TY - JOUR
T1 - 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
AU - Brugts, Jasper J.
AU - Isaacs, Aaron
AU - De Maat, Moniek P.M.
AU - Boersma, Eric
AU - Van Duijn, Cock M.
AU - Akkerhuis, K. Martijn
AU - Uitterlinden, Andre G.
AU - Witteman, Jacqueline C.M.
AU - Cambien, Francois
AU - Ceconi, Claudio
AU - Remme, Willem
AU - Bertrand, Michel
AU - Ninomiya, Toshiharu
AU - Harrap, Stephen
AU - Chalmers, John
AU - MacMahon, Stephen
AU - Fox, Kim
AU - Ferrari, Roberto
AU - Simoons, Maarten L.
AU - Danser, A. H.Jan
PY - 2011/3
Y1 - 2011/3
N2 - 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 10/4 mmHg. 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.
AB - 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 10/4 mmHg. 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.
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U2 - 10.1097/HJH.0b013e328341d117
DO - 10.1097/HJH.0b013e328341d117
M3 - Article
C2 - 21157371
AN - SCOPUS:79951673075
VL - 29
SP - 509
EP - 519
JO - Journal of Hypertension
JF - Journal of Hypertension
SN - 0263-6352
IS - 3
ER -