Imatinib is associated with significant toxicities, including myelosuppression, oedema, and hypersensitivity, with considerable interpatient variability. Pharmacokinetic and pharmacogenomic factors contribute, but comprehensive biomarkers are yet to be identified. A retrospective cohort study was conducted on 154 gastrointestinal stromal tumour (GIST) patients receiving imatinib. Steady-state concentrations of imatinib and its metabolite were measured using liquid chromatography-tandem mass spectrometry. Thirty-five genetic polymorphisms in signaling, transporter, and immune genes were genotyped, and multivariate logistic regression was performed, adjusting for clinical covariates. The study found a significant correlation between myelosuppression and imatinib plasma concentration, along with genetic polymorphisms in FLT1, MAPK1, PDGFRB, and SHC1. Peripheral oedema was more prevalent in females and associated with PDGFRB polymorphisms. Hypersensitivity was linked to EGFR and CXCL14 polymorphisms. These findings identify novel pharmacogenetic markers for imatinib-induced toxicities, supporting the potential of personalized treatment strategies through genetic testing and therapeutic drug monitoring. Further validation in larger cohorts is needed.

Type 2 diabetes (T2D) is a complex, polygenic disease with substantial health impact. Despite extensive genome-wide association studies (GWAS) identifying risk loci, therapeutic translation remains limited. We applied a Bayesian Linear Regression (BLR) multi-trait gene set model to prioritize druggable gene sets, integrating GWAS summary statistics with drug-gene interaction data from the Drug Gene Interaction Database (DGIdb). For each drug group, defined at the ATC 4th level, we calculated posterior inclusion probabilities (PIP) to assess relevance. Known antidiabetic agents showed strong associations with T2D, validating the model. Additionally, carboxamide derivatives, fibrates, uric acid inhibitors, and various immunomodulatory and antineoplastic agents demonstrated significant genetic relevance. Gene-level analyses highlighted key T2D-associated genes, including PPARG, KCNQ1, TNF, and GCK. Notably, bezafibrate, a PPAR pan-agonist, demonstrated substantial genetic overlap with T2D loci, supporting its potential in metabolic disease. This study introduces a genetically informed pipeline for drug repurposing based on multi-trait gene set analysis.

Genetic variation in CYP2C19 is linked to variable efficacy in antiplatelet therapies like clopidogrel. Patients with CYP2C19*2 and *3 loss of function alleles show reduced enzyme function, leading to lower active drug levels and higher risks of thromboembolic and cardiovascular events. Point-of-care CYP2C19 testing offers a personalized approach to antiplatelet therapy. We conducted a systematic review of literature assessing point-of-care CYP2C19 testing to individualize antiplatelet therapy in cardiovascular patients compared to standard therapies. The review followed PRISMA guidelines and identified 146 articles, of which 3 randomized controlled trials (RCTs) were comprised. The three studies included 6945 patients; 3483 received genotype-guided therapy, and 3462 received standard care. Efficacy and safety outcomes were compared between groups. Point-of-care genotype-guided therapy improved primary outcomes and lowered bleeding rates compared to conventional therapy. However, the benefit varied, with most trials demonstrating improved efficacy and safety outcomes of various statistical significance levels. Meta-analysis of pooled data (n = 3,424) showed a significant reduction in major adverse cardiovascular events (MACE) with point-of-care genotype-guided therapy (RR = 0.56, 95% CI 0.41-0.76, p = 0.0002; moderate heterogeneity I² = 48%) while bleeding outcomes did not differ significantly (RR = 0.74, 95% CI 0.35-1.56, p = 0.42; I² = 51%). PROSPERO registration (CRD42023378028).

Pharmacogenomics (PGx) test results are returned variably across healthcare settings, which can lead to challenges particularly when results require immediate intervention to avoid adverse consequences. While several return of result models exist in literature, a standard-of-care has not been established. We propose a model to safely return PGx results in the context of scaled and sustained PGx testing: an institutional protocol to integrate new PGx results into patient care.

5-15% of all colorectal cancers (CRCs) are mucinous. Mucinous CRCs are associated with an inhibited response to standard adjuvant and neoadjuvant therapies. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme, which modulates the activity of multiple splicing factors. SRPK1 under-expression is associated with resistance to platinum-based chemotherapeutic agents in multiple tumor types. The objectives of this study were to evaluate SRPK1 expression in mucinous CRC and to explore the potential relationship between differential SRPK1 expression and oxaliplatin resistance in mucinous CRC. Rectal cancer and CRC Tissue Microarrays (TMA) were stained with SRPK1 to compare expression between mucinous and non-mucinous tumors. SRPK1 expression was analyzed in mucinous and non-mucinous CRC cell lines. Cells were treated with oxaliplatin to explore differences in treatment response. Mucinous cells were transfected with an SRPK1 CRISPR/Cas9 lentiviral activation plasmid to investigate the relationship between SRPK1 expression and oxaliplatin resistance. The TMA cohorts included 117 patients with mucinous and 441 patients with non-mucinous CRC. SRPK1 was found to be under-expressed in both the mucinous rectal cancer (P < 0.001) and CRC cohorts (P = 0.003). On univariate analysis, SRPK1 under-expression was found to be associated with worse 5-year OS (P = 0.001). Treatment of mucinous CRC cells with oxaliplatin did not result in a significant increase in cell death (P = 0.149). However overexpression of SRPK1 following transfection with a CRISPR/CAS9 activation plasmid resulted in a significant increase in sensitivity of these cells to oxaliplatin treatment (P = 0.029). SRPK1 is under-expressed in mucinous CRC, and under-expression is associated with worse OS. This may be due to the positive effects of SRPK1 on oxaliplatin sensitivity.

Pharmacogenomics (PGx) testing aims to identify the most appropriate drug and dose for individual patients based on their genetic profiles. In Jordan, patients with genetic disorders often use multiple medications, some of which have clinical guidelines recommending PGx testing.

Pharmacogenomic services are commonly pharmacist-led, yet pharmacists report poor knowledge and confidence in application. This study evaluated an experiential teaching approach to enhance students' confidence and knowledge in pharmacogenomics. Customised modules were delivered to three cohorts of second-year undergraduate pharmacy students. Cohort A received lectures and a tutorial; Cohort B added self-testing; Cohort C (same as B) added a case-based workshop and assignment. Students were predominantly female (64%) and half were younger than 20 years old. Self-perceived confidence, assessed using pre- and post-module surveys, significantly improved across all cohorts, in applying pharmacogenomic skills, recognising pharmacists' roles and perceptions towards self-testing. Students who self-tested in Cohort C reported greater confidence (e.g., "patient education testing risks": 26% test vs 0% no test). Knowledge, assessed using examination scores ranged from 70-74% across cohorts, showing no significant differences. Our findings suggest that experiential learning enhances confidence, supporting greater integration of pharmacogenomics into future practice.

Predictive safety risk biomarkers for drug-induced liver injury (DILI) are critically needed to enhance patient risk stratification and minimize adverse outcomes. This study aims to identify genomic markers associated with increased mortality in toxic liver disease, using the KEM® (Knowledge Extraction and Management) explainable Artificial Intelligence platform. From 225 participants diagnosed with toxic liver disease within the UK Biobank cohort, data were consolidated, including survival outcomes, clinical phenotypes, comorbidities, and 36 394 genomic single nucleotide polymorphisms (SNPs) focusing on liver-related pathways. Fifteen SNPs were found to be significantly associated with increased mortality risk, notably rs73158145 in the PRKAG2 gene. Predictive models built on these selected SNPs achieved a mean accuracy of 85%, outperforming models without pre-selection (68.9% accuracy). Further validation in independent cohorts is planned to confirm the clinical relevance of these biomarkers.

It has been proposed that mitochondrial DNA variations can affect mitochondrial function, increasing the risk of drug-induced liver injury. This study aims to explore the association between mitochondrial DNA (mtDNA) variants and anti-tuberculosis drug-induced liver injury (ATT_DILI) in Korean tuberculosis patients. Whole mitochondrial genomes from 185 patients (61 with ATT_DILI and 124 without liver injury) were sequenced. Comparative analyses examined mtDNA variants, variant counts, and haplogroups between the two groups, adjusted with Bonferroni correction. The m.16189 T > C variant, associated with reduced mtDNA copy number, was more frequent in ATT_DILI cases (39.3%) than in controls (29.0%). Logistic regression suggested a potential association (odds ratio 4.92, 95% confidence interval 1.14-21.23, p = 0.033), though this significance was lost after correction. No significant differences in mtDNA variant counts or haplogroups were observed between groups. While mtDNA variants and haplogroups appear to have a limited role in predicting ATT_DILI risk, the m.16189 T > C variant warrants further investigation.

Depression affects around 10% of the Swiss population. While SSRIs are commonly prescribed, only 30-40% of patients achieve remission. Pharmacogenetic (PGx) factors may explain part of this high rate of SSRI treatment failure. This study examined antidepressant (AD) switching among Swiss patients using escitalopram, focusing on whether they switched to ADs with PGx dosing guidelines (PGx AD) or ADs without PGx dosing guidelines (non-PGx ADs). Data from Swiss health insurance records identified 41 275 patients who used escitalopram between July 2020 and June 2022. While 6.4% (n = 2 638) switched to another antidepressant, only 35.4% of these opted for a PGx AD. Men, younger adults showed higher switching rates, whereas patients on antipsychotic medications switched less. Individuals younger than 20 years old and women were more likely to switch to PGx AD whereas the elderly were less likely to switch to PGx AD.

This review describes healthcare cost effectiveness/savings for pharmacogenetics (PGx) and relevant clinical outcomes in selected common health conditions. PGx allows targeted drug treatment based on genotype and phenotype. Studies highlight how PGx testing reduces the morbidity and mortality of adverse drug reactions (ADRs) by predicting unexpected drug metabolism due to genetic variation in cytochrome P450 enzymes (CYPs) and drug-drug interactions caused by altered CYP enzyme phenotype. Despite many available PGx testing platforms and PGx-guided treatments, clinical implementation remains challenging and slow due to limited (1) insurance coverage and reimbursement of testing and pharmacist interpretation, (2) outcome data such as evidence showing the benefits of preemptive PGx testing for efficacy or ADR prevention, and (3) promotion of PGx testing among healthcare professionals. Of these, cost is the most significant barrier to patients and the healthcare system. This review describes how PGx testing can be cost effective or cost saving for payors and the healthcare system, especially for depression, cardiovascular disease, and ADRs.

Pharmacogenetics (PGx) is increasingly implemented in the adult population, but its potential in children remains uncertain. The aim of this study was to investigate PGx drug utilization in children in Switzerland, using Helsana claims data between 2017 and 2021. We identified 82 drugs with paediatric guideline annotations associated with variants in 24 genes from the Pharmacogenomics Knowledgebase. Of 159 172 children continuously insured, 66.1% claimed at least one PGx drug during the study period. The three PGx drugs with the highest user numbers were systemically administered ibuprofen (59.1%), ondansetron (8.3%), and locally administered fluorouracil (7.5%). Over 96% of all potential drug-gene interactions were caused by seven genes (CYP2C9, CYP2D6, DPYD, CYP2C19, MT-RNR1, CACNA1S, and RYR1). The high number of children claiming PGx drugs in Switzerland implies that a significant number of children could benefit from PGx testing.

Optimising opioid therapy is challenging due to variable patient responses linked to genetic variation. Pharmacogenomic-guided prescribing holds promise for personalisation, but its clinical effectiveness requires evaluation. We performed a systematic review and meta-analysis of RCTs comparing pharmacogenomic-guided versus standard opioid prescribing in adults. Adhering to PRISMA, we assessed risk of bias (RoB 2) and evidence certainty (GRADE). Six RCTs met inclusion criteria from 2496 screened articles. Meta-analysis showed pharmacogenomic-guided prescribing was associated with significantly reduced opioid consumption (SMD -0.38, 95% CI -0.67 to -0.08, p = 0.01). However, no significant difference in pain intensity was observed between groups (SMD -0.31, 95% CI -0.89 to 0.27, p = 0.30). Evidence regarding adverse events was limited to one trial, which reported a statistically significant reduction in incidence in the pharmacogenomic group (median [IQR]: 1 [0-2] vs. 3 [1-5]; p < 0.01). Further research is needed to determine if pharmacogenomics can improve opioid therapy outcomes.

This study investigates combine effect of low BMI and possible pharmacogenetic influence of ABC gene polymorphisms in treatment responses of BC patients. BMI was analysed prior to commencement of chemotherapy. Clinical response was evaluated by radiological imaging and categorised as per RECISTv.1 criteria. SNPs (C1236T, C3435T, C58626A) in ABCB1 and ABCC2 gene were selected. 148 patients were analysed using PCR-RFLP. ABCC2 (58626AA) was significantly associated with treatment non-responsiveness in all genetic models namely dominant (OR 2.954; [1.442-6.051]; p = 0.003), recessive (OR 5.723; [2.48-13.20]; p < 0.0001), codominant (χ 21.219; p < 0.0001). The proportion of ORR and NRs were significantly different between low (<18.5) and high (≥18.5) BMI classes (OR 16.097; [7.12-36.35]; p < 0.0001). Furthermore, when treatment response was combined with BMI groups, significant associations were observed for C58626A SNP across all genetic models among low BMI group: dominant (OR 3.324; [1.012-10.406]; p = 0.041), recessive (OR 7.250; [1.533-34.278]; p = 0.012) and codominant (χ 8.657; p = 0.013). Both PFS (35.31 months; p = 0.005) and OS (39.75 months; p = 0.032) were lowered among AA genotype (ABCC2) while the hazard risk of this genotype was further increased in low BMI patients (HR 1.963). 3435CT genotypes in ABCB1 gene showed 87% reduction in risk of death (HR 0.13; p = 0.025). Low BMI independently and jointly with 58626AA genotype of ABCC2 gene was responsible for poor chemotherapy response and survival outcome among AC-T regimen receiving BC patients. Together, this study underscores the importance of genetic counselling and nutritional assessment for favourable treatment outcomes.

We evaluated the ability of large language models (LLMs) to generate clinically accurate pharmacogenomic (PGx) recommendations aligned with CPIC guidelines. Using a benchmark of 599 curated gene-drug-phenotype scenarios, we compared five leading models, including GPT-4o and fine-tuned LLaMA variants, through both standard lexical metrics and a novel semantic evaluation framework (LLM Score) validated by expert review. General-purpose models frequently produced incomplete or unsafe outputs, while our domain-adapted model achieved superior performance, with an LLM Score of 0.92 and significantly faster inference speed. Results highlight the importance of fine-tuning and structured prompting over model scale alone. This work establishes a robust framework for evaluating PGx-specific LLMs and demonstrates the feasibility of safer, AI-driven personalized medicine.

Bladder cancer (BC) is a highly prevalent form of cancer worldwide, and cisplatin (CDDP) resistance poses a major challenge to patients. Cytoplasmic linker-associated protein 2 (CLASP2) is a member of the microtubule plus-end tracking protein family and is involved in the regulation of microtubule dynamics. In this study, we evaluated the influence of CLASP2 on BC progression and cisplatin resistance. Levels of CLASP2, HNRNPA1, NONO, ZRANB2, FUS, KHSRP and QKI in BC tissues and cells were tested by RT-qPCR. Protein levels of CLASP2 and KHSRP were detected by Western blot. Cell viability and IC50 of cisplatin-treated BC cells were measured by CCK-8. Cell proliferation and apoptosis were determined using colony formation assay and flow cytometry, respectively. RNA immunoprecipitation (RIP) and Co-immunoprecipitation (Co-IP) experiments were adopted to verify target genes of CLASP2. Cellular localization of CLASP2 and MAPRE1 was detected utilizing immunofluorescence staining. The xenograft tumor model was established in BALB/c nude mice. We found that iCLASP2 levels were increased in CDDP-resistant BC tissues and cells. Suppression of CLASP2 impeded BC cell proliferation and alleviated their resistance to CDDP. KHSRP positively influenced the stability of CLASP2 mRNA. There was a protein interaction between CLASP2 and MAPRE1. Silencing KHSRP or MAPRE1 reversed the effect exerted of CLASP2 on BC cells. CLASP2 decreased the sensitivity of BC to CDDP in vivo. Our results imply that CLASP2 contributes to tumorigenesis and cisplatin resistance in BC via targeting MAPRE1, thereby promoting BC progression and providing a new therapeutic target for BC treatment.

Childhood cancer survivors (CCS) often suffer from cardiac disease (CD) after treatment that included anthracycline and radiotherapy involving the heart. However, the variability in CD occurrence cannot be explained solely by these treatments, suggesting the existence of genetic predisposition. We conducted a systematic review searching on Medline-PubMed and Scopus, to identify studies reporting associations between genetic factors and CD in CCS. We included studies published up to 11 April 2023, with no lower limit, and assessed the quality of genetic associations by the Q-genie tool. As a result, 20 studies were included (15 case-control and five cohorts), revealing several genes and variants associated with cardiomyopathy, among which, SLC28A3-rs7853758, RARG-rs2229774, P2RX7-rs208294 and P2RX7-rs3751143 variants gave the most consistent findings. This review highlights the necessity to establish a set of clinically useful genes and variants to identify patients most at risk of developing cardiomyopathy, and to implement monitoring and prevention strategies.