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.Correspondence to Vibha Bhatnagar, MD, MPH, VA San Diego Healthcare System,

SNP Analysis, Genome Wide Association Studies and Pharmacogenetic implications of Acute Myocardial Infarction

“…[19] This SNP was associated with two other variants, rs4341, and rs4344 that influence drug therapy for Fluvastatin, Thiazides, Furosemide, Spironolactone, Pravastatin, and Ramipril respectively. [20][21] [22] These drugs, especially Fluvastatin, are prescribed for hypercholesterolemia and for prevention of cardiovascular diseases. [23] For the gene MIA3, with the sole SNP variant association of variants rs10495197 and rs17163303, it was found that each of the SNPs individually has the potential to influence the drug therapy for Vancomycin.…”

Cardiovascular pharmacogenetics

“…The pharmacogenetic value of the ACE alleles is that the outcomes of these HF treatments can be predicted according ACE genotype (McNamara et al, 2001;McNamara et al, 2004). It was suggested that blood pressure response to ACE inhibitors can be predicted according to the ACED/I genotype (Bhatnagar et al, 2007). However further studies showed that blood pressure response variability to ACE inhibitors is due to a complex polygenic effect of other RAAS polymorphisms, and are not only angiotensin gene related (Pilbrow et al, 2007;Su et al, 2007).…”

Hereditary Determinants of Human Hypertension

“…35 Molecular heterosis (more extreme phenotype for heterozygotes than either homozygote class, sometimes called "overdominance") was noted in a study of ACE locus polymorphisms on response to ACE inhibition in hypertension. 54 Detection of heterosis explicitly requires analysis of diploid genotype (rather than simply allele) effects on a trait. 55 To assess the genotype effect of the ACE locus on ACE inhibitor responsiveness, hypertensive patients in the African American Study of Kidney Disease and Hypertension trial (AASK) taking ACE inhibitor ramipril were genotyped at 3 intronic polymorphisms spanning the biologically active regions of the ACE locus.…”

“…60 As noted above under genetic complexity, black hypertensive patients with ACE homozygous genotypes at G12269A (or haplotypes) responded to ramipril significantly faster than those with a heterozygous genotype or haplotype. 54 …”