Pharmacogenetics and genomics最新文献

Background: Pharmacogenetic testing plays a key role in personalized pharmacotherapy and improving treatment outcomes; however, its benefit in clinical hyperpolypharmacy (≥ 10 chronic drugs) remains uncertain.

Objective: This study assessed the impact of extensive pharmacogenetic testing in hyperpolypharmacy patients. The primary outcome was the number of actionable drug-gene interactions (DGIs) per patient; secondary outcomes included clinical recommendations, clinician adherence, and DGIs with potential for severe adverse events.

Design: This intervention included 100 hyperpolypharmacy inpatients (≥ 10 drugs) from Maasstad Hospital internal ward and Antes psychiatry ward. Eligible patients (≥ 18 years) underwent a 14-gene pharmacogenetic panel test. A multidisciplinary team reviewed drug-gene interactions (DGIs), evaluated medical records, and implemented monitoring or medication adjustments as needed.

Results: An average of 4.7 (interquartile range: 4.0-5.5) actionable variants in the tested pharmacogenes per patient was identified, resulting in at least one DGI in 46% of the patients, with an average of 0.6 DGI per patient. After evaluation by the multidisciplinary team, 12 out of 64 DGIs (19%) led to recommendations for interventions, with an adherence rate of 67%. In 5% of patients, the identified DGI could potentially be associated with a higher risk of hospitalization or mortality.

Conclusion: Systematic pharmacogenetic panel testing in clinical hyperpolypharmacy patients identified at least one DGI in 46% of the patients. Of these DGIs, 19% led to a recommendation for intervention. This study demonstrates that pharmacogenetic panel testing holds the potential to optimize pharmacotherapy in clinical hyperpolypharmacy patients.

Background: Major depressive disorder (MDD) and bipolar disorder (BD) are common, disabling conditions. Despite associated morbidity and premature mortality, current treatments have modest efficacy and response to treatment highly variable. Contributing factors to variability in response include influence of common genetic variations in the pharmacokinetic and/or pharmacodynamic action of medications. As such, attention has turned toward the identification of genetic markers that could assist with determining who will respond or not to psychotropic treatment. Results of studies to date are promising but primarily have been small. This study aims to evaluate the efficacy of a pharmacogenetic (PGx)-based decision support tool among adults with MDD and BD.

Methods: This single-site, single (rater) blinded, randomized controlled trial with two arms evaluates the 24-week efficacy of a PGx-based support tool for adults with MDD or BD. Participants are randomized to receive PGx testing or standard prescribing. Participants provide DNA samples at baseline, but only those (including clinicians) randomized to the former receive the results at the start of their study participation. It is not mandatory for clinicians to follow the test recommendations. Remission rate (primary outcome), change in depression symptoms, drop-out rate, medication adherence, and medication side effects (secondary outcomes) are assessed at 4-, 8-, 12-, and 24-week postbaseline by a blinded rater. Analyses will follow an intention-to-treat approach and use mixed models for repeated measures.

Discussion: Treatment response to medication for severe mood disorders is highly variable and less than optimal. This trial will provide evidence as to whether a PGx-based support tool is an efficacious strategy to inform selection and dosing of pharmacotherapy among adults with severe mood disorders. Importantly, it will do so independently and with a larger sample size than previous studies.

Trial registration: This trial is registered under the number ACTRN12621001374853 (11 Oct 2021).

Objective: The pathogenic mechanisms of antituberculosis drug-induced liver injury (AT-DILI) remain unclear. Isoniazid and rifampicin may lead to hepatic accumulation of protoporphyrin IX in which heme synthesis ferrochelatase (FECH), a key rate-limiting enzyme, potentially plays an important role. This study aimed to investigate the combined effects of FECH gene polymorphisms and promoter methylation on AT-DILI risk in the Eastern Chinese population.

Methods: A 1 : 1 matched case-control study was conducted, detecting one CpG island in the FECH promoter and four single-nucleotide polymorphisms (SNPs). A multivariate conditional logistic regression was used to estimate the association between genotypes and the risk of AT-DILI by the odds ratios (OR) with 95% confidence intervals (CIs). Additive and multiplicative interactions between methylation status and SNPs were further analyzed: additive interactions via the relative excess risk due to interaction (RERI) with 95% CIs, and multiplicative interactions by incorporating methylation-SNP product terms into regression models.

Results: Overall, 182 cases and 182 controls were included. Neither FECH promoter methylation (adjusted OR: 0.978, 95% CI: 0.408-1.560, P = 0.509) nor the four SNPs showed individual associations with AT-DILI risk (P > 0.05). Crossover analyses revealed no significant genotype-methylation interactions (P > 0.05). Both additive (rs17063905 RERI: -0.556, P = 0.691) and multiplicative interaction models (rs17063905, OR: 0.723, P = 0.615) demonstrated no synergistic effects between methylation and polymorphisms.

Conclusion: This research finds no significant association between FECH promoter methylation status in the CpG island, polymorphisms, or their interactions and the risk of AT-DILI.

Background: Dehydroepiandrosterone (DHEA) is considered an endogenous steroid hormone precursor, and 17-ß estradiol (E2) is one of the estrogen steroid hormones. Of the 13 known human cytosolic sulfotransferases (SULTs), SULT2B1a has been shown to be expressed in steroid hormone-responsive tissues such as the prostate, ovary, and placenta, as well as the fetal brain. Previous studies have demonstrated that SULT2B1a is capable of sulfating 3β-hydroxysteroids such as DHEA and pregnenolone. The present study aimed to investigate the effects of human SULT2B1 single-nucleotide polymorphisms (SNPs) on the enzymatic characteristics of SULT2B1a allozymes in mediating the sulfation of DHEA and E2.

Methods: To inspect the effects of SNPs of the SULT2B1 gene on the sulfation of DHEA and E2 by SULT2B1a allozymes, 13 recombinant SULT2B1a allozymes were produced, expressed, and purified using established procedures. Thirteen SULT 2B1a nonsynonymous missense coding SNPs (cSNPs) were selected among numerous identified human SULT 2B1a SNPs by a comprehensive database search. The corresponding cDNAs, packaged in pGEX-2TK expression vector, and encoding the selected 13 SULT2B1a allozymes, have been generated by performing site-directed mutagenesis. These were then bacterially expressed in BL21 E. coli cells and purified using glutathione-Sepharose affinity chromatography. The purified allozymes were tested for their ability to sulfonate DHEA and E2.

Results: In terms of the kinetic parameters, the wild-type SULT2B1a exhibited higher enzyme affinity toward DHEA than with E2. In comparison with the wild-type SULT2B1a, the purified allozymes displayed differential sulfating activities toward DHEA and E2.

Conclusion: Accordingly, these findings indicate an apparent effect of SULT2B1 cSNPs on the sulfating activities of SULT2B1a allozymes toward DHEA and E2, and may provide for a better understanding of the pharmacokinetics of DHEA and E2 in individuals with differing SULT2B1a genotypes.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis, shaped by both environmental and genetic factors. While genome-wide association studies have identified several IPF risk loci, the genetic basis remains incomplete, especially in non-European populations.

Methods: We performed an exome-wide association study in 186 Korean IPF patients and 262 healthy controls using the Illumina HumanExome v1.1 BeadChip to discover novel exonic variants linked to IPF susceptibility. Logistic regression was used to test associations, adjusting for age, sex, and smoking history. Functional implications were evaluated through structural modeling and protein stability predictions.

Results: After quality control, 23 737 single-nucleotide polymorphisms (SNPs) were analyzed. The variant rs1047406 (T>C) in the PEBP4 gene was significantly associated with IPF under a codominant model (odds ratio = 1.94, 95% confidence interval = 1.42-2.65, P < 0.05 after correction). Haplotype analysis, including three nearby SNPs, further supported this association. In-silico analyses predicted that the E11G substitution caused by rs1047406 reduces protein stability and may disrupt proper folding. GTEx eQTL data showed that the minor allele is linked to altered PEBP4 expression in several tissues. PEBP4 is known to regulate phosphoinositide 3-kinase/protein kinase B and nuclear factor kappa B pathways, both implicated in fibrotic remodeling.

Conclusion: A novel PEBP4 variant associated with IPF was identified in a Korean population, likely affecting protein function and expression. These findings underscore the importance of ethnic-specific studies and support PEBP4 as a candidate gene in IPF, meriting further validation.

It is unknown how many people in the US have had pharmacogenetic (PGx) testing and whether people want to be tested. We conducted a nationally representative survey of the general US adult population to determine the prevalence of adults that have had PGx testing using a validated confidential online survey, the Non-Medical Use of Prescription Drugs Program. A weighted logistic regression was used to test health characteristics associated with PGx testing and determine those who desire to be tested. The analysis included 29 146 individuals who completed the survey, which represents approximately 260 000 000 adults in the US. The prevalence of US adults who have been PGx tested is 6.6% [95% confidence interval (CI): 6.2-7.0]. Only 32.2% (95% CI: 31.5-32.9), an estimated 79 million individuals, desired PGx testing. Adults who had or want PGx testing were more likely to be female, have higher education, be students, current or former members of the military, use medications, and have a mental health disorder. The prevalence of adults who have been PGx tested remains low in the US. There are knowledge gaps about the benefits of PGx testing that must be bridged to increase implementation.

Irinotecan treatment is often complicated by gastrointestinal, hematological, and infusion-related toxicities, the latter of which typically presents as acute cholinergic syndrome (ACS). While genetic variation in UGT1A1 increases toxicity risk, fewer studies have investigated variation in other genes. This study aimed to assess the impact of variation in other genes involved in irinotecan pharmacokinetics with irinotecan-related toxicity. This was a retrospective study of patients receiving standard irinotecan doses (180 mg/m2) with available genetic and clinical data. The primary analysis was to investigate the impact of carboxylesterase (CES) genetic variation on irinotecan infusion-related ACS. Exploratory secondary analyses evaluated variation in CES1, CES2, UGT1A7, UGT1A9, ABCB1, ABCG2, ABCC2, and SLCO1B1 with severe toxicity, treatment modification, diarrhea, and neutropenia. Univariate associations with P less than 0.05 were adjusted for UGT1A1*28 and UGT1A1*6 genotype. A total of 93 patients were included in this analysis. CES1 variants were not associated with infusion-related ACS. In the exploratory analysis, CES1 rs3785161 AA was associated with an increased likelihood of severe irinotecan toxicity (37 vs. 16%; P = 0.034), and ABCG2 rs2231142 AA/AC was associated with an increased likelihood of severe neutropenia (33 vs. 8%; P = 0.017). CES1 and ABCG2 variants may increase the risk of irinotecan toxicity. Further studies are needed to validate these associations to justify prospective studies investigating the clinical benefits of genetics-guided irinotecan dosing.

Background: Warfarin is a commonly used oral anticoagulant for managing thromboembolic events after cardiac valve surgery. However, its optimal dose varies between individuals, often requiring trial and error to determine. This study aimed to investigate the association of polymorphisms in the CYP2C9 and VKORC1 genes with warfarin dose requirements in an Iranian population undergoing cardiac valve replacement.

Materials and methods: A total of 140 patients recieving warfarin after cardiac valve replacement surgery were enrolled. Patients were monitored for their daily warfarin dose and international normalized ratio for at least 3 months post-surgery. Genotyping of CYP2C9 rs1057910 and VKORC1 rs2884737 was conducted using the tetra-primer amplification refractory mutation system -PCR method. Associations between genotypes and warfarin dose were analyzed using linear regression. A P value < 0.05 was considered statistically significant.

Results: Patients with the heterozygous AC genotype of CYP2C9 rs1057910 required a significantly lower warfarin dose than those with the wild-type genotype ( P < 0.05). Although variation in warfarin dose was observed among patients with different VKORC1 rs2884737 genotypes, the association was not statistically significant. Including patients' demographic covariates in the regression model did not alter the observed genotype-dose associations.

Conclusion: The CYP2C9 rs1057910 variant was significantly associated with daily warfarin dose requirements, suggesting its potential role in guiding idividualized dosing. In contrast, VKORC1 rs2884737 showed no significant association in this population, despite previous findings in other ethnic groups.

Introduction: Praziquantel (PZQ) is commonly used to treat schistosomiasis; however, there is considerable interindividual variability in its efficacy, partly because of genetic variation. Data on this relationship is scarce across Africa - where schistosomiasis is prevalent. This study aimed to investigate the pharmacokinetic/pharmacodynamic and pharmacogenetic relationship between PZQ and its metabolites in a Zimbabwean population infected with Schistosoma haematobium by leveraging dried blood spots (DBS) and mass spectrometry (MS).

Methods: DBS were obtained from 38 Zimbabwean participants on PZQ treatment at four-time points (0.5, 1.5, 2.5, and 4 h). We compared two extraction methods for recovering PZQ and its metabolites from the DBS cards and performed MS analysis to determine the concentrations. A random forest model was used to determine whether CYP1A2 , CYP2C9 , CYP2C19 , CYP2D6 , CYP3A4 , and CYP3A5 known variants were predictive of PZQ efficacy. The relationships between PZQ/metabolite concentration, metabolite ratio, and drug exposure with genotype were determined using a one-way analysis of variance.

Results: An acetonitrile and water (4 : 1) mixture was determined to be optimal for recovering PZQ and its metabolites from the DBS cards. Subsequent MS analysis identified PZQ and six metabolite compounds - including phase 1 metabolites (-2H)-O-PZQ, O2-PZQ, and 4-OH-PZQ. Pooled MS sampling was comparable to individual MS sampling for determining pharmacokinetic profiles at the 2.5 and 4-h time points. The (-2H)-O-PZQ and O2-PZQ metabolites had significantly higher concentrations in participants with CYP2C9*1/*9 and *9/*9 versus those with CYP2C9*1/*1. CYP1A2 rs2069514-A (formerly *1C ) and rs762551-A ( CYP1A2*30 ; formerly *1F ) were observed to alter PZQ pharmacokinetic profiles; however, differences in analyte concentrations across the corresponding genotypes were NS.

Conclusion: We show that low-cost microsampling using DBS and MS is feasible for detecting and quantifying PZQ and its metabolites. Furthermore, our pharmacogenetics analysis elucidates the impact of known cytochrome P450 variants on PZQ drug response in an African setting.

Propofol is commonly used to sedate patients, but variations in how individuals metabolize the drug may affect dosing requirements. The objective of this study was to explore how genetic variations in CYP450 enzymes, particularly CYP2B6 , influence propofol metabolism in ICU patients receiving mechanical ventilation. Genetic variants of CYP2B6 , CYP2C9 , CYP2C19 , and CYP3A5 were collected from an institutional genetic data repository. Patients were dichotomized into low and high metabolic activity for each enzyme, and the mean weight- and time-normalized propofol dose administered was compared between groups via t test. There was no significant difference in average daily propofol dose between patients with low and high CYP2B6 activity (11 vs. 11 mg/kg/h, P  = 0.78), or any of the other CYP enzymes analyzed (all P  > 0.05). This study could not replicate previous studies indicating that patients carrying genetic variants with diminished CYP2B6 activity required lower propofol doses. Future studies with prospectively collected dosing and outcomes data, and measurement of plasma drug concentrations, may provide insights into personalized propofol dosing strategies.