Renin gene polymorphisms and haplotypes, blood pressure, and responses to renin-angiotensin system inhibition.
Renin catalyzes the rate-limiting step of the renin-angiotensin system. A T allele variant at position -5312 within a distal enhancer region has been reported to increase in vitro renin gene transcription. Among 387 White bank employees, ambulatory blood pressures were higher in 133 -5312T allele carriers than in 254 CC homozygotes-mean differences [99% confidence interval] between carriers and homozygotes for daytime and night-time systolic/diastolic pressure were 2.5[0.4,4.6]/1.7[0.2,3.2] and 2.4[0.5,4.4]/1.5[0.1,2.9] respectively. Ambulatory pressure estimates for the only common renin haplotype including the -5312T variant (-5312T, 5090C, 5912A, 9479A, 10194G), were statistically significantly higher than estimates for all other haplotypes. Among 259 White hypertensive participants in a randomized double-blind clinical trial comparing a renin antagonist, aliskiren, with an angiotensin receptor blocker, losartan, plasma renin activity did not differ with renin -5312C/T genotype. Nocturnal blood pressure reductions with losartan 100 mg daily were significantly greater in -5312T allele carriers than in CC homozygotes (mean[standard error]; -12.9[3.7]/-7.9[2.4] versus -7.1[2.5]/-4.2[1.6]) whereas with aliskiren 150 and 300 mg daily, lesser reductions were observed in -5312T allele carriers than in CC homozygotes (-5.4[2.0]/-4.1[1.3] versus -10.1[1.4]/-6.5[1.1]; P<0.03 for treatmentxgenotype interaction for night-time systolic and diastolic pressures). Hence, the -5312 renin C/T enhancer polymorphism does contribute to blood pressure variation in Whites and also appears to predict responses to inhibition of the renin-angiotensin system. These findings suggest that genotyping at this locus may aid in the identification of susceptibility to hypertension and in the selection of optimal therapy for individual hypertensive patients.
Moore
Niamh
N
Molecular and Cellular Therapeutics, RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Dicker
Patrick
P
O'Brien
John K
JK
Stojanovic
Milos
M
Conroy
Ronán M
RM
Treumann
Achim
A
O'Brien
Eoin T
ET
Fitzgerald
Desmond
D
Shields
Denis
D
Stanton
Alice V
AV
D000328:Adult; D000368:Aged; D000577:Amides / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D018660:Blood Pressure Monitoring, Ambulatory; D016009:Chi-Square Distribution; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005650:Fumarates / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D016014:Linear Models; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; C446481:aliskiren; D012083:Renin; D019808:Losartan