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

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 (<= 107mmHg) 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.