The impact of human CES1 genetic variation on enzyme activity assessed by ritalinic acid/methylphenidate ratios.

The present clinical trial investigated the impact of selected SNPs in CES1 on the metabolic activity of the enzyme. For this purpose, we used methylphenidate (MPH) as a pharmacological probe and the d-RA/d-MPH (metabolite/parent drug) ratios as a measure of enzymatic activity. This metabolic ratio (MR) was validated against the AUC ratios (AUC /AUC ).

Novel approach for CES1 genotyping: integrating single nucleotide variants and structural variation.

Aim: Development of a specific procedure for genotyping of CES1A1 (CES1) and CES1A2, a hybrid of CES1A1  and the pseudogene CES1P1.

Materials & Methods: The number of CES1A1 and CES1A2  copies and that of CES1P1  were determined using real-time PCR. Long range PCRs followed by secondary PCRs allowed sequencing of single nucleotide variants in CES1A1 and CES1A2.

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.

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.

Novel procedure with improved resolution and specificity for amplification and differentiation of variants of the gene encoding carboxylesterase 1.

Carboxylesterase 1 (CES1) is implicated in the metabolism of several commonly used drugs and other xenobiotics. The gene encoding this enzyme, CES1, is duplicated in some individuals. The original gene copy is called CES1A1.

The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects.

Aims: This study investigated the influence of CES1 variations, including the single nucleotide polymorphism (SNP) rs71647871 (G143E) and variation in copy number, on the pharmacokinetics of a single oral dose of 10 mg methylphenidate.

Methods: CES1 genotype was obtained from 200 healthy Danish Caucasian volunteers. Based on the genotype, 44 (19 males and 25 females) were invited to participate in an open, prospective trial involving six predefined genotypes: three groups with two, three and four CES1 copies, respectively; a group of carriers of the CES1 143E allele; a group of individuals homozygous for CES1A1c (CES1VAR); and a group having three CES1 copies, in which the duplication, CES1A2, had increased transcriptional activity.

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.

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.

Distribution of HLA-G extended haplotypes and one HLA-E polymorphism in a large-scale study of mother-child dyads with and without severe preeclampsia and eclampsia.

The etiological pathways and pathogenesis of preeclampsia have rendered difficult to disentangle. Accumulating evidence points toward a maladapted maternal immune system, which may involve aberrant placental expression of immunomodulatory human leukocyte antigen (HLA) class Ib molecules during pregnancy. Several studies have shown aberrant or reduced expression of HLA-G in the placenta and in maternal blood in cases of preeclampsia compared with controls.

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.

Potential role of the porcine superoxide dismutase 1 (SOD1) gene in pig reproduction.

In a recent study we confirmed that QTL regions on pig chromosomes 11, 13, and 15 are associated with reproduction traits in the pig. Within these regions the genetic variation was largest on chromosome 13. The QTL region on this chromosome was therefore studied further to identify genes known to contribute to litter size.

Investigation of candidate regions influencing litter size in Danish Landrace sows.

Selection for increased litter size has been one of the main objectives in Danish pig breeding since 1992. This selection has led to an average increase of 0.30 piglets/litter per year for Landrace and Yorkshire sows, resulting in an average litter size of 15.

A study of the occurrence of monochorionic and monozygotic twinning in the pig.

In humans as well as in most farm animals, monozygotic twins have been described. Nevertheless, only a few reports of twinning in the pig have been published. It has been suggested that monozygotic twins are formed during the first 14 days of pregnancy.

Porcine Parkin: molecular cloning of PARK2 cDNA, expression analysis, and identification of a splicing variant.

Parkin, encoded by the PARK2 gene, is an E3 ligase which functions as an integral component of the cytoplasmic ubiquitin/proteasomal protein degradation pathway. Mutations in the PARK2 gene, resulting in the loss of parkin function, leads to autosomal recessive juvenile Parkinsonism (AR-JP). This work reports the cloning and characterization of the porcine (Sus scrofa) PARK2 cDNA (SsPARK2) and splicing variants hereof.