title: Angiotensin-converting enzyme gene polymorphism predicts the time-course of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial.
abstract: 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: University of California San Diego, La Jolla, USA. vbhatnag@ucsd.edu
authors: Vibha
authors: V
authors: Bhatnagar
authors: Daniel T
authors: DT
authors: O'Connor
authors: Nicholas J
authors: NJ
authors: Schork
authors: Rany M
authors: RM
authors: Salem
authors: Caroline M
authors: CM
authors: Nievergelt
authors: Brinda K
authors: BK
authors: Rana
authors: Douglas W
authors: DW
authors: Smith
authors: George L
authors: GL
authors: Bakris
authors: John P
authors: JP
authors: Middleton
authors: Keith C
authors: KC
authors: Norris
authors: Jackson T
authors: JT
authors: Wright
authors: Deanna
authors: D
authors: Cheek
authors: Leena
authors: L
authors: Hiremath
authors: Gabriel
authors: G
authors: Contreras
authors: Lawrence J
authors: LJ
authors: Appel
authors: Michael S
authors: MS
authors: Lipkowitz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017257:Ramipril / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril