Pharmacogenomics最新文献

Rationale: Preemptive pharmacogenetic (PGx) testing offers a promising approach to personalized antidepressant treatment by identifying genetic variations influencing drug metabolism. By focusing on CYP2D6 and CYP2C19 genes, this strategy aims to improve treatment response, minimize adverse effects, and optimize dosing in patients with depression.

Objectives and methods: This systematic review evaluates the effectiveness of preemptive PGx testing, primarily for CYP2D6 and CYP2C19, in enhancing antidepressant treatment outcomes. A comprehensive search of databases, including PubMed and Embase, was conducted to identify relevant studies. The review included randomized controlled trials and meta-analyses that assessed PGx testing in relation to treatment response and remission. Data on clinical outcomes were extracted and analyzed.

Results: PGx testing led to improved antidepressant response rates and remission at 8- and 12-week follow-ups compared to treatment-as-usual (TAU). However, where data were available, benefits were less pronounced after six months of follow-up. The findings suggest that PGx testing plays an important role in achieving earlier remission, while TAU requires a longer time to achieve remission.

Conclusion: Preemptive pharmacogenetic testing for CYP2D6 and CYP2C19 could enhance early antidepressant treatment outcomes, offering a valuable tool for personalized medicine. Further research is required to explore implementation challenges in diverse clinical settings.

Inflammatory bowel disease (IBD) poses a major therapeutic challenge due to its chronic course and variable treatment responses. Genetic polymorphisms significantly influence drug efficacy, prompting this review to analyze their role in treatment non-response. A systematic literature search (PubMed/Scopus) using terms like "genetic polymorphism," "non-response," and "IBD" identified 25 relevant studies. Key findings linked TNFα (-308 G > A), TNFRSF1A, and TNFRSF1B polymorphisms to reduced anti-TNFα therapy effectiveness. TPMT variants correlated with thiopurine toxicity, while CYP3A4 and CYP3A5 polymorphisms altered tacrolimus metabolism. These genetic markers could serve as predictive tools for personalized IBD treatment, emphasizing the potential of genetic screening in clinical practice. Future research should integrate multi-omics approaches to refine predictive models and advance precision medicine, ultimately improving patient outcomes through tailored therapeutic strategies.

Introduction: Rosuvastatin has become a good choice in the statin group because it has shown greater efficacy in reducing lipid levels than other statins, allowing patients to reach their therapeutic goal more quickly. To date, research has shown a broad relationship between the kinetics and efficacy of this drug and the phenotype of two transporters, OATP1B1 and BCRP, encoded by SLCO1B1 and ABCG2 genes. However, there are many other genes whose variation may also affect the treatment.

Objective: To conduct a systematic review including all information on the kinetics, measured by AUC and C_max parameters; efficacy, by reduction in lipid levels and carotid intima-media thickness; and safety of rosuvastatin, by the occurrence of adverse events.

Methods: A search of the published literature was conducted in PubMed using the term "rosuvastatin AND pharmacogenetics" (PROSPERO code: CRD420251041953).

Results: A total of 37 articles were included, investigating 40 genes.

Conclusions: The importance of ABCG2 in drug kinetics and efficacy and of SLCO1B1 in kinetics is confirmed, as is the possible association of CYP3A5 with efficacy and safety and of APOC1 with efficacy. There are also positive results for other genes that should be studied further to confirm their association with rosuvastatin.

Colorectal cancer is one of the most prevalent cancers worldwide. We have thus focused on studies on the association of genetic polymorphisms with treatment response and adverse effects in colorectal cancer patients. This review highlights the inter-individual and inter-population genetic variations in ABC transporters and their association with variability in drug response. Several studies report the association of specific ABC transporter gene polymorphisms with the risk of developing colorectal carcinoma and the clinical outcomes in patients undergoing chemotherapy. It is important to understand genetic polymorphisms and genetic profiling for colorectal cancer patients in the context of personalized medication. This review is built on a comprehensive knowledge of the pharmacogenetics of colorectal carcinoma with a special focus on ABC polymorphism.

Aims: Dihydropyrimidine dehydrogenase (DPYD) plays a critical role in the metabolism of fluoropyrimidine-based chemotherapies such as 5-fluorouracil (5-FU), capecitabine, and tegafur. Genetic variants in DPYD can lead to partial or complete enzyme deficiency, resulting in toxic accumulation of these drugs and severe, sometimes fatal, adverse reactions.

Materials & methods: Whole‑exome sequencing data from 1,612 individuals were analyzed for DPYD variants. Variants were classified as decreased, no function, or potentially deleterious. Comparative allele frequency analysis was performed using global population datasets to identify inter-population differences.

Results and conclusion: A total of 95 individuals (5.3%) carried at least one decreased or no function DPYD variant, indicating a significant prevalence of clinically actionable genotypes in this Indian cohort. The most frequent variant, c.1236 G > A (HapB3), was found in 53 individuals (3.28%), supporting its relevance in the Indian population. Comparative analysis revealed distinct population patterns and novel variants not captured in current guidelines. These results support the urgency in implementing preemptive DPYD genotyping to avoid adverse drug reactions and further studies to gather evidence on rare and novel variants in the Indian population. To the best of our knowledge, this is the largest population analysis of DPYD variants from India.

Buprenorphine, a semi-synthetic opioid, is used to treat Opioid Use Disorder (OUD) and as an analgesic. Buprenorphine's benefits over other opioids include longer duration of action, lower abuse potential, and a ceiling effect to serious adverse effects such as respiratory depression. This is a literature review of gene variants affecting the pharmacokinetics and pharmacodynamics of buprenorphine from databases, such as PubMed. Genetic polymorphisms related to metabolism and receptor binding of buprenorphine can alter the pharmacokinetics and response to buprenorphine. Specifically, genetic variants in CYP3A4, UGT2B7, OPRM1, PDYN, and SLC6A3 may affect metabolism and clinical response to buprenorphine. There is strong evidence linking polymorphism in Cytochrome P450 3A4 (CYP3A4) and UDP-Glucuronosyltransferase-2B7 (UGT2B7), enzymes involved in buprenorphine metabolism, with dosing requirements, treatment of OUD, and pain relief. Response to buprenorphine, an effective treatment for opioid use disorder and pain management, differs significantly based on several human genetic variations. However, there is currently insufficient evidence for the clinical significance of individualized treatment of buprenorphine based on genetic variants. Therefore, it is crucial that future research should prioritize evaluating the feasibility and clinical significance of individualized risk predictions and personalized dosing of buprenorphine.

Graft-versus-host disease (GvHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation (HSCT), contributing to increased morbidity and mortality. Thus, continuous development of novel prophylactic and therapeutic approaches is crucial for GvHD prevention and management. With the current development of personalized medicine and a more patient-oriented approach, pharmacogenetics has the potential to become a critical factor in optimizing the prophylaxis and treatment of GvHD. This review explores the role of pharmacogenetic variants in prophylaxis and management of GvHD, including drugs such as calcineurin inhibitors, methotrexate, mycophenolate mofetil, cyclophosphamide, and corticosteroids. A deeper understanding of these genetic factors could help in developing a more personalized approach to GvHD management, improving clinical outcomes and minimizing adverse effects. This review underscores the need for more pharmacogenetic association studies, as well as for incorporating pharmacogenetic testing into clinical practice to refine drug selection and dosing strategies in GvHD treatment.

Nemours Children's Health (NCH) is a large, multi-state pediatric health system in the United States with hospitals and outpatient locations across Delaware, New Jersey, Pennsylvania, and Florida. NCH has maintained consistent effort in pharmacogenomic (PGx) research through the Center for Pharmacogenomics and Translational Research since 2003. In 2018, NCH funded the development of a dedicated Clinical Pharmacogenomics Service (CPGxS) to support PGx testing and return of results across the NCH enterprise. The CPGxS consultant-based service provides clinical PGx testing and supports PGx-focused research. Over the past seven years, the CPGxS has developed an in-house PGx testing platform, integrated a PGx clinical decision support (CDS) system into the electronic medical record (EHR), established a comprehensive consultant clinic, and provided a broad variety of education opportunities for providers, patients, and trainees. In this institutional profile, we highlight the development of a PGx program and related efforts across a multi-state pediatric-specific healthcare system.

Background: Nifedipine, a substrate of ATP-binding cassette superfamily G member 2 (ABCG2), is a tocolytic agent. This study aimed to construct a scoring system by exploring the association between ABCG2 polymorphisms and the treatment response of nifedipine in pregnant women.

Methods: This study was conducted at a tertiary medical center. Eight single-nucleotide polymorphisms from the ABCG2 gene were selected. The adjusted OR (AOR) were calculated using multivariable analysis. A risk scoring system was constructed by dividing the AOR of independent risk factors by the minimum AOR to predict treatment failure.

Results: A total of 69 patients were analyzed for treatment failure. Maternal age ≥33 years, contraction interval <4 minutes, and contraction intensity ≥20 mmHg were clinical risk factors associated with treatment failure. Patients with the ABCG2 rs2622604 and rs4148157 experienced an 8.6-fold and 4.3-fold increased risk of treatment failure, respectively. The predicted risks of treatment failure of patients who scored 0, 1-2, 3-4, 5-6, 7-8, and 9 points were 2.8%, 9.1%, 26.0%, 55.4%, 81.4%, and 93.9%, respectively.

Conclusion: This novel risk scoring system may aid clinicians in identifying patients less likely to respond to nifedipine, improving individualized care in preterm labor management.

Objective: To explore the impact of low miR-369-3p expression on the resistance of PC-9 cells to osimertinib.

Methods: The PC-9/AZD9291 cell line was established with osimertinib. Real-time quantitative PCR was employed to measure the expression levels of miR-369-3p in both PC-9 and PC-9/AZD9291 cells, and Western blotting was utilized to detect PTPN12 protein expression. A dual-luciferase reporter assay was conducted to investigate the target relationship between miR-369-3p and PTPN12. CCK8 assays were performed to evaluate the impact of miR-369-3p inhibition on drug resistance.

Results: In comparison to PC-9 cells, there was a significant upregulation of miR-369-3p and downregulation of PTPN12 protein in PC-9/AZD9291 cells (p < 0.05). Transfection with the miR-369-3p inhibitor resulted in decreased levels of miR-369-3p and increased expression of PTPN12 protein in PC-9/AZD9291 cells (p < 0.05). Conversely, transfection with miR-369 mimics led to an increase in miR-369-3p levels accompanied by a decrease in PTPN12 protein (p < 0.05). Notably, treatment with the miR-369-3p inhibitor lowered the IC50 value for PC-9/AZD9291 cells; however, following downregulation of PTPN12 using PTPN12-siRNA, sensitivity due to low expression of miR-369-3p was significantly diminished (p < 0.05).

Conclusion: miR-369-3p plays a crucial role in modulating drug resistance in PC-9/AZD9291 cells against osimertinib through regulation of PTPN12.