N,Peto R,Collins R,Prospective Studies Collaboration.Age-specific relevance of usual blood pressure to vascular mortality:a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002; 360: 1903-1913.
48. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low dose asprin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancent. 1998; 351: 1755-1762.
49. Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A; FEVER Study Group.The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens. 2005; 23 (12): 2157-2172.
50. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on Valsartan or amlodipine: the VALUE randomized trial. Lancet. 2004; 363 (9426): 2022-2031.
51. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, Mclnnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005; 366 (9489): 895-906.
52. European Working Party. An international trial of antihypertensive therapy in elderly patients. Objectives, protocol and organization. European Working Party on High Blood Pressure in the Elderly (EWPHE). Arch Int Pharmacodyn Ther. 1985; 275 (2): 300-334.
53. Fagard RH, Staessen JA, Thijs L, et al. Response to antihypertensive therapy in older patients with sustained and nonsustained systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Circulation. 2000; 102 (10): 1139-44.
54. Wang JG, Staessen JA, Gong L, Liu L. Chinese trial on isolated systolic hypertension in the elderly. Systolic Hypertension in China (Syst-China) Collaborative Group. Arch Intern Med. 2000; 160 (2): 211-220.
55. Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for the management of hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007; 25: 1105-1187.
56. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000; 355 (9207): 865-872.
57. Somes GW, Pahor M, Shorr RI, et al. The role of diastolic blood pressure when treating isolated systolic hypertension. Arch Intern Med. 1999; 159 (17): 2004-2009.
58. Morgan TO, Anderson AI, MacInnis RJ. ACE inhibitors, beta-blockers, calcium blockers,and diuretics for the control of systolic hypertension.Am J Hypertens.2001;14(3):241-247.
59.Eastern stoke and coronary heart disease collaborative research group.Blood pressure,cholesterol,and stroke in eastern Asia.The Lancet.1998;352:1801-1807.
60.Bots ML,Witteman JC,Hofman A,et al.Low diastolic blood pressure and atherosclerosis inelderly subjects.The rotterdam study.Arch Intren Med.1996;156(8):843-848.
61.刘同树.白领高血压的临床特点.中国医学论坛报.2005;31(26):5版.
62.Holzgreve H.Where now the diuretics in antihypertensive treatment?Eur Heart J.1992;13 Suppl G:104-108.
63.Savage PJ,Pressel SL,Curb JD,et al.Influence of long-term,low-dose,diuretic-based,antihypertensive therapy on glucose,lipid,uric acid,and potassium levels in older men and women with isolated systolic hypertension:The Systolic Hypertension in the Elderly Program.SHEP Cooperative Research Group.Arch Intern Med.1998;158(7):741-751.
64.Curb JD,Pressel SL,Cutler JA,et al.Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension.Systolic Hypertension in the Elderly Program Cooperative Research Group.JAMA.1996;276(23):1886-1892.
65.Furberg CD,Pasty B,Cuter JA.Blood pressure and cardiovascular disease.In:Yusuf S,eds,E~dence Based Cardiology.London:BMJ Books,1998.235.
66.Materson BJ.Variability in response to antihypertensive drug treatment.Hypertension.2004;43(6):1166-1167.
67.Psaty BM,Smith NL,Heckbert SR,et al.Diuretic therapy,the alpha-adducin gene variant,and the risk of myocardial infarction or stroke in persons with treated hypertension.JAMA.2002;287(13):1680-1689.
68.Turner ST,Schwartz GL,Chapman AB,et al.C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic.Hypertension.2001;37(2 Part 2):739-743.
69.Maitland-van der Zee AH,Turner ST,Schwartz GL,et al.Amultilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide.Pharmacogenet Genomics.2005;15(5):287-293.
1.Chobanian,A.V.et al.The Seventh Report of the Joint National Committee on Prevention,Detection,Evaluation,and Treatment of High blood pressure:the JNC 7 report.JAMA.2003;289:2560 -2572.
2.Kearney PM,Whelton M,Reynolds K,et al.Global burden of hypertension:analysis of worldwide data.Lancet.2005;365(9455):217-223.
3.卫生部科技部国家统计局.中国居民营养与健康现状.2004年10月12日.
4.Klag MJ,Whelton PK,Randall BL,et al.Blood pressure and end-stage renal disease in men.N Engl J Med.1996;334:13-18.
5.Collins R,Peto R,MacMahon S,et al.Blood pressure,stroke,and coronary heart disease.Part 2:Short-term reductions in blood pressure:overview of randomised drug trials in their epidemiological context.Lancet.1990;335:827-838.
6.Zandi-Nejad K,Luyckx VA,Brenner BM.Adult hypertension and kidney disease:the role of fetal programming.Hypertension.2006;47:502-508.
7.Thorp ML,Eastman L,Smith DH,Johnson ES.Managing the burden of chronic kidney disease.Dis Manag.2006;9:115-121.
8.Topaloglu R.Progression to renal failure.Turk J Pediatr.2005;47(Suppl):3-8.
9.Suzuki H,Kanno Y,Nakamoto H,et al.Decline of renal function is associated with proteinuria and systolic blood pressure in the morning in diabetic nephropathy.Clin Exp Hypertens.2005;27: 129-138.
10. Ward R. Familial aggregation and genetic epidemiology of blood pressure. In Laragh, J. H. and Brenner, B. M. (eds), Hypertension: Pathophysiology, Diagnosis, and Management. 2nd edn. Raven Press, New York. 1995.
11.Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration. Lancet. 2000; 356: 1955-1964.
12. Sciarrone, M. T. et al. ACE and α-adducin polymorphism as markers of individual response to diuretic therapy. Hypertension. 2003; 41: 398 - 403.
13. Cadman, P. E. O' Connor, D. T. Pharmacogenomics of hypertension. Curr Opin Nephrol Hypertens. 2003; 12: 61-70.
14. Marteau, J. B. Zaiou, M. Siest, G. Visvikis-Siest, S. Genetic determinants of blood pressure regulation. J Hypertens. 2005; 23: 2127-2143.
15. The ALLHAT Officers and Coordinators for ALLHAT Collaborative Research Group: Major outcomes in highrisk hypertensive patients randomised to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA. 2002; 288: 2981-2997.
16.Kaplan NM. Clinical Hypertension. Treatment of Hypertension: Drug Therapy, 8th ed. Philadelphia, Lippincott Williams & Wilkins, 2002.
17. Roses AD. Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat Rev Genet. 2004; 5 (9) : 645-656.
18. Beermann B, Groschinsky -Grind M. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin Pharmacol. 1977; 12(4): 297-303.
19.Ullrich KJ. Specificity of transporters for "organic anion and cations" in the kidney. Biochim BiophysActa. 1994; 1197: 45-62.
20.Prichard JB, MillerDS. Mechanisms mediating renal secretion of organic anions and cations. Physiol Rev. 1993; 73: 765-796.
21. Enomoto A, Endou H. Roles of organic anion transporters (OATs) and a urate transporter (URAT1) in the pathophysiology of human disease. Clin Exp Nephrol. 2005; 9:195-205.
22. Sekine T, Miyazaki H, Endou H. Molecular physiology of renal organic anion transporters. Am J Physiol Renal Physiol. 2006; 290: F251-F261.
23. Hasannejad H, Takeda M, Taki K, et al. Interactions of human organic anion transporters with diuretics. J Pharmacol Exp Ther. 2004; 308 (3): 1021-1029.
24. Monroy A, Plata C, Hebert SC, Gamba, G. Characterization of the thiazide-sensitive Na+-Cl - cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol. 2000; 279: F161 -F169.
25. Mastroianni N, Bettinelli A, Bianchetti M, et al. Novel molecular variants of the Na - Cl cotransporter gene are responsible for Gitelman syndrome. Am J Hum Genet. 1996; 59: 1019-1026.
26.Simon DB, Nelson WC, Bia MJ, et al. Gitelman' s variant of Bartter' s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na - Cl cotransporter. Nat Genet. 1996; 12: 24-30.
27. Takeuchi K, Kure S, Kato T, et al. Association of a mutation in thiazide-sensitive Na - Cl cotransporter with familial Gitelman' s syndrome. J Clin Endocrinol Metab. 1996; 81: 4496-4499.
28.Xu B, English JM, Wilsbacher JL, et al. WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. J Biol Chem. 2000; 275: 16795-16801.
29. Verissimo F, Jordan P. WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. Oncogene. 2001; 20: 5562-5569.
30. Wilson FH, Kahle KT, Sabath E, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A. 2003; 100: 680-684.
31. Yang CL, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest. 2003; 111: 1039 -1045.
32.Wilson FH, Disse-Nicodeme S, Choate KA, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001; 293: 1107-1112.
33. Wilson FH, Kahle KT , Ernesto Sabath et al. Molecular pathogenesis of inherited hypertension with hyperkalemia : The Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci USA. 2003; 100: 680-684.
34.International HapMap Consortium. A haplotype map of the human genome. Nature. 2005; 437: 1299-1320.
35. Moreno E, Tovar-Palacio C, de los Heros P, et al. A single nucleotide polymorphism alters the activity of the renal Na+:C1- cotransporter and reveals a role for transmembrane segment 4 in chloride and thiazide affinity. J Biol Chem. 2004; 279(16): 16553-16560.
36. Newhouse SJ, Wallace C, Dobson R, et al. Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension (BRIGHT) study. Hum Mol Genet. 2005; 14: 1805-1814.
37. Yamauchi K, Rai T, Kobayashi K,et al. Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proc Natl Acad Sci USA. 2004; 101: 4690-4694.
38. Erlich PM, Cui J, Chazaro I, et al. Genetic variants of WNK4 in whites and african Americans with hypertension. Hypertension. 2003; 41: 1191-1195.
39. Baima J, Nicolaou M, Schwartz F, et al. Evidence for linkage between essential hypertension in humans and a putative locus on chromosome 17 in Caucasians. Hypertension. 1999; 34: 4-7.
40. Fedorova, L. Fedorov, A. Introns in gene evolution. Genetica. 2003; 118:123-131.
41. Blackwood EM, Kadonaga JT. Going the distance: a current view of enhanceraction. Science. 1998; 281: 60-63.
42. LLewinsky RH, Jensen TG, Moller J, et al. T-13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro. Hum Mol Genet. 2005; 14: 3945-3953.
43. Smith CW, Valcdrcel J. Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem Sci. 2000; 25 (8): 381-388.
44. Blencowe BJ. Exonic splicing enhancers: Mechanism of action, diversity and role in human genetic diseases. Trends Biochem Sci 2000; 25: 106- 110.
45. Carlini DB, Genut JE. Synonymous SNPs provide evidence for selective constraint on human exonic splicing enhancers. J Mol Evol. 2006; 62 (1): 89-98.
46. Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007; 315 (5811): 525-528.
47. Delaloy C, Lu J, Houot AM, et al. Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform. Mol Cell Biol. 2003; 23: 9208-9221.
48. Xu BE, Stippec S, Chu PY, et al. WNK1 activates SGK1 to regulate the epithelial sodium channel. Proc Natl Acad Sci U S A. 2005; 102 (29): 10315-10320.
49. Kahle KT, Macgregor GG, Wilson FH, et al. Paracellular Cl-permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension. Proc Natl Acad Sci U S A. 2004; 101 (41):14877-14882.
50. Eraly SA, Vallon V, Vaughn DA, et al. Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J Biol Chem. 2006; 281:5072-5083.
51.Psaty BM, Smith NL, Heckbert SR, et al. Diuretic therapy, the alpha-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA. 2002; 287: 1680 - 1689.
52. Bis JC, Smith NL, Psaty BM, et al. Angiotensinogen Met235Thr polymorphism,angiotensin converting enzyme inhibitor therapy,and the risk ofnonfatal stroke or myocardial infarction in hypertensive patients.Am J Hypertens.2003;16:1011-1017.
53.Wang XF,Lin RY,Wang SZ,et al.Association study of variants in two ion-channel genes(TSC and CLCNKB) and hypertension in two ethnic groups in Northwest China.Clin Chim Acta.2008;388(1-2):95-98.
54.Matsuo A,Katsuya T,Ishikawa K,et al.G2736A polymorphism of thiazide-sensitive Na-Cl cotransporter gene predisposes to hypertension in young women.J Hypertens.2004;22(11):2123-2127.
55.Matayoshi T,Kamide K,Takiuchi S,et al.The thiazide-sensitive Na(+)-Cl(-) cotransporter gene,C1784T,and adrenergic receptorbeta3gene,T727C,may be gene polymorphisms susceptible to the antihypertensive effect of thiazide diuretics.Hypertens Res.2004;27(11):821-33.
1. Chapman AB, Schwartz GL, Boerwinkle E, et al. Predictors of antihypertensive response to a standard dose of hydrochlorothiazide in African-American an Caucasians with essential hypertension. Kidney Int. 2002; 1 (3): 1047-1055.
2. Sander C. Genomic medicine and the future of health care. Science. 2000; 287 (5460): 1977-1978.
3. Vesell ES. Therapeutic lessons from pharmacogenetics. Ann Intern Med. 1997; 126 (8): 653-5.
4. Kalow W, Tang BK, Endrenyil. Hypothesis: comparisons of inter-and intraindividual variations can substitute for twin studies in drug research. Pharmacogenetics. 1998; 8: 283-289.
5. Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003; 348: 529-537.
6. Gonzalez FJ, Radek C, Daniel W , et al. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature. 1988; 331 (6155): 442.
7. Evans WE, McLeod HL. Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med. 2003; 348: 538-549.
8. International HapMap Consortium. A haplotype map of the human genome. Nature. 2005; 437: 1299-1320.
9. McGovern PG, Pankow JS, Shahar E, et al. Recent trends in acute coronary heart disease: mortality, morbidity, medical care, and risk factors. The Minnesota Heart Survey Investigators. N Engl J Med. 1996; 334: 884-890.
10. Chobanian, A. V. et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High blood pressure: the JNC 7 report. JAMA. 2003; 289: 2560-2572.
11. The ALLHAT Officers and Coordinators for ALLHAT Collaborative Research Group: Major outcomes in highrisk hypertensive patients randomised to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA. 2002; 288: 2981-2997.
12. Kaplan NM. Clinical Hypertension. Treatment of Hypertension: Drug Therapy, 8th ed. Philadelphia, Lippincott Williams & Wilkins, 2002.
13. Roses AD. Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat Rev Genet. 2004; 5 (9): 645-656.
14. Beermann B, Groschinsky -Grind M. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin Pharmacol. 1977; 12 (4): 297-303.
15. Hasannejad H, TakedaM, Taki K, et al. Interactions of human organic anion transporters with diuretics. J Pharmacol Exp Ther. 2004; 308 (3): 1021-1029.
16. Monroy A, Plata C, Hebert SC, Gamba, G. Characterization of the thiazide-sensitive Na+-Cl - cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol. 2000; 279: F161 -F169.
17. Wilson FH, Kahle KT, Sabath E, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A. 2003; 100: 680-684.
18. Yang CL, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest. 2003; 111: 1039 -1045.
19. Matayoshi T, Kamide K, Takiuchi S, et al. The thiazide-sensitive Na(+)-Cl(-) cotransporter gene, C1784T, and adrenergic receptor-beta3 gene, T727C, may be gene polymorphisms susceptible to the antihypertensive effect of thiazide diuretics. Hypertens Res. 2004; 27 (11): 821-833.
20. Wilson FH, Disse-Nicodeme S, Choate KA, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001; 293: 1107-1112.
21. Yamauchi K, Rai T, Kobayashi K,et al. Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proc Natl Acad Sci USA, 2004, 101: 4690-4694.
22. Erlich PM, Cui J, Chazaro I, et al. Genetic variants of WNK4 in whites and african Americans with hypertension. Hypertension. 2003; 41: 1191 - 1195.
23. Baima J, Nicolaou M, Schwartz F, et al. Evidence for linkage between essential hypertension in humans and a putative locus on chromosome 17 in Caucasians. Hypertension. 1999; 34: 4-7.
24. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic. Hypertension. 2005; 46 (4): 758-765.
25. He FJ, Markandu ND, Mac Gregor GA. Importance of the renin system for determining blood pressure fall with acute salt restriction in hypertensive and normotensive whites. Hypertension. 2001; 38: 321 - 325.
26. Sciarrone MT, Stella P, Barlassina C, et al. ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy. Hypertension. 2003; 41 (3): 398-340.
27. Wu ShouLing, Li DongQing, Li HongFen, et al. polymorphism of ACE and a -adducin genes and antihypertensive effects of hydrochlorothiazide. Chin J Hypertension. 2005; 13 (11): 697-700.
28. Duncan JA, Scholey JW, Miller JA. Angiotensin II type 1 receptor gene polymorphisms in humans: physiology and pathophysiology of the genotypes. Curr Opin Nephrol Hypertens. 2001; 1: 111-116.
29. Miller JA, Thai K, Scholey JW. Angiotensin II type 1 receptor gene polymorphism predicts response to losartan and angiotensin II. Kidney Int. 1999; 56 (6): 2173-2180.
30. Frazier L, Turner ST, Schwartz GL, et al. Multilocus effects of the rennin -angiotensin -aldosterone system genes on blood pressure response to a thiazide diuretic. Pharmacogenomics J. 2004; 4 (1): 17-23.
31. Shihara N, Yasuda K, Moritani T, et al. The association between Trp64Arg polymorphism of the beta 3-adrenergic receptor and autonomic nervous system activity. J Clin Endocrinol Metab. 1999; 84: 1623-1627.
32. Nelson WJ , Hammerton RW. A membrane-cytoskeletal complex containing Na+, K+-ATPase, ankyrin, and fodrin in Madin-Darby canine kidney (MDCK) cells: implications for the biogenesis of epithelial cell polarity. J Cell Biol. 1989; 108 (3): 893-902.
33. Glorioso N, Manunta P, Filigheddu F, et al. The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study. Hypertension. 1999; 34: 649-654.
34. Turner ST, Chapman AB, Schwartz GL, Boerwinkle E. Effects of endothelial nitric oxide synthase, alpha-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide. Am J Hypertens. 2003; 16 (10):834-839.
35. Davis BR, Arnett DK, Boerwinkle E, et al. Antihypertensive therapy, the alpha-adducin polymorphism, and cardiovascular disease in high-risk hypertensive persons: the Genetics of Hypertension-Associated Treatment Study. Pharmacogenomics J. 2007; 7 (2): 112-122.
36. Psaty BM, Smith NL, Heckbert SR, et al. Diuretic therapy, the alpha-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA. 2002; 287 (13): 1680-1689.
37. SiffertW, Naber C, Walla M, RitzE. G protein b3 subunit 825T allele and its potential association with obesity in hypertensive individuals. J Hypertens. 1999; 17: 1095-1098.
38. Schunkert H, Hense H, Doring A, Riegger G, Siffert W. Association between a polymorphism in the G protein b3-subunit gene and lower renin and elevated diastolic blood pressure levels. Hypertension. 1998. 32: 510-513.
39. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic. Hypertension. 2001; 37 (2 Part 2): 739-743.
40. Lynch AI, Boerwinkle E, Davis BR, et al. Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension. JAMA. 2008; 299 (3): 296-307.
