Pharmacodynamic Impact of Carboxylesterase 1 Gene Variants in Patients with Congestive Heart Failure Treated with Angiotensin-Converting Enzyme Inhibitors

Abstract

Background: Variation in the carboxylesterase 1 gene (CES1) may contribute to the efficacy of ACEIs. Accordingly, we examined the impact of CES1 variants on plasma angiotensin II (ATII)/angiotensin I (ATI) ratio in patients with congestive heart failure (CHF) that underwent ACEI dose titrations. Five of these variants have previously been associated with drug response or increased CES1 expression, i.e., CES1 copy number variation, the variant of the duplicated CES1 gene with high transcriptional activity, rs71647871, rs2244613, and rs3815583. Additionally, nine variants, representatives of CES1Var, and three other CES1 variants were examined.

Methods: Patients with CHF, and clinical indication for ACEIs were categorized according to their CES1 genotype. Differences in mean plasma ATII/ATI ratios between genotype groups after ACEI dose titration, expressed as the least square mean (LSM) with 95% confidence intervals (CIs), were assessed by analysis of variance.

Results: A total of 200 patients were recruited and 127 patients (63.5%) completed the study. The mean duration of the CHF drug dose titration was 6.2 (SD 3.6) months. After ACEI dose titration, there was no difference in mean plasma ATII/ATI ratios between subjects with the investigated CES1 variants, and only one previously unexplored variation (rs2302722) qualified for further assessment. In the fully adjusted analysis of effects of rs2302722 on plasma ATII/ATI ratios, the difference in mean ATII/ATI ratio between the GG genotype and the minor allele carriers (GT and TT) was not significant, with a relative difference in LSMs of 0.67 (95% CI 0.43-1.07; P = 0.10). Results of analyses that only included enalapril-treated patients remained non-significant after Bonferroni correction for multiple parallel comparisons (difference in LSM 0.60 [95% CI 0.37-0.98], P = 0.045).

Conclusion: These findings indicate that the included single variants of CES1 do not significantly influence plasma ATII/ATI ratios in CHF patients treated with ACEIs and are unlikely to be primary determinants of ACEI efficacy.

Fig 1. Plasma angiotensin I (ATI) concentration and plasma ATII/ATI ratio after angiotensin-converting enzyme inhibitor (ACEI) ingestion in patients with congestive heart failure after completion of dose titration.

Values are plotted against the time in hours from ACEI (enalapril, ramipril, or trandolapril) ingestion until blood sample collection. Δ: Plasma ATII/ATI ratio, □: Plasma ATI concentrations.

Fig 2. Linkage disequilibrium (LD) relationships between single nucleotide polymorphisms (SNPs) of CES1A1.

The top of the figure shows SNPs and the bottom of the figure shows LD relationships as well as LD blocks of highly coupled variants. The strength of LD was determined by R² statistics.

Fig 3. Distribution of the plasma angiotensin II (ATII)/ATI ratios (A) and logarithmic-transformed ATII/ATI ratios (B) according to CES1A1 rs2302722 genotypes.