P-124: Study with carboxylesterase 1 gene variants in hypertensive patients - in relation to the responsiveness to angiotensin converting enzyme inhibitor

Abstract

Essential hypertension has a heritability as high as 30–50%, but its genetic causes have not been determined despite intensive investigations. Because the renin-angiotensin system (RAS) plays a central role in the control of blood pressure, many attentions regarding to the genetic variations of RAS have been attracted. In the most recent guideline (JNC 7) for the treatment of hypertension, angiotensin converting enzyme (ACE) inhibitor has been recommended as a compelling indication in the all of high-risk conditions. We investigated the genetic backgrounds that distinguish responder from non-responder for the ACE inhibitors with using analyses of single nucleotide polymorphism (SNPs) of RAS and ACE related genes.

In the 76 hypertensive patients, after the informed consent, imidapril (ACE inhibitor: 5–10mg/day orally) were given for 16 weeks and they were distinguished to responder (R: n=49) and non-responder (NR: n=27). The analyses of 265 SNPs, mainly RAS and ACE related genes, were performed using Taqman method.

SNP in the carboxylesterase 1 (CES1) gene promoter (-814 adenosine (A)/ cytosine (C) polymorphism) were attracted our attentions. The frequencies of the CC genotype and C allele of −814A/C were significantly higher in the R subjects than in the NR subjects (genotype; p=0.019, allele; p=0.007). These tendencies derived from male subjects (genotype; p=0.016, allele; p=0.001). On the other hand, there were no significant differences in these genetics frequencies between non-hypertensive and hypertensive subjects. Among the promoter assays using cell culture of CES1 gene, −814C was found to have a higher transcription rate than that −814A.

Imidapril is a pro-drug type of ACE inhibitor, which is metabolized to pharmacologically active metabolite, imidaprilat, by the carboxylesterase 1. Some of other ACE inhibitors, such as enalapril, are also pro-drugs and metabolized similarly to active forms by CES1. These findings suggest that the transcriptional activity of promoter might be involved in response to ACE inhibitors.

To clear a genetic variant of the carboxylesterase may allow to predict in advance the effects of a ACE inhibitor and most recommended choice of antihypertensive agent within some of first-line drugs in the order-made therapy for the hypertensive patients.

Am J Hypertens (2004) 17, 78A–78A; doi: 10.1016/j.amjhyper.2004.03.198

SNPs, ACE Inhibitor, Carboxylesterase1