Ditte Bjerre

Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics

CES1 is involved in the hydrolysis of ester group-containing xenobiotic and endobiotic compounds including several essential and commonly used drugs. The individual variation in the efficacy and tolerability of many drugs metabolized by CES1 is considerable. Hence, there is a large interest in individualizing the treatment with these drugs. The present review addresses the issue of individualized treatment with drugs metabolized by CES1. It describes the composition of the gene encoding CES1, reports variants of this gene with focus upon those with a potential effect on drug metabolism and provides an overview of the protein structure of this enzyme bringing notice to mechanisms involved in the regulation of enzyme activity. Subsequently, the review highlights drugs metabolized by CES1 and argues that individual differences in the pharmacokinetics of these drugs play an important role in determining drug response and tolerability suggesting prospects for individualized drug therapies. Our review also discusses endogenous substrates of CES1 and assesses the potential of using metabolomic profiling of blood to identify proxies for the hepatic activity of CES1 that predict the rate of drug metabolism. Finally, the combination of genetics and metabolomics to obtain an accurate prediction of the individual response to CES1-dependent drugs is discussed.

Linkage and whole genome sequencing identify a locus on 6q25–26 for formal thought disorder and implicate MEF2A regulation

Formal thought disorder is a major feature of schizophrenia and other psychotic disorders. It is heritable, found in healthy relatives of patients with schizophrenia and other mental disorders but knowledge of specific genetic factors is lacking. The aim of this study was to search for biologically relevant high-risk variants. Formal thought disorder was assessed in participants in the Copenhagen Schizophrenia Linkage Study (N=236), a unique high-risk family study comprised of six large pedigrees. Microsatellite linkage analysis of formal thought disorder was performed and subsequent haplotype analysis of the implicated region using phased microsatellite and SNP genotypes. Whole genome sequencing (N=3) was used in the attempt to identify causative variants in the linkage region. Linkage analysis of formal thought disorder resulted in a single peak at chromosome 6(q26-q27) centred on marker D6S1277, with a maximum LOD score of 4.0. Phasing and fine mapping of the linkage peak identified a 5.5Mb haplotype (chr6:162242322-167753547, hg18) in 31 individuals, all belonging to the same pedigree sharing the haplotype from a common ancestor. The haplotype segregated with increased total thought disorder index score (P=4.9 × 10(-5)) and qualitatively severe forms of thought disturbances. Whole genome sequencing identified a novel nucleotide deletion (chr6:164377205 AG>A, hg18) predicted to disrupt the potential binding of the transcription factor MEF2A. The MEF2A binding site is located between two genes previously reported to associate with schizophrenia, QKI (HGNC:21100) and PDE10A (HGNC:8772). The findings are consistent with MEF2A deregulation conferring risk of formal thought disorder.

Nomenclature for alleles of the human carboxylesterase 1 gene

General information State: Published Organisations: Department of Bio and Health Informatics, Integrative Systems Biology, Department of Biotechnology and Biomedicine Authors: Rasmussen, H. B. (Ekstern), Madsen, M. B. (Ekstern), Bjerre, D. (Ekstern), Ferrero, L. (Ekstern), Linnet, K. (Ekstern), Thomsen, R. (Ekstern), Jorgens, G. (Ekstern), Dalhoff, K. (Ekstern), Stage, C. (Ekstern), Stefansson, H. (Ekstern), Hankemeier, T. (Ekstern), Kaddurah-Daouk, R. (Ekstern), Brunak, S. (Intern), Taboureau, O. (Intern), Nzabonimpa, G. S. (Intern), Jeppesen, P. (Ekstern), Kaalund-Jørgensen, K. (Ekstern), Kristensen, K. E. (Ekstern), Pagsberg, A. K. (Ekstern), Plessen, K. J. (Ekstern), Hansen, P. E. (Ekstern), Werge, T. (Ekstern), Dyrborg, J. (Ekstern), Lauritzen, M. B. (Ekstern), Hughes, T. (Ekstern) Number of pages: 3 Pages: 78-80 Publication date: 2017 Main Research Area: Technical/natural sciences

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers

This study investigated the influence of variations in the carboxylesterase 1 gene (CES1) on the pharmacokinetics of enalapril. Forty‐three healthy, Danish, Caucasian volunteers representing different pre‐defined genotypes each received 10 mg of enalapril. At specified time‐points, plasma concentrations of enalapril and the active metabolite enalaprilat were measured. The volunteers were divided into six different groups according to their genetic profile of CES1: group 1 (control group, n = 16) with two CES1 copies without non‐synonymous SNPs in the exons; group 2 (n = 5) with four copies of CES1; group 3 (n = 6) harbouring the G143E polymorphism; group 4 (n = 2) with three CES1 copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n = 4) harbouring the CES1A1c variant; and group 6 (n = 10) with three CES1 copies and the common promoter with low transcriptional activity of the duplication. The median AUC of enalaprilat in the control group was not significantly different from any of the other five groups (297 ng/ml x h in the control group versus 310, 282, 294, 344 and 306 ng/ml x h in groups 2–6, respectively). The terminal half‐life of enalaprilat was significantly longer in group 6 compared with the control group (26.7 hr versus 12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations of CES1 had a clinically relevant impact on the metabolism of enalapril.

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

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.

Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants

The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d‐MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two‐compartment disposition model with absorption transit compartments. Novel effects of rs115629050 and CES1 diplotypes, as well as previously reported effects of rs71647871 and body weight, were included in the final model. Assessment of the independent and combined effect of CES1 covariates identified several specific risk factors that may result in severely increased d‐MPH plasma exposure.

Comment on Xie et al.: The effects of CES1A2 A(-816)C and CYP2C19 loss-of-function polymorphisms on clopidogrel response variability among Chinese patients with coronary heart disease.

We read the recent publication by Xie et al. [1] with great interest. These investigators reported that platelet inhibition achieved with clopidogrel was associated with an A(− 816)C variation in the duplicated version of the carboxylesterase 1 gene (CES1), designated CES1A2. For genotyping of the A(− 816)C variation, a previously developed allele-specific PCR procedure, based on a wild-type forward primer, a mutational forward primer, and a common reverse primer, was used [2].

Reappraisal of the genetic diversity and pharmacogenetic assessment of CES1

The CES1 gene encodes a hydrolase that metabolizes important drugs. Variants generated by exchange of segments with CES1P1 complicate genotyping of CES1. Using a highly specific procedure we examined DNA samples from 200 Caucasians and identified 46 single nucleotide variants (SNVs) in CES1 and 21 SNVs in CES1A2, a hybrid composed of CES1 and CES1P1. Several of these SNVs were novel. The frequencies of SNVs with a potential functional impact were below 0.02 suggesting limited pharmacogenetic potential for CES1 genotyping. In silico PCR revealed that the majority of the primer pairs for amplification of CES1 or CES1A2 in three previous studies lacked specificity, which partially explains a limited overlap with our findings.