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.

Fig. 1

Summary of African American Study of Kidney Disease and Hypertension Genomics Study. One thousand and ninety-four participants were recruited for the AASK Trial. Of these, 853 participated in the AASK Genomics Study, 347 of whom had adequate DNA and randomized to treatment with an angiotensin-converting enzyme inhibitor, ramipril.

Fig. 2

Angiotensin-converting enzyme (ACE) gene, and the polymorphisms evaluated in this study. Base pairs are numbered with respect to the translational start codon (ATG). Solid boxes represent exons (numbered 1–26), while joining diagonal lines are introns. The extensively studied ACE Ins/Del polymorphism is located in intron 16.

Fig. 3

Days to target mean arterial pressure (MAP) (≤107 mmHg) by ACE genotypes, randomized to usual MAP (≤107 mmHg). Kaplan–Meier curves by ACE polymorphism genotypes for those randomized to a usual MAP (≤107 mmHg) are shown here. Those with a homozygous genotype at G12699A or C17888A responded faster than those with a heterozygous genotype (P = 0.03 and 0.003, respectively). The day on which 25, 50 and 75% of participants reached target MAP is shown in tabular form beside the graph.

Fig. 4

Combined model: days to target mean arterial pressure (MAP) (≤107 mmHg) by ACE haplotypes, randomized to usual MAP (≤107 mmHg). Combined Kaplan–Meier curves, by ACE haplotypes (ACA, GTG or GCA), for those randomized to a usual MAP (≤107 mmHg) are shown here. Those with two copies of the same ACE haplotype (i.e. homozygous haplotypes) responded faster than those with one copy (i.e. heterozygous haplotypes; P = 0.01). The day on which 25, 50 and 75% of participants reached target MAP is shown in tabular form beside the graph.