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PubMed2026

MT-RNR1 genotype testing for preventing aminoglycoside-mediated ototoxicity: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).

Aminoglycosides are broad-spectrum antibiotics used in the management of severe infections. Aminoglycosides are associated with nephrotoxicity and ototoxicity. Although dosing strategies such as once-daily administration and therapeutic drug monitoring have reduced the incidence of nephrotoxicity, ototoxicity remains unpredictable and may occur at therapeutic concentrations. A strong association between specific mitochondrial DNA variants in MT-RNR1 (m.1555A > G, m.1494C > T and m.1095 T > C) and aminoglycoside-induced hearing loss exists. These variants (frequency ~1 in 330 individuals across populations) predispose to irreversible, sensorineural hearing loss following aminoglycoside exposure, sometimes after a single dose. Avoidance of aminoglycosides is recommended at any detectable variant level. In England, laboratory-based MT-RNR1 testing is nationally commissioned, whereas point-of-care testing in time-critical settings like neonatal sepsis is delivered in some centres. Approximately 20% of aminoglycoside use is predictable providing opportunities for pre-emptive pharmacogenetic testing. Where MT-RNR1 testing results are unavailable and clinical urgency is high, aminoglycoside treatment should not be delayed. Early health economic evidence suggests that point-of-care testing in neonates may be cost-saving by preventing lifelong hearing loss. Regulatory and Health Technology Assessment bodies support targeted implementation of testing alongside further evidence generation. Overall, integration of MT-RNR1 pharmacogenetic testing offers a feasible and proportionate strategy to reduce harm while preserving access to life-saving antibiotic therapy. This guideline is grounded in the latest evidence in this field but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk-benefit profile, ensuring that therapy is optimized to maximize benefits while minimizing potential harms.

Humans↗

PubMed2026

UGT1A1 genotype testing for irinotecan: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).

Irinotecan, a topoisomerase I inhibitor, is available as both non-pegylated and pegylated formulations. The non-pegylated formulation is licensed for use in advanced colorectal cancer either in combination with other agents or as monotherapy. However, it is also used off-label across a range of gastrointestinal malignancies and in rare malignancies such as glioblastoma and sarcomas. The pegylated formulation is licensed for use as combination therapy in adult patients with metastatic pancreatic adenocarcinoma. Irinotecan is hydrolysed to its active metabolite, SN-38, which is predominantly inactivated by the enzyme uridine diphosphate glucuronosyltransferase UGT1A1. UGT1A1 is encoded by the gene UGT1A1, which is polymorphically expressed, with allele frequencies varying across populations. Poor metabolizers carry two variants that reduce UGT1A1 enzyme expression or activity, leading to increased risk of irinotecan toxicity. Any patient who is about to be prescribed irinotecan for an epithelial malignancy should have pharmacogenetic testing, to identify clinically relevant UGT1A1 variants, where testing is available. Irinotecan dose should be reduced by 30% at Cycle 1 treatment in poor metabolizers for all indications, with doses titrated thereafter based on tolerability and neutrophil counts. The lack of evidence precludes us from making any recommendation for rare malignancies such as sarcomas. Our guideline is consistent with other international pharmacogenetics prescribing guidelines. This guideline is grounded in the latest evidence but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk-benefit profile, ensuring that therapy is optimized to maximize benefits while minimizing potential harms.

Humans↗

PubMed2026

Current knowledge in pharmacogenomics and precision medicine: perspectives of the PGRN global PGx committee on improving drug therapies in underrepresented ethnic populations.

A precision medicine strategy is likely to be more impactful, when pharmacogenomics (PGx) guided selection of drugs and dosage wherever applicable is implemented across the globe. In regions where resources are disproportionately distributed, PGx implementation in routine clinical care can play a critical role in ensuring the optimal use of limited healthcare infrastructure. At present, PGx data from the majority of the distinct ethnic populations across Asia, Africa, and South America is limited. While international consortia, working groups, and scientific bodies have made significant contributions toward evaluating the evidence for PGx implementation, the majority of existing guidelines and recommendations are derived primarily from studies conducted in a limited number of ethnic groups. Precision Medicine Initiatives in countries like Korea, Taiwan, and Malaysia and PGx organizations like the African Institute of Biomedical Science and Technology (AiBST), Consortium for Genomics & Therapeutics in Africa (CGTA), implementation of pharmacogenetic testing for the effective care and treatment in Africa, Greater Middle East (GME) whole exome sequencing program, Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF), Latin American Society of Pharmacogenomics and Personalized Medicine (SOLFAGEM), Latin American Network for Validation and Implementation of Pharmacogenomic Clinical Guidelines (RELIVAF), IndiGen initiative, Southeast Asian Pharmacogenomics Research Network (SEAPharm), are working toward consolidating the PGx presence in these regions.

Precision Medicine↗

PubMed2026

The impact of pharmacogenetic-informed care on medication adherence and psychological factors associated with adherence: A narrative review.

Improvement in medication adherence is often proposed as a potential advantage of pharmacogenetic-guided prescribing over a traditional one-size-fits-all approach. This paper provides a review of the published literature and presents the findings of studies that measure adherence to medication as an outcome of pharmacogenetic-informed care, or that measure the impact of pharmacogenetic-informed care on psychological factors that are associated with medication adherence. Adherence-related psychological factors are mapped to the Theoretical Domains Framework (TDF) to provide insight into how participants interact with pharmacogenetic-informed care as an intervention and to consider this in the context of medication adherence. A total of 23 studies were included, with 10 quantitative studies measuring medication adherence outcomes associated with pharmacogenetic-informed care. Five of these studies found a statistically significant improvement in adherence in the pharmacogenetic-tested group, two reported a small but non-significant trend, and three showed no difference. Additionally, 13 studies examined the impact of pharmacogenetic-informed care on psychological factors related to adherence. These factors were mapped to 10 TDF domains: knowledge (8 studies); social/professional role and identity (1); beliefs about capabilities (2); optimism (4); beliefs about consequences (10); intentions (5); goals (1); memory, attention and decision processes (7); social influences (4); and emotion (8). The findings suggest that although the evidence for pharmacogenetic-informed care improving medication adherence is mixed and limited, pharmacogenetic-informed care appears to positively influence psychological factors that may support adherence. These include improving knowledge, supporting decision-making and generally being perceived as a positive experience by patients.

adherence↗

PubMed2025

Guidelines From the French-Speaking Society for Histocompatibility and Immunogenetics (SFHI) for Harmonisation of HLA Genotyping in Autoimmune Diseases, Drug Hypersensitivity and Pharmacogenetics.

HLA molecules play a central role in the adaptive immune response. Their high polymorphism influences individual susceptibility to various autoimmune diseases and certain drug-induced hypersensitivities. In France, HLA genotyping is classified as a medical genetics procedure and is strictly regulated. The Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI) has established national guidelines outlining clinically validated indications, required resolution levels and interpretation criteria based on robust data. These guidelines are particularly relevant for common clinical contexts, including autoimmune diseases and pharmacogenetic testing. Well-established associations include HLA-DQB1*02/DQA1*05 (DQ2) and HLA-DQB1*03:02/DQA1*05 (DQ8) with celiac disease, HLA-B*27 with spondyloarthritis, HLA-DQB1*06:02 with type 1 narcolepsy, HLA-A*29 with Birdshot chorioretinopathy and several pharmacogenetic risk alleles such as HLA-B*57:01 (abacavir), HLA-B*15:02 and HLA-A*31:01 (carbamazepine) and HLA-B*58:01 (allopurinol). In immunotherapy, the efficacy of tebentafusp has been shown to depend on HLA-A*02:01 positivity. HLA alleles must be interpreted as relative risk factors, not absolute predictors. Critical analysis of HLA-related scientific literature requires consideration of the genotyping technique, typing resolution, allele frequencies within the studied population and environmental factors. High-resolution typing is essential in pharmacogenetics and recommended in selected autoimmune disorders. Interpretation should be conducted by qualified medical biologists, integrating clinical context, allelic diversity and recent technological advances, particularly next-generation sequencing. HLA genotyping represents a valuable tool in diagnosis and risk assessment, with increasing importance in the era of personalised medicine.

Humans↗

PubMed2026

Clinical Function Assignment of NAT2 Alleles by the Clinical Pharmacogenetics Implementation Consortium Pharmacogene Curation Expert Panel.

NAT2 encodes arylamine N-acetyltransferase 2, a key enzyme in the phase II metabolism of arylamines and arylhydrazines. NAT2 is highly polymorphic, resulting in variable distributions of rapid and poor metabolizers across global populations. Here, we detail the process undertaken by the Clinical Pharmacogenetics Implementation Consortium (CPIC) NAT2 Pharmacogene Curation Expert Panel (PCEP) to assign clinical function to NAT2 star (*) alleles using CPIC's standard terminology. Given the observed impact of NAT2 genetic variability on drug response, CPIC convened the NAT2-PCEP to standardize clinical allele function assignments. The NAT2-PCEP is comprised of multidisciplinary and international members, including researchers, clinicians, and implementers with expertise in pharmacogenomics and NAT2 molecular biology. Extensive in vitro and clinical literature was curated from PubMed and other sources to assess NAT2 genotype-to-phenotype concordance as well as the biochemical function of NAT2 star alleles. The NAT2-PCEP assigned allele clinical function using CPIC's standard terminology (increased, decreased, uncertain, and unknown function) to 59 star alleles cataloged by the Pharmacogene Variation Consortium (PharmVar). Two alleles, NAT2*1 and NAT2*4, were assigned increased function (historically known as rapid), 40 alleles were assigned decreased function (historically known as slow), 10 alleles were assigned uncertain function, and seven alleles were assigned unknown function. Rigorous evidence review and in-depth PCEP discussion were crucial in determining these function assignments. The findings reported here underscore the importance of standardized allele functional terms and diplotype-to-phenotype assignments to further the clinical implementation of NAT2 pharmacogenetic test results.

Arylamine N-Acetyltransferase↗

PubMed2026

Development of a PCR-based technique for genotyping UGT1A1 gene and distribution of rs3064744 alleles in the Russian population.

BACKGROUND: Accurate determination of tandem thymine-adenine (TA) repeat numbers in the UGT1A1 promoter region (rs3064744) is essential for diagnosing Gilbert's syndrome and personalizing therapy with toxic agents like irinotecan and atazanavir. However, traditional polymerase chain reaction (PCR) assays face severe limitations due to the AT-rich sequence and overlapping melting temperatures (Tm) of the highly homologous 7TA and 8TA alleles. In this context, melting curve analysis (MCA) employing fluorophore-quencher systems has emerged as a promising alternative. The purpose of this study was to develop a novel genotyping approach combining optimized aPCR-MCA analysis with an automated classifier to overcome the limitations posed by the differentiation of highly homologous alleles and to demonstrate its practical application, providing the distribution of rs3064744 genotypes across four regional cohorts of the Russian population. METHODS: A specialized Dual Head 1D-convolutional neural network (1D-CNN) ensemble with Test-Time Augmentation (TTA) was developed. The model was trained and internally validated on 1,620 engineered plasmid samples, and independently evaluated on an external clinical test set of 440 unique patient genomic DNA specimens. Real-time PCR was performed on CFX96 and DTprime platforms. Additionally, population-wide screening was conducted on 997 archival clinical samples from Moscow, Sakha (Yakutia), Dagestan, and Rostov regions. RESULTS: While 5TA and 6TA alleles were easily separated, absolute Tm distributions of 7TA and 8TA alleles overlapped significantly, and non-uniform Tm shifts of 0.8 °C-1.4 °C occurred across platforms. Conventional absolute Tm thresholding was therefore inadequate. By assessing relative morphological curve divergence against co-amplified 7TA/7TA and 7TA/8TA reference anchors, the 1D-CNN ensemble neutralized instrument noise. It achieved 100% accuracy on internal validation and 100% concordance (440/440) with clinical reference pyrosequencing. Population screening revealed that Dagestan, Yakutia, and Rostov cohorts closely align with the European population. Rare 5TA and 8TA alleles were detected at low frequencies in Yakutia and Moscow. CONCLUSION: Combining LNA-modified aPCR-MCA with a comparative 1D-CNN model successfully circumvents thermodynamic limitations and eliminates human operator bias. This integrated system offers an accessible, high-throughput, and clinically valid solution for routine UGT1A1 pharmacogenetic testing.

1D-CNN↗

PubMed2024

Associations between (pharmaco-)genetic markers and postoperative pain after inguinal hernia repair - a prospective study protocol.

BACKGROUND: Postoperative pain is a common complication following surgery, with severity and duration varying between patients. Chronic postoperative pain after inguinal hernia surgery has an incidence rate of approximately 10%. Risk factors for acute and chronic pain following hernia surgery include age, sex, psychosocial factors, and demographic background. Additionally, genetic polymorphisms in enzymes involved in pain mechanisms, as well as the metabolism of analgesics might influence pain perception, pain development, and response to pain medications. Key enzymes include the catechol-o-methyltransferase (COMT), the µ-opioid receptor 1 (OPRM1), and the cytochrome P450 2D6 (CYP2D6). CYP2D6 plays a crucial role in metabolizing analgesics such as tramadol, codeine, and oxycodone. It is also suspected to be involved in the synthesis of catecholamines and endogenous morphines suggesting a potential role in pathophysiology of pain. We hypothesize that the CYP2D6 activity influences the development of postoperative pain after hernia surgery. METHODS: This study is a prospective, observational, multicenter association study investigating adult patients scheduled for inguinal hernia surgery using a robotic-assisted (rTAPP) approach. Patients are enrolled during the preoperative surgical consultation. A buccal swab is collected for genetic testing at this time. Pain at the site of the hernia is assessed using the validated EuraHSQoL score preoperatively and at 2, 4, and 6 weeks postoperatively. Additionally, information on co-medication and details of the surgery will be collected. The planned number of participants is 350 patients. The primary objective is to analyze the association between different genotype-predicted CYP2D6 phenotypes and patient-reported pain intensity 6 weeks after surgery. Secondary objectives include the association between further genetic variants, such as the COMT rs4680 and OPRM1 rs1799971 genotype, and pain severity. Additionally, the potential of pharmacogenetic panel testing to optimize analgesic therapy in hernia surgery patients will be explored. DISCUSSION: The findings of this study are expected to provide valuable insights into identifying patients at higher risk for postoperative pain before surgery. This knowledge could pave the way for tailored interventions during and after surgery for these specific patients. TRIAL REGISTRATION: Deutsches Register Klinischer Studien https://www.drks.de/DRKS00034796 Registered on August 07, 2024.

Genetic Association Studies↗

PubMed2025

Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease.

BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

Humans↗

PubMed2026

Beyond enrichment: pharmacogenetic heterogeneity in treatment-resistant depression.

OBJECTIVES: Genetic variation has been proposed as a potential contributor to antidepressant nonresponse, but its role in treatment-resistant depression (TRD) remains unclear. This study used pharmacogenetics (PGx) to characterize genetic variation in TRD and determine whether actionable PGx variation and drug-gene interaction (DGI) mismatch were associated with antidepressant nonresponse and TRD burden. METHODS: This observational study included 158 individuals with TRD recruited from outpatient clinics in Western Australia. Genotype and genotype-predicted phenotypes for CYP2B6, CYP2C19, and CYP2D6 were derived from commercial PGx testing and compared with ethnicity-matched reference populations from ClinPGx. Antidepressant-specific DGIs were classified as actionable or nonactionable according to Clinical Pharmacogenetics Implementation Consortium guidelines, and unsupervised clustering was used to identify clusters based on these actionability profiles. Analyses were performed to determine if actionable PGx variation, cluster membership, or PGx mismatch was associated with TRD burden (number of failed antidepressant trials). RESULTS: PGx variation in the TRD cohort was consistent with population expectations, with no evidence of enrichment for actionable PGx variants. Clustering identified six clusters with distinct and gene-specific patterns of PGx variation independent of demographic and clinical characteristics. However, neither PGx mismatch nor cluster membership were associated with TRD burden. CONCLUSION: These findings suggest that actionable PGx phenotypes are neither enriched in TRD nor associated with greater TRD severity. Rather, the results indicate that TRD does not represent a single, unified PGx-predicted 'poor pharmacological responder' phenotype but instead reflects a biologically heterogeneous collection of distinct PGx profiles.

antidepressants↗

PubMed2026

Organoids in translation: a bench-to-bedside framework for pancreatic cancer precision medicine.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a 5-year survival rate of < 13%. Standard treatments such as FOLFIRINOX or gemcitabine/nab-paclitaxel yield modest response rates, underscoring the urgent need for precision oncology approaches. Patient-derived organoids (PDOs) preserve the genomic, phenotypic, and histopathological features of the source tumor and offer a promising platform for drug screening, biomarker development, and personalized therapy. However, a systematic evaluation of their translational capacities is lacking. METHODS: A systematic review was conducted according to the PRISMA 2020 guidelines (PROSPERO registration pending) using PubMed, EMBASE, and Cochrane CENTRAL (December 10, 2024) to identify English-language PDAC PDO studies that incorporated therapeutic testing. Ninety-five studies met the inclusion criteria. Data extraction captured >75 variables per study, including spanning culture methodology, therapeutic profiling, biomarker integration, and clinical correlation. A 13-domain weighted Translatability Scoring Framework adapted from Wehling et al. assessed predictive validity, biomarker strength, pharmacogenetics, and clinical trial alignment. Scores ranged from 0 to 5 and were categorized as good (>4.0), moderate (3.0-4.0), or low (<3.0) translational potential. RESULTS: Of the 95 studies, 70.5% have been published since 2021, reflecting the rapid growth in this field. The mean PDO generation success rate was 89.7%, with the primary tumor tissue being the predominant source (48.4%). Only 24.8% were directly linked to clinical trials and 5.3% incorporated multi-omic profiling. The median translatability score was 3.13 (range, 1.72-4.59): 45.3% of the studies had low translatability, 50.5% moderate, and only 4.2% had good translational potential. High-scoring studies consistently combine multi-omic biomarker platforms, in vivo validation, clinical outcome correlation, and prospective trial integration. Conversely, the weakest domains were pharmacogenetics, endpoint strategies, and biomarker validation, limiting their overall clinical relevance. CONCLUSIONS: PDOs have demonstrated strong feasibility and in vitro clinical correlation in PDAC; however, their clinical translation remains constrained by limited multi-omic integration, absence of pharmacogenomic modeling, and sparse clinical trial embedding. Standardization of protocols, adoption of harmonized and clinically relevant endpoints, and systematic incorporation of biomarker-driven co-clinical trial frameworks are urgently needed to transition PDOs from promising experimental surrogates to validating precision oncology tools capable of informing therapeutic decision-making in PDAC.

Humans↗

PubMed2026

HLA and non-HLA genetic analyses reveal suggestive variants associated with statin-induced liver injury.

BACKGROUND: Statins are widely prescribed for cardiovascular risk reduction and are generally well tolerated. However, they can cause drug-induced liver injury (DILI), and the genetic factors contributing to statin-DILI remain poorly understood. METHODS: HLA association and genome-wide association (GWAS) studies were conducted to identify genetic variants associated with statin-DILI. High-confidence cases (n=71) were identified from the Drug-Induced Liver Injury Network (DILIN) and compared with statin-exposed controls without liver injury (n=551) from the Indiana Biobank. Association testing was performed across ancestries and within ancestry, adjusting for age, sex, and three principal components of genotypes. Top variants were further evaluated in non-statin DILI cases and unexposed controls. In addition, we investigated the frequency of candidate variants among a comprehensive list of pharmacogenetic variants related to statins. RESULTS: HLA-DQA1*03:01 was significantly associated with increased risk of statin-DILI (OR=3.49, 95% CI 2.21-5.51, p-value=1.27×10-7), with enrichment observed across multiple ancestry groups, particularly non-Hispanic Black and Hispanic individuals. From the GWAS, three loci showed suggestive associations (p-value <5×10-06) with statin-DILI, including rs35197737 in RGS1 (OR=5.03, 95% CI 1.11-3.66, p=1.14×10-7), rs75629598 in FRMD4A (OR=4.4, 95% CI=2.33-8.12, p=3.97×10-6), and rs7658630 in the intergenic region on chromosome 4 (OR=4.86, 95% CI 2.66-8.85, p=2.68×10-7). No pharmacogenetic variants revealed statistical significance. CONCLUSION: We identified HLA and non-HLA genetic variants associated with statin DILI. Future studies with larger sample sizes should confirm these observations.

Humans↗

PubMed2026

Pharmacogenomic and drug interactions risk in cardio-oncology: A precision medicine perspective for India.

Cardio-oncology patients may face complex treatment regimens due to the concurrent existence of cancer and cardiovascular disease, leading to a considerable polypharmacy burden. This significantly increases the prospect of drug-drug interactions (DDIs) and gene-drug interactions. The majority of these interactions arise from comparable pharmacokinetic and pharmacological pathways associated with drug transporters and cytochrome P450 enzymes. The significance of pharmacogenomics in tailored treatment strategies are emphasised by the fact that genetic variability enhances individual differences in drug response, safety, and efficacy. This narrative review focus on the effects of key genetic polymorphisms (e.g., DPYD, CYP2C19, and CYP2C9) on the metabolism and efficacy of commonly prescribed anticancer and cardiovascular medications such as fluoropyrimidines, clopidogrel, and warfarin. In addition it explore the role of pharmacogenomic variants on drug-drug interactions within the field of cardio-oncology. The study ultimately emphasizes the necessity of precision medicine in India to address the genetic diversity and underrepresentation in global genomic databases. The absence of pharmacogenomic testing, infrastructural deficiencies, financial constraints, and insufficient clinical integration hinder the widespread use of this technology in India. The Genome India Project and other national initiatives establish the foundation for pharmacogenomic-guided therapy. Utilizing genetic data, together with artificial intelligence-based predictive tools, for clinical decision-making may enhance medication safety and yield optimal outcomes in Indian cardio-oncology patients.

Humans↗

PubMed2026

Fluoropyrimidine Cardiotoxicity: Role of Uridine Triacetate and Pharmacogenomic Insights from a Case of 5-FU-Induced Cardiogenic Shock.

Fluoropyrimidines, including 5-fluorouracil and capecitabine, are widely used antimetabolite agents and remain central to the treatment of several solid tumors, particularly gastrointestinal malignancies. However, they are a well-established cause of chemotherapy-related cardiotoxicity. Although coronary vasospasm is the best recognized manifestation, fluoropyrimidine cardiotoxicity encompasses a broad clinical spectrum, ranging from chest pain and arrhythmias to acute heart failure, and, rarely, fulminant cardiogenic shock. This review discusses severe fluoropyrimidine-associated cardiotoxicity through the illustrative presentation of a young woman without previous cardiovascular disease who developed acute biventricular dysfunction and cardiogenic shock shortly after first exposure to FOLFIRINOX, requiring temporary mechanical circulatory support. Administration of uridine triacetate within the recommended therapeutic window was associated with rapid recovery of ventricular function. Cardiac magnetic resonance imaging demonstrated diffuse myocardial edema without late gadolinium enhancement, consistent with reversible toxic-inflammatory myocardial injury. Expanded genomic analysis identified dihydropyrimidine dehydrogenase and thymidylate synthase variants not detected by standard pretreatment pharmacogenetic screening. In this study we examine the pathophysiological mechanisms of fluoropyrimidine cardiotoxicity, the rationale for uridine triacetate in severe presentations, and the potential role of expanded pharmacogenomic profiling within a precision cardio-oncology framework.

Humans↗

PubMed2026

Survey to inform personalised prescribing in a British South Asian community: pharmacogenomics and traditional medicine use.

BACKGROUND: Pharmacogenomics (PGx) uses genetic information to personalize medication, reducing adverse reactions and improving efficacy. Despite its promise, low public awareness and disparities in PGx acceptability among under-represented groups may exacerbate health inequalities. The objective of this study was to elucidate a British South Asian community's attitudes toward personalised prescribing. METHODS: Adults of Bangladeshi or Pakistani ancestry from the Genes & Health (G&H) study completed a survey. Community feedback guided theme prioritization. Multivariable logistic regression analyses (controlling for age and gender) explored relationships among survey variables, and case-control Genome Wide Association Studies (GWAS) and candidate variant enrichment analysis examined the genetic architecture underlying herbal remedy use. RESULTS: Out of 553 respondents (57% female, mostly aged 25-54), 72% reported medication inefficacy, and 54% experienced side effects. Herbal remedies were widely used (66%), notably Black seed (39%), Turmeric (37%), and Ginger (36%). Participants who reported not using traditional or herbal medicines had higher medication adherence MARS-5 scores (Odds Ratio (OR) 1.10, 95% Confidence Interval (CI) 1.05-1.16, p < 0.0002). All three commonly used herbal remedies inhibit the pharmacogenomically variable CYP2C9 enzyme responsible for metabolising commonly used medications. 58% of respondents were willing to provide DNA samples for PGx testing, yet 70% agreed that they would be more likely to take medication as instructed if PGx results suggested the medicine would suit them. Concerns about PGx testing were common (27%), especially among non-English speakers. Most (69%) were concerned about misuse of PGx data, particularly by pharmaceutical companies (82%). Importantly, 87% demanded stronger PGx data protections compared to other health data. CONCLUSIONS: Compared to a national UK population, the surveyed subpopulation reported higher rates of adverse drug reactions (ADRs) and perceived medication inefficacy, yet fewer respondents indicated willingness to undergo PGx testing. This highlights the need for tailored implementation strategies and underscores the importance of engaging underrepresented populations in policy development. The inverse relationship between medication adherence and herbal remedy use indicates an association between cultural health practices and medication behaviours that merits further investigation. Increased awareness of the common use of these CYP2C9 inhibitors and further research into the genetic architecture underlying herbal remedy use are warranted.

Humans↗

PubMed2026

Clinically Relevant Pharmacogenomic Variant Frequencies in Kazakh, Russian, and Uzbek Population Groups Residing in Kazakhstan.

Central Asian populations remain underrepresented in pharmacogenomic research, limiting the availability of population-specific data for genotype-informed prescribing and precision medicine. This study analyzed clinically relevant pharmacogenomic variant frequencies in Kazakh, Russian, and Uzbek population groups residing in Kazakhstan using genome-wide genotype data from 1301 individuals: Kazakh (n = 1111), Russian (n = 156), and Uzbek (n = 34). ClinPGx, a PharmGKB-based clinical annotation framework that prioritizes variant-drug associations according to levels of evidence, was used to select variants with evidence levels 1A, 1B, and 2A. In total, 112 directly genotyped variants were retained for population-specific allele and genotype frequency analysis. All 112 variants were queried against the gnomAD v4.1 genome and exome reference datasets. Of these, matching allele-frequency data for the predefined reported allele were available in at least one of the two gnomAD datasets for 103 variants, whereas for 9 variants the VEP-based query did not return a matching gnomAD frequency for that allele. Frequencies were reported for the same predefined reported allele across all groups, and differences between the study groups were assessed using 95% confidence intervals, Fisher's exact tests, and false discovery rate correction. Genotype counts and the proportions of individuals carrying at least one copy of the reported allele were also summarized for all selected variants. Several pharmacogenomic variants showed population-specific frequency patterns, including NUDT15 rs116855232, SLCO1B1 rs4149056, VKORC1 rs9934438, and UGT1A1 rs10929302. Comparison with gnomAD showed that the observed frequencies were variant-specific and could not be consistently approximated by a single broad genetic ancestry group. Reference-based population structure analysis provided additional ancestry context and supported separate reporting by population group. The study did not evaluate clinical outcomes or make individual prescribing recommendations, and the small Uzbek sample size limits the precision of frequency estimates for this group, particularly for rare variants. Overall, this study provides a clinically prioritized pharmacogenomic frequency resource for underrepresented population groups in Kazakhstan and supports broader Central Asian representation in pharmacogenomic implementation research.

Central Asia↗

PubMed2026

Comparative Effectiveness of Pharmacogenomics for Treatment of Depression.

PURPOSE/BACKGROUND: Pharmacogenomics (PGx), or the use of genetic information to assess drug-gene interactions, is an important step toward precision medicine. It is unclear if clinician use of PGx yields better outcomes for their patients. This study compared the effectiveness of combinatorial PGx-guided plus guideline-informed treatment (PGx+GIT) with guideline-informed treatment (GIT) alone to improve well-being in individuals with major depressive disorder. METHODS/PROCEDURES: Eligible participants (N=201) were randomized to PGx+GIT or GIT alone. PGx was measured with the proprietary GeneSight combinatorial test. PGx+GIT participant clinicians received test results within 2 business days to inform decisions about medication changes. Participants completed the World Health Organization Well-Being Index (WHO-5), Patient Health Questionnaire (PHQ-9), and PROMIS Profile physical functioning and social roles and activity domains every 2 weeks for 2 months and then every 2 months for the remaining 10 months. Monthly medication changes operationalized as necessary clinical adjustments were tracked with the medication recommendation tracking form. FINDINGS/RESULTS: Both groups improved average well-being over the 12-month study period (model-based change in WHO-5 per log (week) [95% CI]: 4.1 [3.3, 5.0] PGx+GIT and 4.8 [4.0, 5.5] GIT). PGx+GIT did not result in superior improvement in well-being (model-based difference [95% CI]: -0.6 [-1.8, 0.5], P =0.270), or any secondary outcomes. The effect of randomized treatment on well-being was not moderated by depression severity, number of previous failed medications for major depressive disorder, or presence of a comorbid condition. IMPLICATIONS/CONCLUSIONS: These data suggest PGx+GIT was not superior to GIT alone, possibly due to a ceiling effect of GIT, or PGx did not yield better results.

Humans↗

PubMed2025

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

Humans↗