Pharmacogenomics最新文献

Aim: To summarize the effects of single nucleotide polymorphisms (SNPs) on the pharmacokinetics of allopurinol to control uric acid levels.Methods: A comprehensive search was conducted in PubMed, Web of Science and Scopus databases from inception to January 2024, includes 17 articles focusing on SNPs and pharmacokinetics of allopurinol and oxypurinol.Results: A total of 11 SNPs showed a significant association with pharmacokinetics of allopurinol and oxypurinol, as well as their potential clinical implications.Conclusion: SNPs in ATP-binding cassette super-family G member 2 (ABCG2), solute carrier family 2 member 9 (SLC2A9), solute carrier family 17 member 1 (SLC17A1), solute carrier family 22 member 12 (SLC22A12), solute carrier family 22 member 13 (SLC22A13) and PDZ domain containing 1 (PDZK1) genes were associated with allopurinol clearance, while SNPs in aldehyde oxidase 1 (AOX1) genes involved in metabolism of allopurinol. SNPs in gremlin 2, DAN family BMP antagonist (GREM2) gene impacted uric acid control, but the specific mechanism governing the expression of GREM2 remains unknown. Our study indicated that the identified SNPs show contradictory effects, reflecting inconsistencies and differences observed across various studies.

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.

Background: Macrolides are widely used antibiotics, but adverse drug reactions (ADRs), particularly in genetically predisposed individuals, can compromise their safety. This study examines the impact of pharmacogenetic markers on macrolide safety in participants with bacterial complications of influenza.

Objective: To evaluate how polymorphisms in genes encoding transporter proteins (ABCB1) and enzymes (CYP3A4, CYP3A5) influence ADR risk during macrolide therapy.

Methods: A prospective study included 100 participants with lower respiratory tract bacterial complications of influenza treated with azithromycin or erythromycin for five days. Genotyping targeted ABCB1 (3435C>T), CYP3A4 (C>T intron 6), and CYP3A5 (6986A>G) polymorphisms. ADRs were monitored daily and correlated with genetic markers.

Results: The ABCB1 (3435C>T) polymorphism was associated with higher rates of abdominal pain and diarrhea in CT and TT genotypes (OR = 2.12, p = 0.043). The CYP3A4 (C>T intron 6) polymorphism increased ADR risk in erythromycin-treated participants (OR = 24.0, p = 0.0339). No significant effects were observed for CYP3A5 (6986A>G).

Conclusion: Genetic polymorphisms in ABCB1 and CYP3A4 genes predict macrolide-related ADRs. Pharmacogenetic screening could improve macrolide safety, particularly for genetically susceptible individuals.

Aim: To evaluate the association between irinotecan safety and the UGT1A1 gene polymorphism in colorectal cancer (CRC) patients.Materials & methods: The studies were systematically searched and identified from three databases (PubMed, Embase and The Cochrane Library) until 28 February 2023. The relationships were evaluated using pooled odds ratio (OR).Results: A total of 30 studies out of 600 were included, comprising 4471 patients. UGT1A1*28 was associated with a statistically significant increase in the OR for diarrhea (OR: 1.59, 95% CI = 1.24-2.06 in the additive model; OR = 3.24, 95% CI = 2.01-5.21 in the recessive model; and OR = 1.95, 95% CI = 1.42-2.69 in the dominant model) and neutropenia (OR = 1.70, 95% CI = 1.40-2.06 in the additive model; OR = 4.10, 95%CI = 2.69-6.23 in the recessive model; and OR = 1.93, 95% CI = 1.61-2.31 in the dominant model). Subgroup analysis indicated consistent associations in both Asian and non-Asian populations. UGT1A1*6 was associated with a statistically significant elevation in the OR for diarrhea (only in the recessive model, OR = 2.42; 95% CI = 1.14-5.11) and neutropenia (across all genetic models).Conclusion: The UGT1A1*28 and UGT1A1*6 alleles might be a crucial indicator for predicting irinotecan safety in CRC.

Aim: Thiopurine drugs are used in the treatment of various diseases including inflammatory bowel disease. Thiopurine-S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are the crucial enzymes involved in thiopurines metabolism. The present study aims to investigate in Tunisian patients, the influence of genetic and nongenetic factors on thiopurine drugs pharmacokinetics.Experimental approach: We have included patients having received thiopurine drugs and have undergone 6-thioguanine nucleotides (6-TGN) concentration monitoring. The identification of TPMT and ITPA polymorphisms was performed using the polymerase chain reaction-restriction fragment length polymorphism method. The impact of both genetic and nongenetic factors on the variability of the 6-TGN C/D ratio was analyzed through a stepwise multiple regression model.Key results: One hundred and twenty-three patients were included in the study. For TPMT, the most frequent variant allele was TPMT*3B (3.3%). For ITPA, the predominant polymorphism was the c.IVS2 + 21A> C (7%). We have demonstrated that only gender, the TPMT*3A and TPMT*3C alleles are significantly involved on the variability of thiopurines pharmacokinetics.Conclusion: Our study is the first to evaluate, in African patients, the impact of both genetic and nongenetic factors on the thiopurine drugs pharmacokinetics. Considering the narrow therapeutic range of these drugs, TPMT genotyping combined with 6-TGN blood concentration monitoring may enhance their efficacy and safety.

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: 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.