Angiotensin-converting enzyme gene polymorphism predicts the time-course of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial

Vibha Bhatnagar, Daniel T. O'Connor, Nicholas J. Schork, Rany M. Salem, Caroline M. Nievergelt, Brinda K. Rana, Douglas W. Smith, George L. Bakris, John P. Middleton, Keith C. Norris, Jackson T. Wright, Deanna Cheek, Leena Hiremath, Gabriel Contreras, Lawrence J. Appel, Michael S. Lipkowitz

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2082-2092
Number of pages11
JournalJournal of hypertension
Volume25
Issue number10
DOIs
StatePublished - Oct 2007

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Keywords

  • Angiotensin-converting enzyme
  • Hypertension
  • Polymorphisms
  • Renal failure

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Bhatnagar, V., O'Connor, D. T., Schork, N. J., Salem, R. M., Nievergelt, C. M., Rana, B. K., Smith, D. W., Bakris, G. L., Middleton, J. P., Norris, K. C., Wright, J. T., Cheek, D., Hiremath, L., Contreras, G., Appel, L. J., & Lipkowitz, M. S. (2007). Angiotensin-converting enzyme gene polymorphism predicts the time-course of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial. Journal of hypertension, 25(10), 2082-2092. https://doi.org/10.1097/HJH.0b013e3282b9720e