Articles
Clinical Pharmacology & Therapeutics (2008); 85, 1, 36–44 doi:10.1038/clpt.2008.194
Promoter Polymorphisms in ACE (Angiotensin I–Converting Enzyme) Associated With Clinical Outcomes in Hypertension
AD Johnson1,2, Y Gong3,4, D Wang1, TY Langaee3,4, J Shin3,4, RM Cooper-DeHoff3,4,5, NJ Schork6, P Binkley7, CJ Pepine5, JA Johnson3,4,5 and W Sadee1,7
- 1Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, Ohio, USA
- 2The Framingham Heart Study, Framingham, Massachusetts, USA
- 3Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville, Florida, USA
- 4Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA
- 5Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
- 6Scripps Genomic Medicine, Scripps Health and The Scripps Research Institute, La Jolla, California, USA
- 7Division of Cardiovascular Medicine and the Dorothy Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA
Correspondence: W Sadee, (wolfgang.sadee@osumc.edu)
Received 16 May 2008; Accepted 21 August 2008; Published online 22 October 2008.
Abstract
Genetic variants of ACE are suspected risk factors in cardiovascular disease, but the alleles responsible for the variations remain unidentified. To search for regulatory polymorphisms, allelic angiotensin I–converting enzyme (ACE) mRNA expression was measured in 65 heart tissues, followed by genotype scanning of the ACE locus. Marked allelic expression imbalance (AEI) detected in five African-American subjects was associated with single-nucleotide polymorphisms (SNPs) (rs7213516, rs7214530, and rs4290) residing in conserved regions 2–3 kb upstream of ACE. Moreover, each of the SNPs affected transcription in reporter gene assays. SNPs rs4290 and rs7213516 were tested for associations with adverse cardiovascular outcomes in hypertensive patients with coronary disease (International Verapamil SR Trandolapril Study Genetic Substudy (INVEST-GENES), n = 1,032). Both SNPs were associated with adverse cardiovascular outcomes, largely attributable to nonfatal myocardial infarction in African Americans, showing an odds ratio of 6.16 (2.43–15.60) (P < 0.0001) for rs7213516. The high allele frequency in African Americans (16%) compared to Hispanics (4%) and Caucasians (<1%) suggests that these alleles contribute to variation between populations in cardiovascular risk and treatment outcomes.
