Pharmacogenomics最新文献

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.

Background: Green tea extract was tested for the secondary prevention of colorectal adenoma in the placebo-controlled MIRACLE trial. Genome-wide screening on adenoma recurrence was performed in n = 550 participants 3 years after randomization to green tea or placebo intake.

Methods: Single Marker Analysis followed by regression analyses was calculated for all 700.078 markers assuming an additive genetic model and including all covariates from the main MIRACLE trial analysis. The outcome was an adenoma rate at 3-year follow-up colonoscopy comparing participants carrying a genetic variant versus wildtype.

Results: The gene showing the strongest association with the outcome in both, SMA as well as regression analysis, was the organic anion transporter SLCO1A2. In the variant carriers, the adenoma frequency was 41.4% in the green tea group and 35.7% in the placebo group (RR 1.16 [0.81; 1.65] p = 0.61), whereas in the nonvariant carriers, the frequency of reoccurrence was 54.5% in the green tea group and 66.5% in the placebo group (RR 0.82 [0.69; 0.97], p = 0.03).

Conclusion: Individuals with genetic variants in the transporter SLCO1A2 may be protected against colon adenoma irrespective of the green tea intake. In nonvariant carriers of SLCO1A2, green tea was associated with a clear benefit in outcome (18% risk reduction).

Background: Pharmacogenetics uses individuals' genetic profiles to optimize drug treatment and prevent adverse reactions. One strategy to obtain information on pharmacogenes is to reuse sequencing data for a pharmacogenetic passport, providing information preemptively to healthcare professionals for utilization throughout a patient's lifetime.

Aim: To explore stakeholders' perceived barriers and facilitators and future perspectives of implementing a pharmacogenetic passport based on experiences from reusing sequencing data, in a Dutch University Medical Center.

Methods: Semi-structured interviews were conducted among 21 stakeholders. Interviews were analyzed using thematic analysis, and themes were grouped under the constructs of structure, culture, and practice.

Results: Perceived implementation barriers included inadequate data infrastructure, limited knowledge of pharmacogenetics, lack of (visible) guidelines, unequal access, unclear division of tasks and unclear procedures, and other hospital priorities. Perceived facilitators included the ease, efficiency, and affordability to obtain pharmacogenetic test results from reused sequencing data, stakeholders' positive attitudes about patient impacts of a pharmacogenetic passport, and that patient control of their health data is provided.

Conclusion: When considering the implementation of a pharmacogenetic passport, strategies can be developed to diminish barriers and strengthen facilitators. It is important to focus on data infrastructure, (visibility of) guidelines, clear division of tasks, and pharmacogenetic education.

Tuberculosis is the leading cause of death from a single infectious agent globally, with the highest burden in low-and middle-income countries. Successful treatment requires prolonged administration of multiple drugs. The increasing threat of multidrug-resistant tuberculosis has prompted the development of a robust pipeline for new drugs. While generally safe and well tolerated, adverse drug reactions (ADRs) to TB drugs have a considerable impact on treatment outcomes. Pharmacogenetic testing has been implemented for some diseases to identify at-risk individuals and prevent ADRs. For tuberculosis treatment, the use of pharmacogenetic testing to optimize complex regimens and avoid ADRs is appealing, but there has been minimal implementation. To improve the use of pharmacogenetics, understanding both the pharmacology of relevant drugs and population-specific pathophysiology of ADRs are essential. This review highlights the major treatment-limiting ADRs with TB drugs, the current understanding of drug metabolic pathways, ADR pathophysiology, and known pharmacogenetic risk alleles. We highlight research gaps and barriers to meaningful clinical use and implementation of pharmacogenomic testing to prevent adverse reactions to TB drugs.

Pharmacogenomics (PGx) has the potential to revolutionize hypertension management by tailoring antihypertensive therapy based on genetic profiles. Despite significant advances in genomic research, the clinical translation of PGx in hypertension remains challenging due to genetic complexity, variability in drug response, and implementation barriers. This review explores the genetic basis of hypertension, highlighting key pharmacogenomic markers that influence antihypertensive metabolism and efficacy, including CYP2D6, CYP3A4, UMOD, and ACE polymorphisms. We also examine the role of Mendelian randomization, polygenic risk scores in drug development and stratifying hypertension treatment response. While PGx offers opportunities for personalized medicine - such as reducing trial-and-error prescribing and improving adherence - several obstacles hinder its widespread adoption. These include limited clinical actionability, lack of large-scale randomized controlled trials, cost constraints, and concerns about equity and accessibility. Furthermore, drug-gene interactions and phenoconversion add complexity to implementation. Emerging technologies, including artificial intelligence-driven prescribing, microbiome integration, and pharmacoepigenomics, may enhance PGx precision in hypertension management. However, further research, clinical validation, and policy frameworks are necessary before PGx can be routinely incorporated into hypertension care. This review critically evaluates both the promise and limitations of PGx in hypertension, offering insights into the future of precision medicine in cardiovascular health.