Prognostic impact of carboxylesterase 1 gene variants in patients with congestive heart failure treated with angiotensin-converting enzyme inhibitors

OBJECTIVE: Most angiotensin-converting enzyme inhibitors (ACEIs) are prodrugs activated by carboxylesterase 1 (CES1). We investigated the prognostic importance of CES1 gene (CES1) copy number variation and the rs3815583 single-nucleotide polymorphism in CES1 among ACEI-treated patients with congestive heart failure (CHF). METHODS: Danish patients with chronic CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were categorized according to their CES1 variants and followed up for up to 10 years. Risk for cardiovascular death and all-cause death was modeled by Cox proportional hazard analyses. RESULTS: A total of 491 ACEI-treated patients were included in the analyses. After a mean follow-up of 5.5 years, we found no difference in the risk for cardiovascular death and all-cause death between patients having three [hazard ratios (HRs) 1.06 (95% confidence interval (CI) 0.77-1.45) and 1.16 (95% CI 0.88-1.52)] or four [HRs 0.88 (95% CI 0.39-2.01) and 1.37 (95% CI 0.74-2.54)] CES1 copies and those with two copies, respectively. Similarly, no difference in the risk for cardiovascular and all-cause death was found for patients heterozygous [HRs 0.91 (95% CI 0.70-1.19) and 0.88 (95% CI 0.69-1.12)] or homozygous [HRs 0.58 (95% CI 0.30-1.15) and 0.82 (95% CI 0.48-1.39)] for the rs3815583 minor allele versus patients homozygous for the major allele. The active promoter of CES1A2 and the rs71647871 single-nucleotide polymorphism minor allele were detected at very low frequencies. CONCLUSION: This study did not support the use of CES1 copy number variation or rs3815583 as a predictor of fatal outcomes in ACEI-treated patients with CHF.