Pharmacogenomics最新文献

Aim: To survey Veterans Health Administration providers who prescribed tramadol or codeine to patients with known genotyping for cytochrome 2D6 (CYP2D6) to ascertain awareness of their patient's pharmacogenetic (PGx) test status, whether these results influenced prescribing, perceived benefit of PGx testing, and resources needed to obtain and deliver PGx testing information.Materials & methods: A provider survey was conducted of those who prescribed tramadol or codeine in a patient genotyped for CYP2D6.Results: Of 876 eligible providers, 220 completed the survey. Ten percent were aware that their patient received a PGx test, 64% had not ordered any PGx test related to any medication in the prior year, 55% strongly agreed or agreed that PGx testing is or will be valuable to guide pain medication prescriptions, 29% felt that the evidence base for PGx testing is very strong or moderately strong, 22% responded likely or extremely likely to order a future PGx test, and 51% felt that it would be either very important or fairly important to have a local subject matter expert as a resource for PGx testing.Conclusion: There are modifiable factors that the Veterans Health Administration could address to optimize PGx testing for pain management.

Aim: To investigate the associations between genetic polymorphisms in immunorelated genes and PBMC-induced cytotoxicity to breast cancer cell with the treatment of trastuzumab in vitro.Methods: Trastuzumab-mediated cytotoxicity of peripheral blood mononuclear cells (PBMC) from 148 healthy donors and 13 BC patients was analyzed by flow cytometry. 16 SNPs in 7 immunorelated genes were genotyped by Sequenom Mass Array Genotype Platform.Results: Cytotoxicity in the trastuzumab treated PBMCs were significantly higher than those of the basal group. A wide variability in trastuzumab-mediated cytotoxicity was observed, and PBMC from individuals with the CD247 rs16859030 T genotype generated increased cytotoxicity than those with the CC genotype.Conclusion: The CD247 rs16859030 polymorphism affects trastuzumab-mediated cytotoxicity in vitro.

Aim: Valproic acid (VPA) is a classic broad-spectrum antiepileptic drug, with significant pharmacokinetic variability. Genetic polymorphisms contribute to this variability, influencing both VPA trough serum concentration (VPA concentration) and VPA-induced liver injury. Our study aims to investigate the association between polymorphisms of uridine diphosphate glucuronyl transferase (UGT) 1A6, UGT2B7 and VPA concentration and screen for potential genetic loci affecting VPA-induced liver injury.Methods: This study included epilepsy patients treated with VPA. PCR-RFLP method was used to determine the genotypes of UGT1A6 and UGT2B7. Chemiluminescent microparticle immunoassay was used to measure VPA concentration. Multiple linear regression and logistic regression were employed to analyze factors influencing VPA concentration and VPA-induced liver injury, respectively.Results: The correlation between UGT polymorphism and VPA concentration was analyzed in 133 samples. For VPA-induced liver injury, 105 patients were analyzed, with 29 in the liver injury group and 76 in the control group. Our finding showed patients with the UGT1A6-T19G variant had significantly lower VPA concentrations compared with wild-type patients and UGT1A6-T19G, A541G, A552C and UGT2B7-C802T, G211T, A268G polymorphisms showed no impact on VPA-induced liver injury.Conclusion: This study demonstrated UGT1A6-T19G polymorphisms affected the VPA concentration, providing a theoretical basis for the individualized clinical use of VPA.

Background: Dolutegravir (DTG) is an antiviral agent used for the treatment of HIV, however, there is uncertainty over the influence of genetic variation on DTG exposure, and whether it has clinical implications for the efficacy or toxicity in different populations. This systematic review aims to create an overview of the impact of pharmacogenomics (PGx) on DTG exposure, efficacy, and toxicity.

Methods: Publications up to 14 November 2023 were searched and articles were selected on the following criteria: original research articles providing data on people with HIV, data on PGx and either PK or PD or both PD and PGx.

Results: 711 records were identified, and after screening 10 articles were included. Commonly analyzed genes across the articles were UGT1A1, ABCB1, ABCG2, and NR1I2. The most reported variant associated with PD variability was in SLC22A2, with carriers at higher risk of neuropsychiatric adverse events.

Conclusions: This review concludes that while PGx testing may help explain some variability in DTG pharmacokinetics when combined with therapeutic drug monitoring (TDM), current evidence is insufficient to support its routine clinical use. The role of PGx research for DTG remains relevant, especially in specific patient populations where interindividual PK variations are still unexplained.

Aim: MicroRNA 27a (miR-27a) regulates post-transcriptionally DPD activity. We have analyzed the association of MIR27A rs895819T>C variation, that modulates miR-27a expression, with fluropyrimidine-induced toxicity. Materials & methods: MIR27A rs895819T>C genotyping was conducted by TaqMan® allelic discrimination assay in 313 FP-treated cancer patients. Results: In overdominance (TC vs TT + CC), TC genotype was associated with grade 3-4 toxicity (p = 0.002), any grade toxicity (p = 0.052), and delayed drug administration or therapy discontinuation (p = 0.038). Odds of grade 3-4 toxicity were increased by both DPYD deficiency (OR: 8.923; p = 0.006) and MIR27A rs895819 TC genotype (OR: 3.865; p = 0.002). Conclusion: MIR27A rs895819 TC genotype is an independent risk factor for fluoropyrimidine-associated toxicity in the Greek population. Thus, MIR27A rs895819TC patients can be closely monitored for fluoropyrimidine-induced severe toxicity.

Aim: The study aims to identify high-impact single nucleotide polymorphisms (SNPs) in miRNA target sites of genes associated with lung cancer.Materials & methods: Lung cancer genes were obtained from Uniprot KB. miRNA target site SNPs were mined from MirSNP, miRdSNP and TargetScan. SNPs were shortlisted based on binding impact, minor allele frequency and conservation. Gene expression was analyzed in genes with high-impact SNPs in healthy versus lung cancer tissue. Additionally, enrichment, pathway and network analyzes were performed.Results: 19 high-impact SNPs were identified in miRNA target sites of lung cancer-associated genes. These SNPs affect miRNA binding and gene expression. The genes are involved in key cancer related pathways.Conclusion: The identified high-impact miRNA target site SNPs and associated genes provide a starting point for case-control studies in lung cancer patients in different populations.

Introduction: IL-6 and IL-10 may affect the activity of cytochrome P450 (CYP) 3A enzymes involved in tacrolimus (Tac) metabolism. Moreover, the effect of IL-6 and IL-10 on Tac pharmacokinetics may differ with respect to the genetic variations in their genes.Aim: To examine the influence of IL-6 and IL-10 gene polymorphisms on Tac dose requirements and exposure over a 5-year period following kidney transplantation. Univariate and standard multivariate linear regression and Monte Carlo analysis were performed to investigate potential covariates influencing Tac dose-adjusted trough concentration (C₀/D) in various post-transplantation periods.Materials & methods: IL-6 (-174G > C), IL-10 (-1082G > A, -819C > T and -592C > A) genotype, Tac daily dose, C₀, C₀/D and intrapatient variability data were collected from 113 patients.Results: Multivariate regression analysis and accompanied Monte Carlo simulation underscore the importance of considering IL-6 -174G > C and IL-10 -1082G > A gene polymorphisms, alongside Tac metabolic phenotype and post-transplantation period, when tailoring Tac dosage regimen.Conclusion: This study provides valuable insights regarding the individualized adjustment of Tac treatment in various post-transplantation periods.

We explore the relationship between epigenetic aging and drug metabolism. We review current evidence for changes in drug metabolism in normal aging, followed by a description of how epigenetic modifications associated with age can regulate the expression and functionality of genes. In particular, we focus on the role of epigenome-wide studies of human and mouse liver in understanding these age-related processes with respect to xenobiotic processing. We highlight genes encoding drug metabolizing enzymes and transporters revealed to be affected by epigenetic aging in these studies. We conclude that substantial evidence exists for epigenetic aging impacting drug metabolism and transport genes, but more work is needed. We further highlight the promise of pharmacoepigenetics applied to enhancing drug safety in older adults.