OBJECTIVE: It has yet to be determined whether genotyping at the angiotensin-converting enzyme (ACE) locus is predictive of blood pressure response to an ACE inhibitor. METHODS:Participants from the African American Study of Kidney Disease and Hypertension trial randomized to theACE inhibitor ramipril (n = 347) were genotyped at three polymorphisms on ACE, just downstream from the ACE insertion/deletion polymorphism (Ins/Del): G12269A, C17888T, and G20037A. Time to reach target mean arterial pressure (</=107 mmHg) was analyzed by genotype and ACE haplotype using Kaplan-Meier survival curves and Cox proportional hazard models. RESULTS: Individuals with a homozygous genotype at G12269A responded significantly faster than those with a heterozygous genotype; the adjusted (average number of medications and baseline mean arterial pressure) hazard ratio (homozygous compared to heterozygous genotype) was 1.86 (95% confidence limits 1.32-3.23; P < 0.001 for G12269A genotype). The adjusted hazard ratio for participants with homozygous ACE haplotypes compared to those heterozygous ACE haplotypes was 1.40 (1.13-1.75; P = 0.003 for haplotype). The ACE genotype effects were specific for ACE inhibition (i.e., not seen among those randomized to a calcium channel blocker), and were independent of population stratification. CONCLUSIONS:African-Americans with a homozygous genotype at G12269A or homozygous ACE haplotypes responded to ramipril significantly faster than those with a heterozygous genotype or heterozygous haplotypes, suggesting that heterosis may be an important determinant of responsiveness to an ACE inhibitor. These associations may be a result of biological activity of this polymorphism, or of linkage disequilibrium with nearby variants such as the ACE Ins/Del, perhaps in the regulation of ACE splicing.
RCT Entities:
OBJECTIVE: It has yet to be determined whether genotyping at the angiotensin-converting enzyme (ACE) locus is predictive of blood pressure response to an ACE inhibitor. METHODS:Participants from the African American Study of Kidney Disease and Hypertension trial randomized to the ACE inhibitor ramipril (n = 347) were genotyped at three polymorphisms on ACE, just downstream from the ACE insertion/deletion polymorphism (Ins/Del): G12269A, C17888T, and G20037A. Time to reach target mean arterial pressure (</=107 mmHg) was analyzed by genotype and ACE haplotype using Kaplan-Meier survival curves and Cox proportional hazard models. RESULTS: Individuals with a homozygous genotype at G12269A responded significantly faster than those with a heterozygous genotype; the adjusted (average number of medications and baseline mean arterial pressure) hazard ratio (homozygous compared to heterozygous genotype) was 1.86 (95% confidence limits 1.32-3.23; P < 0.001 for G12269A genotype). The adjusted hazard ratio for participants with homozygous ACE haplotypes compared to those heterozygous ACE haplotypes was 1.40 (1.13-1.75; P = 0.003 for haplotype). The ACE genotype effects were specific for ACE inhibition (i.e., not seen among those randomized to a calcium channel blocker), and were independent of population stratification. CONCLUSIONS: African-Americans with a homozygous genotype at G12269A or homozygous ACE haplotypes responded to ramipril significantly faster than those with a heterozygous genotype or heterozygous haplotypes, suggesting that heterosis may be an important determinant of responsiveness to an ACE inhibitor. These associations may be a result of biological activity of this polymorphism, or of linkage disequilibrium with nearby variants such as the ACE Ins/Del, perhaps in the regulation of ACE splicing.
Authors: Donna K Arnett; Barry R Davis; Charles E Ford; Eric Boerwinkle; Cathie Leiendecker-Foster; Michael B Miller; Henry Black; John H Eckfeldt Journal: Circulation Date: 2005-06-20 Impact factor: 29.690
Authors: D R Berlowitz; A S Ash; E C Hickey; R H Friedman; M Glickman; B Kader; M A Moskowitz Journal: N Engl J Med Date: 1998-12-31 Impact factor: 91.245
Authors: Vibha Bhatnagar; Erin P Garcia; Daniel T O'Connor; Victoria H Brophy; John Alcaraz; Erin Richard; George L Bakris; John P Middleton; Keith C Norris; Jackson Wright; Leena Hiremath; Gabriel Contreras; Lawrence J Appel; Michael S Lipkowitz Journal: Am J Nephrol Date: 2009-11-12 Impact factor: 3.754
Authors: Jamison Chang; Jennie Z Ma; Qing Zeng; Sylvia Cechova; Adam Gantz; Caroline Nievergelt; Daniel O'Connor; Michael Lipkowitz; Thu H Le Journal: Am J Physiol Renal Physiol Date: 2012-12-05
Authors: Vibha Bhatnagar; Daniel T O'Connor; Victoria H Brophy; Nicholas J Schork; Erin Richard; Rany M Salem; Caroline M Nievergelt; George L Bakris; John P Middleton; Keith C Norris; Jackson Wright; Leena Hiremath; Gabriel Contreras; Lawrence J Appel; Michael S Lipkowitz Journal: Am J Hypertens Date: 2009-01-01 Impact factor: 2.689