A pharmacogenetic analysis of determinants of hypertension and blood pressure response to angiotensin-converting enzyme inhibitor therapy in patients with vascular disease and healthy individuals

被引：42

作者：

Brugts, Jasper J. ^{[1
]}

Isaacs, Aaron ^{[2
]}

de Maat, Moniek P. M. ^{[3
]}

Boersma, Eric ^{[1
]}

van Duijn, Cock M. ^{[2
]}

Akkerhuis, K. Martijn ^{[1
]}

Uitterlinden, Andre G. ^{[4
,5
]}

Witteman, Jacqueline C. M. ^{[5
]}

Cambien, Francois ^{[6
]}

Ceconi, Claudio ^{[7
,8
]}

Remme, Willem ^{[9
]}

Bertrand, Michel ^{[10
]}

Ninomiya, Toshiharu ^{[11
,12
]}

Harrap, Stephen ^{[13
]}

Chalmers, John ^{[11
,12
]}

MacMahon, Stephen ^{[11
,12
]}

Fox, Kim ^{[14
]}

Ferrari, Roberto ^{[7
,8
]}

Simoons, Maarten L. ^{[1
]}

Danser, A. H. Jan ^{[4
]}

机构：

[1] Erasmus MC, Dept Cardiol, Rotterdam, Netherlands

[2] Erasmus MC, Dept Genet Epidemiol, Rotterdam, Netherlands

[3] Erasmus MC, Dept Haematol, Rotterdam, Netherlands

[4] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[5] Erasmus MC, Dept Epidemiol & Biostat, Rotterdam, Netherlands

[6] INSERM, Paris, France

[7] Univ Ferrara, I-44100 Ferrara, Italy

[8] IRCCS, Salvatore Maugeri Fdn, Ferrara, Italy

[9] STICARES Cardiovasc Res, Rhoon, Netherlands

[10] Lille Heart Inst, Lille, France

[11] Univ Sydney, George Inst, Sydney, NSW 2006, Australia

[12] Royal Prince Alfred Hosp, Sydney, NSW, Australia

[13] Univ Melbourne, Melbourne, Vic, Australia

[14] Royal Brompton & Natl Heart Inst, London, England

来源：

JOURNAL OF HYPERTENSION | 2011年 / 29卷 / 03期

关键词：

ACE inhibitors; gene; hypertension; PERGENE; pharmacogenetics; polymorphism; PROGRESS; renin-angiotensin-aldosterone system; (PRO)RENIN RECEPTOR; GENE POLYMORPHISM; PLASMA-RENIN; ASSOCIATION; ALISKIREN; PRORENIN; PERINDOPRIL; EUROPA; DESIGN; HEART;

D O I：

10.1097/HJH.0b013e328341d117

中图分类号：

R6 [外科学];

学科分类号：

1002 ; 100210 ;

摘要：

Aims To investigate whether genetic variation in the renin-angiotensin-aldosterone system (RAAS) and kallikrein-bradykinin pathways is related to hypertension and blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitor therapy in stable coronary artery disease (CAD) patients. Methods and results In 8907 stable CAD patients from the EUROPA trial, 52 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 12 candidate genes within the RAAS and kallikrein-bradykinin pathways were investigated for association with hypertension (defined as BP >= 160/95 mmHg or use of antihypertensives) and BP response to ACE inhibitors, during a 4-week run-in period. All analyses were adjusted for age, sex, body mass index and creatinine clearance and corrected for multiple testing. Results Hypertension was present in 28.3% of the patients (n = 2526); median BP reduction after perindopril was 10/4mmHg. Four polymorphisms, located in the ACE (rs4291), angiotensinogen (rs5049) and (pro) renin receptor (rs2968915; rs5981008) genes were significantly associated with hypertension in two vascular disease populations of CAD (EUROPA) and cerebrovascular disease (PROGRESS; n = 3571). A cumulative profile demonstrated a stepwise increase in the prevalence of hypertension, mounting to a 2-3-fold increase (P for trend < 0.001). Similar associations on hypertension were observed for angiotensinogen in a healthy population (n = 2197). In addition, genetic polymorphisms were identified that significantly modified the BP reduction by ACE inhibitor therapy; however, the observed BP differences were small and did not remain significant after permutation analysis. Conclusion This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals. J Hypertens 29:509-519 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

引用

页码：509 / 519

页数：11

共 40 条

[1] Homogeneous assay of rs4343, an ACE I/D proxy, and an analysis in the British Women's Heart and Health Study (BWHHS) [J].