摘要
原发性高血压是多因素疾病,它是冠心病、脑卒中、左室肥厚、急性心肌梗死等心血管疾病的独立危险因素。目前有研究表明,仅有50%的高血压患者能受益于抗高血压的治疗,不同个体对同一降压药物的反应性存在着明显差异,其影响因素很多,其中遗传因素可能与个体之间降压疗效的差异相关。筛选降压疗效相关基因的研究,对于临床中避免使用无效或低效的抗高血压药物,从而改善目前低控制率现状有重要的意义。
肾素血管紧张素系统(RAS)与激肽释放酶-激肽系统(KKS)是体内参与血压调节的两个重要系统。ACEI主要通过干预RAS及KKS而发挥其降压作用。RAS基因多态性与ACEI降压疗效研究较多,而KKS与ACEI降压疗效相关性研究尚未见报道。近年缓激肽β_2受体(BDKRB2)、内皮型一氧化氮合酶(eNOS)、G蛋白β_3亚单位(GNB3)在血压调节中的作用备受重视。本研究探讨我国汉族原发性高血压患者BDKRB2基因启动子区-58T/C多态性、eNOS基因第7外显子的G894T多态性、GNB3基因第10外显子C825T多态性分布及其与ACEI降压疗效的相关性。
研究对象与方法:本研究对象来源于国内多中心的临床试验,选择1-2级原发性高血压患者(诊断标准参照1999年中国高血压防治指南标准),经安慰剂治疗2周后,分别给予咪达普利5mg/日或贝那普利10mg/日。治疗3周后,如果坐位DBP≥90mmHg,则剂量加倍,继续治疗3周,第6周末观察降压疗效。采用聚合酶链反应(PCR)分
Essential hypertension is a kind of multiple genetic disease,which is the independent risk factors of coronary heart disease, stroke, left ventricular hypertrophy, acute myocardial infarction. Several studies showed only 50% of the patients benefit from antihypertensive drugs. Individuals may respond differently to the same antihypertensive medication. It has been suspected that interindividual variation on the efficacy may be influenced by genetic factors. It is an useful strategy to stduy candidate genes of antihypertensive drugs efficacy.
It is well known that bradykinin β_2 receptor,G protein β_3 subunit, endothelial nitric oxide synthase play the important role in blood pressure regulation.The aim of present study is to investigate the — 58T/C polymorphism of the bradykinin β_2 receptor gene (BDKRB2) , the G894T polymorphism of the endothelial nitric oxide synthase (eNOS) and the C825T polymorphism of G protein β_3 subunit in Chinese essential hypertensive patients and the relationship between genotype and antihypertensive response to ACE inhibitor.
引文
1. Donnelly R, Meredith PA, Elliott HL,et al. Kinetic-dynamic relations and individual responses to enalapril. Hypertens. 1990; 15:301-309
2. Sharma JN, Uma K, Noor AR et al. Blood pressure regulation by the kallinkrein-kinin system. Gen Pharmacol. 1996;27:55-63
3. Hess JF, Borkowski JA, Young GS, et al. Cloning and pharmacological characterization of a human bradykinin(BK-2)receptor. Biochem Biophys??Res Comm. 1992;184:260-268.
4.Braun A, Kammerer S, Maier E,et al. Polymorphisms in the gene for the human β_2-bradykinin receptor: New tools assessing a genetic risk for bradykinin-associated disease. Immunopharmacology. 1996; 33:32-35
5.Mukae S, Aoki S, Itoh S, et al. Promoter polymorphism of the β_2 bradykinin receptor gene is associated with essential hypertension. Jpn Circ J. 1999; 63: 759-762
6.Wang B, Dang AM, Liu GZ. Genetic variation in the promoter region of the β_2 bradykinin receptor gene is associated with essential hypertension in a Chinese Han population. Hypertension Res. 2001;24:299-302
7.Hallberg P, Lind L, Michaelsson K, et al. B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricular mass in response to antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial.J Hypertens. 2003;21(3):621-624
8.Mukae S, Aoki S, Itoh S, et al. β_2 bradykinin receptor gene polymorphism is associated with angiotensin-related cough. Hypertens.2000; 36:127-131
9.Regoli D, Barabe NE. Pharmocology of bradykinin and related kinins.Pharmacol Rev. 1980;32:1-46.10. Burch RM, Kyle DJ. Recent development in the understanding of bradykinin receptors. Life Sci. 1992;50:829-838
11. Katori M, Majima M.The renal kallikrein-kinin system: its role as a safety valve for excess sodium intake, and its attenuation as a possible etiologic factor in salt-sensitive hypertension.Crit Rev Clin Lab Sci. 2003;40(1):43-115.
12. Regoli D, Barabe NE, Drapeau G, et al. Kinin recepter subtypes. J Cardiovasc Pharmacol. 1990;15(6):30-38
13. Pesquero JB, Lindsey CJ,Zeh K, et al. Molecular structure and exppression of bradykinin B2 receptor gene. J Biol Chem. 1994;269:26920-26925
14. Ueda S, Meredith PA, Morton JJ et al. ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (Enalaprilat) in humans. Circulation. 1998; 98:2148-2153
15. Stavroulakis GA, Makris TK, Krespi PG, etal. Predicting response to chronic antihypertensive treatment with fosinopril: the role of angiotensin-coverting enzyme gene polymorphism. Cardiovas drugs and therapy. 2000;14:427-432
16. O'Toole L, Stewart M, Padfield P, et al. Effect of insertion/deletion polymorphism of the angiotensin-converting enzyme gene on response to angiotensin-converting enzyme inhibitors in patients with heart failure. J Cardiovasc pharmacol. 1998; 32:988-99417. Hingorani AD, Jia H, Stevens PA etal. Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition. J Hypertens. 1995; 13:1602-16091. Ignarro LJ. Biological action and properties of endothelium-derived??nitrix oxide formed and released from artery and vein. Circ Res.1989;65:1-21
2.Node K,Kitakaze M,Yoshikawa H,et al. Reduced plasma concentratrtions of nitrogen oxide in individuals with essential hypertension. Hypertens.1997;30(3 pt 1):405-408
3.Veldman BA,Spiering W,Doevendans PA, et al.The Glu298Asp polymorphism of the NOS3 gene as a determinant of the baseline production of nitric oxide. J Hypertens.2002;20:2023-2027
4. Hingorani AD.Endothelial nitric oxide synthase polymorphisms and hypertension.Curr Hypertens Rep. 2003;5(1): 19-25
5.Miyamoto Y, Saito Y,Kajiyama N, et al.Endothelial nitric oxide synthase gene is positively associated with essential hypertension.Hypertens. 1998;32:3-8
6.Shoji M,Tsutaya S, Saito R,et al. Positive association of endothelial nitric oxide synthase gene polymorphism with hypertension in northern Japan. Life Sci.2000;66(26):2557-2562
7.Chen W, Srinivasan SR,Elkasabany A, et al.Combined effects of endothelial nitric oxide synthase gene polymorphism (G894T)and insulin resistance status on blood pressure and familial risk of hypertension in young adults:the Bogalusa Heart Study. AM J Hypertens. 2001;14(10):1046-1052
8.Rossi GP,Taddei S,Virdis A,et al. The T-786C and Glu298Asp??polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol. 2003;41 (6):938-945
9. Kato N, Sugiyama T, Morita H, et al. Lack of evidence for association between the endothelial nitric oxide synthase gene and hypertension. Hypertens. 1999;33:933-936
10. Schneider MP, Erdmann J,Delles C,et al. Functional gene testing of the Glu 298Asp polymorphism of the endothelial nitric oxide synthase.J Hypertens.2000; 18:1767-1773
11. Huang PL, Huang Z, Mashimo H, et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995,377:239-242
12. Marsden PA, Heng HH, Scherer SW, et al. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem. 1993;268(23): 17478-17488
13. Nadaud S,Bonnardeaux A, Lathrop M, et al. Gene structure polymorphism and mapping of the human endothelial nitric oxide synthase gene. Biochem Biophys Res Commun. 1994; 198(3): 1027-1033
14. Tanus-Santos JE, Desai M, Flockhart DA. Effects of ethnicity on the destribution of clinically relevant endothelial nitric oxide variants.Pharmacogenetics. 2001; 11 (8):719-725
15. Association analysis of endothelial nitric oxide synthase gene polymorphism in essential hypertension. AM J Hypertens.2000;13(9):??994-998
16.Lacolley P,Gautier S,Poierir O, et al.Nitric oxide synthase gene polymorphisms,blood pressure and aoticstiffness in normotensive and hypertensive subjects. J Hypertens. 1998; 16:31-35
17.Hingorani AD, Liang CF, Fatibene J, et al. A common variant of the endothelial nitric oxide synthase is a major risk factor for coronary artery disease in thr UK.Circulation. 1999; 100:1515-1520
18.Philip I,Plantefeve G, Vuillaumier BS,et al.G894T polymorphism in the endothelial nitric oxide synthase is associated with an enhanced vascular responsiveness to phenylephrine.Circulation.l999;99:3096-3098
19.Yoshimura M, Yasue H , Nakayama M, et al. A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese. Hum Genet. 1998; 103:65-69
20.Jachymova M, Horky K, Bultas J, et al. Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase with essential hypertension resistant to conventional therapy. Biochem Biophys Res Commun.2001 ;284:426-4301. Siffert W. Enhanced G protein activation in immortantalized lymphoblasts from patients with essential hypertension. J Clin Invest. 1995;96:759-766
2. Pitruck F. Selectively enhanced cellular signaling by G_i protein in essential hypertension. Circ Res. 1996;79:974-9833.Siffert W. Protein and hypertension :an alternative candidate gene approach. Kidney Int. 1998; 53(6): 1466-1470
4.Siffert W, Rosskopf D, Siffert G, et al. Association of a human G-protein β_3 subunit variant with hypertension. Nat Genet .1998;18:45-48
5.Beige J, Hohenbleicher H , Distler A, et al. G-protein beta 3 subunit C835T variant and ambulatory blood pressure in essential hypertension.Hypertens. 1999;33(4): 1049-1051
6.Benjafiels AV, Jeyasingam CL, Nyholt DR, et al. G protein beta 3 subunit gene(GNB3) variant in causation of essential hypertension. Hypertens. 1998; 32(6): 1094-1097
7.Hegele RA, Harris SB, Hanley AJ, et al. G protein beta 3 subunit gene variant and blood pressure variation in Canadian Ojicree. Hypertens. 1998;32(4):688-692
8.Sartori M, Semplicini A, Siffert W, et al.G-protein beta3-subunit gene 825T allele and hypertension: a longitudinal study in young grade I hypertensives.Hypertens. 2003;42(5):909-914
9.Turner ST, Schwartz GL, Chapman AB, et al. C825T polymorphism of the G protein beta 3 subunit and antihypertensive response to a thiazide diuretic.Hypertens.2001;37(2Part 2):739-743
10.Kato N, Sugiyama T, Morita H, et al. G protein beta 3 subunit gene variant and essential hypertension in Japanese. Hypertens. 1998,32(5):935-93811.Brand E, Herrmann SM, Nicaud V, et al. The 825T polymorphism of the G- protein beta3 subunit is not related to hypertension.Hypertens. 1999;33(5): 1175-1178
12.Buchmayer H,Sunder-Plassmann G,Hirschl MM, et al. G-protein beta3 subunit gene (GNB3) polymorphism 825C →T in patients with hypertensive crisis. Crit Care Med. 2000;28(9):3203-3206
13.Huang X, Ju Z, Song Y, et al. Lack of association between the G protein beta(3) subunit gene and essential hypertension in Chinese: a case-control and a family-based study. J Mol Med. 2003; 81(11): 729-735
14. Tsai CH, Yeh HI, Chou Y, et al. G-protein beta3 subunit variant and essential hypertension in Taiwan case-control study. Int J Cardiol.2000;73(2): 191-195
15.Donnelly R, Meredith PA, Elliott HL,et al. Kinetic-dynamic relations and individual responses to enalapril. Hypertens. 1990;15:301-309
16.Ueda S, Meredith PA, Morton JJ et al. ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (Enalaprilat) in humans. Circulation. 1998; 98:2148-2153
17.Stavroulakis GA, Makris TK, Krespi PG etal. Predicting response to chronic antihypertensive treatment with fosinopril: the role of angiotensin-coverting enzyme gene polymorphism. Cardiovas drugs and therapy.2000; 14:427-432
18.O'Toole L, Stewart M, Padfield P, et al. Effect of insertion/deletion??polymorphism of the. angiotensin-converting enzyme gene on response to angiotensin-converting enzyme inhibitors in patients with heart failure. J Cardiovasc pharmacol. 1998;32:988-994
19. Hingorani AD, Jia H, Stevens PA etal. Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition. J Hypertens. 1995; 13:1602-16091. Sharma JN, Uma K, Noor AR, et al. Blood pressure regulation by the kallinkrein-kinin system. Gen Pharmacol. 1996; 27:55-63
2. Hall JM. bradykinin receptors. Gen Pharmacol. 1997;28:1-6.
3. Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins,Kallikreins,Kininogens and kininase. Pharmacol Rev. 1992;44:1-80
4. Sharma JN,Sharma J.Cardiovascular properties of the kallirein-kinin system.Current Medical Research and Opinion.2002; 18(1): 10-17
5. Regoli D, Barabe J. Pharmocology of bradykinin and related kinins. Pharmacol Rev. 1980; 32:1-46
6. Burch RM, Kyle DJ. Recent development in the understanding of bradykinin receptors. Life Sci. 1992;50:829-838
7. Regoli D, Barabe NE, Drapeau G, et al. Kinin recepter subtypes. J Cardiovasc Pharmacol. 1990; 15(6):30-38
8. Pesquero JB, Lindsey CJ,Zeh K, et al. Molecular structure and exppression of bradykinin B2 receptor gene. J Biol Chem. 1994;269:26920-26925
9. Genomic M Yousef, Akbert Chang, Andreas Scorilas, et al. Genomic organization of the haman kallikrein gene family on chromosome 19q13.3-13.4. Bioch and Bio Res Comm. 2000;276:125-133
10. Berge KE, Bakken A, Bohn Met al. Analyses of mutation in the human renal kallikrein(HKLK1) gene and their possible relevance to??blood pressure regulation and risk of myocardial infarction.Clin Genet. 1997; 52:86-95
11. Wang J, Xiong W, Yang Z, et al. Human tissue kallikrein induces hypertension in transgenic mice.Hypertens. 1994;23:236-243
12. Slim R, Torremocha F, Moreau T, et al. Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. J Am Soc Nephrol. 2002; 13(4):968-976
13. Yu H, Song Q, Freedman BI, et al. Association of the tissue kallikrein gene promoter with ESRD and hypertension. Kidney Int. 2002;61(3): 1030-1039
14. Braun A, Kammerer S,Bohme E, et al. Identification of polymorphic sites of the human bradykinin β_2 receptor gene.Biochem Biophys Res Comm. 1995;211:234-240
15. Kammerer S, Braun A, Arnold N, et al. The human bradykinin β_2 receptor: full length Cdna, genomic organization and identification of the regulatory region. Biochem Biophys Res Comm. 1995;211:226-233
16. Braun A, Kammerer S, Maier E, et al. Polymorphisms in the gene for the human β_2-bradykinin receptor: New tools assessing a genetic risk for bradykinin-associated disease. Immunopharmacology. 1996; 33:32-35
17. Braun A, Maier S, Kammerer B, et al.A novel sequence polymophism in the promoter region of the human β_2-bradykinin receptor gene. Human Genet. 1996; 97:688-689.18. Mukae S, Aoki S, Itoh S, et al. Promoter polymorphism of the β_2 bradykinin receptor gene is associated with essential hypertension. Jpn Circ J.1999; 63:759-762
19. Linz W, Wiemer G, Gohlke P, et al. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev. 1995; 47:25-49
20. Mukae S, Aoki S, Itoh S, et al. β_2 bradykinin receptor gene polymorphism is associated with angiotensin-related cough. Hypertens. 2000; 36:127-131
21. Maltals I,Bachvarova M, Maheux P, et al.Bradykinin B2 receptor gene polymorphism is associated with altered urinary albumin/creatinine values in diabetes patients. Can J Physiol Pharmacol. 2002;80(4):323-327
22. Emanueli C, Salis MB, Pinna A, et al. Prevention of diabetes-induced microangiopathy by human tissue kallikrein gene transfer. Circulation. 2002; 106(8):993-999
23.姚合斌,潘长玉,陆思珍,等。激肽系统在实验性糖尿病肾病发展中的作用研究。中国糖尿病杂志,2000,8(6):356-3591.Eschenhagen T. G proteins and the heart. Cell Biol Int. 1993; 17:723-749
2.Asano M, Masuzawa K, Matsuda T, et al. Reduced function of the stimulatory GTP-binding protein in beta adrenoceptor adenylate cyclase system of femoral arteries isolated from spontaneously hypertensive rats. J Pharmacol Exp Ther. 1998;246:709-718
3.Jia H, Hingorani AD, Sharma p, et al. Association of the G_(S) alpha gene with essential hypertension and response to beta-blockade. Hypertens.1999;34(1):8-14
4.Siffert W. Enhanced G protein activation in immortantalized lymphoblasts from patients with essential hypertension. J Clin Invest. 1995;96:759-766
5.Pitruck F. Selectively enhanced cellular signaling by G_i protein in essential hypertension. Circ Res. 1996;79:974-983
6.Siffert W. Protein and hypertension:an alternative candidate gene approach. Kidney Int. 1998; 53(6): 1466-1470
7.Siffert W, Rosskopf D, Siffert G, et al. Association of a human G-protein β_3 subunit variant with hypertension. Nat Genet. 1998; 18:45-48
8.Beige J, Hohenbleicher H, Distler A, et al. G-protein beta 3 subunit C835T variant and ambulatory blood pressure in essential hypertension. Hypertens. 1999; 33(4): 1049-1051
9.Sartori M, Semplicini A, Siffert W, et al. G-protein beta3-subunit gene??825T allele and hypertension: a longitudinal study in young grade I hypertensives. Hypertens. 2003; 42(5):909-914
10.Benjafiels AV, Jeyasingam CL, Nyholt DR, et al. G protein beta 3 subunit gene(GNB3) variant in causation of essential hypertension. Hypertens. 1998; 32(6): 1094-1097
11.Hegele RA, Harris SB, Hanley AJ, et al. G protein beta 3 subunit gene variant and blood pressure variation in Canadian Ojicree. Hypertens.1998; 32(4):688-692
12.Kato N, Sugiyama T, Morita H, et al. G protein beta 3 subunit gene variant and essential hypertension in Japanese.Hypertens. 1998;32(5):935-938
13.Brand E, Herrmann SM, Nicaud V, et al. The 825T polymorphism of the G- protein beta3 subunit is not related to hypertension. Hypertens. 1999;33(5):1175-1178
14.Tsai CH, Yeh HI, Chou Y, et al. G-protein beta3 subunit variant and essential hypertension in Taiwan case-control study. Int J Cardiol.2000;73(2):191-195
15.Huang X, Ju Z, Song Y, et al. Lack of association between the G protein beta(3) subunit gene and essential hypertension in Chinese: a case-control and a family-based study. J Mol Med. 2003; 81(11): 729-735
16. Wang H, Sun N, Gao Y, et al. G protein beta 3 subunit C825T polymorphism and essential hypertension in Chinese. Beijing Da Xue??Xue Bao. 2003; 35(4):423-425
17.Tumer ST, Schwartz GL, Chapman AB, et al. C825T polymorphism of the G protein beta 3 subunit and antihypertensive response to a thiazide diuretic.Hypertens.2001 ;37(2Part 2):739-743
18.Cardiovascular pharmacogenetics: on the way toward individually tailored drug therapy. Kidney Int Suppl. 2003;(84): S168-171
19.Poch E, Gonzalez D,Gome-Angelats E, et al.G-protein beta3 subunit gene variant and left ventricular hypertrophy in essential hypertension.Hypertens. 2000; 35(1 Pt 2):214-218
20.Siffert W, Forster P, Jockel KH, et al. Worldwide ethnic distribution of the G protein beta 3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. J Am Soc Nephrol.1999;10:1921-1930
21.Ryden M, Faulds G, Hoffstedt J, et al. Effect of the (C825T) G beta(3) polymorphism on adrenoceptor-mediated lipolysis in human fat cells. Diabetes. 2002;51:1601-1608
22.Siffert W. G-protein beta3 subunit 825T allele and hypertension. Curr Hypertens Rep. 2003; 5(1):47-531. Dongfeng G; Kristi R; Xigui W, et al. Prevalence, Awareness, Treatment and Control of Hypertension in China. Hypertens. 2002;40:920-930.
2. Motulsky A. Drug reaction, enzymes and biochemical genetics. J Am Med Assoc. 1957; 165:835-837
3. Donnelly R, Meredith PA, Elliott HL, et al. Kinetic-dynamic relations and individual responses to enalapril. Hypertens.1990; 15:301-309
4. Collins E Shattuck lecture-medical and societal consequences of the human genome project. N Engl J Med. 1999; 341:28-37
5. Collins F, Guyer M, Chakravarti A. Variations on a theme:cataloging human DNA sequence variation.Science. 1997; 278:1580-1581
6. Ueda S, Meredith PA, Morton JJ, et al. ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (Enalaprilat) in humans. Circulation. 1998;98:2148-2153
7. Stavroulakis GA, Makris TK, Krespi PG, et al. Predicting response to??chronic antihypertensive treatment with fosinopril: the role of angiotensin-coverting enzyme gene polymorphism. Cardiovas drugs and therapy. 2000; 14:427-432
8. O'Toole L, Stewart M, Padfield P, et al. Effect of insertion/deletion polymorphism of the angiotensin-converting enzyme gene on response to angiotensin-converting enzyme inhibitors in patients with heart failure. J Cardiovasc pharmacol. 1998; 32:988-994
9. Hingorani AD, Jia H, Stevens PA, et al. Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition. J Hypertens. 1995; 13:1602-1609
10. Kurland L, Melhus H, Karlsson J, et al. Aldosterone synthase (CYP11B2)-344C/T polymorphism is related to antihypertensive response: result from the Swedish Irbesartan Left ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. Am J Hypertens. 2002; 15(5):389-393
11. Vormfelde SV, Burckhardt G, Zirk A,et al.Pharmacogenomics of diuretic drugs: data on rare monogenic disorders and on polymorphisms and requirements for further research. Pharmacogenomics. 2003;4(6):701-34
12. Ferrari P, Bianchi G. Genetic mapping and tailored antihyertensive therapy. Cardiovascular Drugs and Therapy.2000; 14:387-395
13. Sciarrone MT, Stella P, Barlassina C, et al. ACE and alpha-adducin??polymorphism as markers of individual response to diuretic therapy. Hypertens. 2003 ;41(3):398-403
14.Turner ST, Schwartz GL, Chapman AB, et al. C825T polymorphism of the G protein beta 3 subunit and antihypertensive response to a thiazide diuretic.Hypertens.2001 ;37(2Part 2):739-743
15.Jia H, Hingorani AD, Sharma p, et al. Association of the G_(S) alpha gene with essential hypertension and response to beta-blockade.Hypertens. 1999;34(1):8-14
16.Mukae S, Aoki S, Itoh S, et al. β_2 bradykinin receptor gene polymorphism is associated with angiotensin-related cough. Hypertens.2000; 36:127-131
17.Mukae S, Itoh S, Aoki S, et al. Association of polymorphisms of the renin-angiotensin system and bradykinin B2 receptor with ACE-inhibitor-related cough. J Hum Hypertens. 2002; 16(12):857-863.