AIMS:Finding suitable psychotropic medications can be a lengthy trial-and-error process, leading to poor symptom control, low adherence, and treatment failure. Pharmacogenomic (PGx) testing can help inform prescribing considerations for some individuals. As PGx becomes more common in Canada, understanding patients' and families' hopes, expectations, and concerns is vital. MATERIALS AND METHODS:This article details our work engaging two advisory councils comprised of five youth with lived/living experience of mental health challenges and five caregivers across four videoconferencing sessions (between June 2025 and February 2026) aimed at co-designing a qualitative study on perceptions of PGx testing for psychotropic medication prescribing among youth and caregivers. Verbal and written input was gathered from council members and incorporated using iterative feedback cycles. RESULTS:The advisory councils challenged our assumptions and ensured the study design aligned with their lived-experience perspectives. Some suggestions differed between youth and caregiver advisors. Impacts included changes to eligibility criteria, flexible participation options to promote accessibility, and the use of inclusive language in study materials. CONCLUSIONS:We recommend that future PGx research actively involves those with lived/living experience to ensure the field is shaped by those it aims to serve.
INTRODUCTION:Our study is the first study, in Tunisia, to investigate the effect of SNPs in CYP3A5, CYP3A4, ABCB1, and POR genes on the response to cyclosporine (CsA). METHODS:In a retrospective study, a total of 78 renal transplant patients receiving CsA and mycophenolate mofetil (MMF) were recruited. Genotyping was performed using PROFLEX-PCR followed by RFLP. RESULTS:We found a significant lower C0/D CsA in patients with at least one CYP3A4*1B allele compared to the wild type (p = 0.001). We found a statistically significant increased risk of acute and chronic rejection associated with carrying CYP3A5*1/*1 or *1/*3 compared to the CYP3A5*3/*3 and of carrying CYP3A*51B/*1B or *1/*1B compared to the CYP3A4*1/*1 (p = 0.001). The occurrence of leukopenia was significantly decreased in patients with at least one CYP3A4*1B allele (p = 0.01). and the occurrence of diarrhea was significantly increased in patients carrying the variant allele of ABCB1-3435C>T (p = 0.005). CONCLUSION:Our results support the usefulness of CsA pharmacokinetics tests in prekidney transplant assessments.
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.
Major depressive disorder (MDD) remains a significant illness worldwide, yet antidepressant therapy often follows an empirical "trial-and-error" approach. Escitalopram, a selective serotonin reuptake inhibitor is approved for MDD and generalized anxiety disorders, while aripiprazole (ARI), an atypical antipsychotic, is used as adjunctive therapy in treatment-resistant depression. Despite the broad availability of these agents, outcomes remain suboptimal. Data from the STAR*D trial indicate that only one-third of patients achieve remission after their first antidepressant trial, with many requiring multiple adjustments. This reactive approach prolongs symptom burden, increases adverse effects, and delays effective treatment.Advances in pharmacogenomics now offer a means to individualize therapy by identifying genetic polymorphisms - such as those found in CYP2C19 and CYP2D6-that influence escitalopram and aripiprazole metabolism and response. This literature review examines the evidence linking pharmacogenomic variability to antidepressant outcomes and explores how implementing genetic-guided prescribing can improve efficacy, reduce adverse effects, and enhance the pharmacists' role in mental health care.
AIM:Attention-deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder, with methylphenidate (MPH) as the first-line treatment. MPH primarily exerts its effects by inhibiting the dopamine transporter (DAT); therefore, variants in the DAT1 gene may affect susceptibility to its adverse effects. METHODS:This study included 47 children and adolescents diagnosed with ADHD according to DSM-5-TR criteria who were receiving MPH treatment. MPH-related adverse effects were assessed using the Barkley Stimulants Side Effects Rating Scale. Participants were categorized into groups based on whether they experienced adverse effects. The exons of the DAT1 gene were sequenced using NGS. RESULTS:A total of 16 variants were identified in the DAT1 gene, including intronic, untranslated region, synonymous, splice-region, and splice polypyrimidine tract variants. One rare intronic deletion variant, c.1032-44_1032-42del, was classified as a VUS. Genetic association analyses identified significant associations for rs1042098 under the genotypic (p = 0.003; BH q = 0.019) and dominant (p = 0.037; BH q = 0.091) models, and for rs6876890 under the genotypic model (p = 0.008; BH q = 0.044). CONCLUSIONS:Our findings suggest that specific DAT1 gene polymorphisms, particularly rs1042098 and rs6876890, may be associated with MPH-related adverse effects in children and adolescents with ADHD.
INTRODUCTION:Drug-induced liver injury affects some people living with HIV (PWH) during antiretroviral therapy (ART). We examined associations of polygenic risk scores (PRS) with liver injury during ART. METHODS:We derived PRS using summary statistics from the Veterans Affairs Million Veteran Program (MVP) and the Penn Medicine BioBank (PMBB). We constructed PRS for individuals of African (AFR) and European (EUR) ancestry in 3,619 treatment-naïve participants from ART-naive studies of the Advancing Clinical Therapeutics Globally (ACTG) network. Liver injury was defined as incident grade 3 or greater alanine aminotransferase (ALT) within 48 weeks. Associations were evaluated by multivariable regression models. RESULTS:Clinical variables associated with higher baseline ALT values included hepatitis B or C virus infection, increasing BMI and age, and male sex. In analyses of liver injury among 1,897 EUR participants (28 cases, 1869 controls) and 1722 AFR participants (21 cases, 1701 controls), HBV was associated with liver injury in both EUR and AFR participants, and HCV in EUR participants (p < 0.001 for each). PRSALT was not independently associated with incident liver injury in either EUR or AFR participants. CONCLUSION:No association was observed between baseline PRSALT and subsequent liver injury following initiation of ART.
BACKGROUND:Reports about relevance of three common and linked ABCB1 polymorphisms (c.2677G>T/A, c.1236C>T, c.3435C>T) for exposure to- and functional outcomes in tacrolimus-treated renal transplant patients are inconsistent. METHODS:Tacrolimus morning troughs/dose-corrected troughs and serum creatinine/estimated glomerular filtration rate (eGFR) were measured on 6th-7th and 8th-10th postoperative day in tacrolimus-mycophenolate-treated renal transplant patients. Exposure was defined as the number of ABCB1 variant alleles (three levels; 0-1 variant = control) or as diplotypes (three levels, wild-type = control). Four target trials were emulated (2 exposure definitions × 2 outcome categories) contrasting exposed and controls for ln-transformed outcomes, and for creatinine/eGFR also on natural scales. Complementary mediation analysis related exposure, troughs, and eGFR. RESULTS:The 173 enrolled patients provided 316 paired trough and creatinine/eGFR values. After correction for strong residual confounding, all GMRs (95% CrI) for troughs remained within the 0.75-1.33 range. All GMRs (95% CrI) for ln-trasformed creatinine/eGFR were within the 0.75-1.33 range. On the natural scale, creatinine/eGFR differences were within -26.5 to 26.5 μmol/L and -5.0 to 5.0 mL/min/1.73 m2, respectively. In mediation analysis, direct, indirect, and total effects were within the same ranges. CONCLUSIONS:Renal transplant recipients subsetted by genotypes across the three common ABCB1 polymorphisms display closely similar tacrolimus troughs and graft function early after transplantation.
Major depressive disorder (MDD) is treated largely by trial and error, despite marked interindividual variation in antidepressant exposure, efficacy and tolerability. Pharmacogenomics (PGx) has therefore been proposed as a route to stratified antidepressant treatment. This Review asks whether current evidence supports that claim by distinguishing actionable drug-gene guidance, clinical utility in broad trial populations and subgroup evidence for stratified care. Contemporary guidance supports genotype-informed prescribing for selected antidepressants, most consistently through CYP2D6 and CYP2C19 and, for selected serotonin reuptake inhibitors, CYP2B6, whereas SLC6A4 and HTR2A are not clinically actionable for antidepressant prescribing. Randomized and pragmatic trials show that PGx reduces drug-gene mismatched prescribing more reliably than symptom outcomes in unselected MDD samples. Meta-analyses suggest small-to-moderate short-term response or remission gains, with larger signals in treatment-exposed, severe or difficult-to-treat patients. PGx is therefore not simply weakly useful for everyone; its strongest current role is selective, subgroup-enriched prescribing where exposure mismatch is plausible. A practical roadmap is to restrict current interpretation to guideline-supported CYP2D6/CYP2C19/CYP2B6 gene-drug pairs, prioritize testing before affected antidepressants or after nonresponse, intolerance or polypharmacy, avoid broad proprietary class assignment, and validate stratified claims in prospective enriched trials.
IntroductionMany people with major depressive disorder (MDD) undergo a lengthy process of trial-and-error before finding a medication that works well for them. Pharmacogenomic (PGx) testing for MDD can help find a suitable antidepressant faster. However, concerns about health equity, and data privacy and security need to be considered before implementing the test.MethodsIn Fall 2024, 30 individuals attended a four-day public deliberation in Vancouver, British Columbia (BC) to provide direction on implementing PGx testing for MDD in BC's publicly funded healthcare system. Participants were recruited to represent a diversity of perspectives and experiences of British Columbians. Information supports included expert speakers and a background booklet. Event transcripts were analyzed using thematic analysis (both inductive and reflexive), while also accounting for participants' knowledge gains over time.ResultsParticipants adopted four policy-relevant positions on implementation: 1) PGx test results should be treated like other lab results; 2) stored in electronic medical records; 3) shared with patients and healthcare professionals in the circle of care; and 4) education about the test will facilitate its widespread use.ConclusionParticipants' positions represent informed, civic-minded, and policy-relevant priorities for the acceptable adoption of PGx testing for MDD in the BC healthcare system and elsewhere.
Despite the promise of personalized medicine, the clinical implementation of pharmacogenomics (PGx) remains limited. Several barriers limiting implementation of PGx have been identified, some of which include provider awareness, uncertainty of clinical utility, and reimbursement issues. As clinical PGx programs have increased, different service models have been established; however, none have been formally described. We aimed to describe and compare current service models to establish a best practice workflow for future PGx programs. Qualitative interviews with 15 PGx providers across the United States were conducted and analyzed using an inductive content analysis approach. All respondents had an e-consult (provider-to-provider) model, with seven also providing a PGx specialty clinic for patients. Reported challenges include lengthy testing processes, scheduling delays, and billing uncertainty. The majority of participants described an ideal PGx workflow as a "low-touch" tiered approach where frontline pharmacists offer testing, and PGx experts are a resource for complex drug-gene interactions. This tiered approach should be explored for future PGx implementations.
Pharmacogenomics (PGx) is transforming how we treat cardiovascular disease (CVD) by enabling us to select and dose drugs based on our genetic profiles. The pharmacokinetics and pharmacodynamics of commonly prescribed cardiovascular drugs are greatly affected by gene-drug interactions, which improve the therapeutic outcome and reduce adverse drug reactions. This narrative review will summarize evidence on the clinical use of pharmacogenomics (PGx) in cardiology published between 2020 and 2025. The pharmacogenes that have been proved to be clinically useful in the genotype-guided therapy include CYP2C19, SLCO1B1, VKORC1, and CYP2D6. An example is that the use of CYP2C19-guided antiplatelet therapy following percutaneous coronary intervention has been linked to a lower risk of major adverse cardiovascular events (MACE). Similarly, SLCO1B1 genotyping can be used to prevent statin-induced myopathy, with VKORC1 and CYP2C9 variant used to warfarin dosing to reduce the risk of bleeding. Emerging technologies such as polygenic risk scores (PRS) and machine learning (ML) are expanding PGx by capturing multi‑gene contributions to drug response. In this critical review, validated gene-drug interactions are critically evaluated, and a translational roadmap is outlined to implement PGx in the cardiovascular practice to achieve precision medicine and to improve patient-specific outcomes.
Interindividual variability in drug response is a challenge in pediatric oncology, where the risk of treatment-related toxicity is exacerbated by narrow therapeutic windows and combination therapies. Pharmacogenetics (PGx) aims to reduce this variability by linking genetic variants to differences in drug pharmacokinetics, efficacy, and toxicity. Although evidence-based pharmacogenetic guidelines are available covering over 100 gene-drug pairs, systematic use of pre-emptive PGx screening is not yet embedded in routine pediatric oncology care. In a recent study, we demonstrated the relevance of pre-emptive PGx screening in pediatric oncology by showing that 16% of 1,151 patients were eligible for genotype-based drug dose or treatment modifications. Building on these findings, we implemented pre-emptive PGx screening into clinical practice of pediatric oncology in the Netherlands. Successful implementation required addressing challenges, including adaptation of existing infrastructure, interpretation of pharmacogenetic results for a pediatric population, integration into electronic health records, and education of clinical staff. We repurposed diagnostic germline whole genome sequencing (WGS) for individual genetic profiling and applied existing pharmacogenetic guidelines to guide drug dosing and treatment decisions. Here, we describe our implementation strategy for pre-emptive PGx screening in pediatric oncology and share insights to support other centers aiming to integrate PGx screening into routine care.
Existing literature demonstrates the benefits of DPYD and UGT1A1 pharmacogenetic (PGx) testing to reduce toxicity from fluoropyrimidines and irinotecan, respectively. The Food and Drug Administration (FDA) has provided UGT1A1-guided irinotecan dosing for 20 years, and in 2025, the FDA and National Comprehensive Cancer Network both updated their guidance to recommend DPYD testing prior to fluoropyrimidine therapy. As such, there is an increasing interest in testing and a need for guidance describing implementation strategies. This review summarizes conclusions from DPYD and/or UGT1A1 implementation initiatives and describes key takeaways related to perspectives, workflow, cost, and supportive care from 32 included articles. Perspectives toward testing were generally positive, although barriers such as turnaround time and cost concerns were still identified. Workflow integration varied by institution, but a clear delineation of duties was consistently necessary. For both DPYD and UGT1A1, real-world studies and modeling data indicate testing is cost-effective. PGx testing was underutilized for supportive care medications despite its relevance, but there is an opportunity to leverage panel-based approaches to increase utilization without additional workflow burden. Description of these key considerations and takeaways reported by those implementing DPYD and/or UGT1A1 PGx testing would be beneficial to institutions in the early phases of implementation.
AIMS:Despite over 400 high-evidence drug-gene associations in pharmacogenomic (PGx) guidelines and drug labels, prioritizing drugs for clinical PGx research remains challenging when local outcome data are limited. In Saudi Arabia, PGx studies have primarily focused on variant frequencies rather than drug-specific outcomes. This study aimed to develop a scalable framework to prioritize most frequently prescribed drugs for future clinical PGx investigation in the Saudi population. PATIENTS AND METHODS:We analyzed 2,035 real-world reports of adverse drug reactions (ADRs) or therapeutic inefficacy across 450 drugs. A multi-criteria scoring framework combined six weighted domains reflecting Genetic Plausibility (prior PGx evidence, family history, onset timing) and Clinical Significance (signal volume, issue level, issue rate). Robustness was assessed using sensitivity analyses and external evidence triangulation. RESULTS:ADRs accounted for ~75% of reports and produced the strongest prioritization signals. Top-ranked drugs showed convergence between real-world clinical signals, guideline-supported PGx mechanisms, and previously reported Saudi genetic data. The framework reproduced three clinically relevant drug-gene associations previously reported in Saudi cohorts. CONCLUSIONS:This Phase-1 initiative provides a structured, reproducible approach for PGx drug prioritization in Saudi Arabia and a practical roadmap for building locally relevant clinical PGx evidence.
BACKGROUND:Late-life depression (LLD) and chronic low back pain frequently co-occur and exacerbate one another. Outcomes with antidepressant treatment in this population are often suboptimal. Pharmacogenetic factors may help explain variability in antidepressant response. Building on prior findings suggesting that SLC6A2 variation predicts venlafaxine response in LLD, we examined whether such genetic associations extend to older adults with chronic low back pain in the ADAPT study (Addressing Depression and Pain Together). METHODS:Older adults with LLD and chronic low back pain received venlafaxine treatment over 20 weeks. The primary analysis focused on the SLC6A2 rs2242446 variant, whereas secondary analyses evaluated 37 variants across 14 candidate genes implicated in depression or pain. Outcomes included percentage improvement in PHQ-9 scores, remission, and time to remission. RESULTS:Genotype data were available for 101 participants. Primary analyses showed no association between SLC6A2 rs2242446 and any outcome measure. In secondary analyses, the serotonin 1A receptor gene (HTR1A) variant rs6295 emerged as the most consistent nominal genetic signal. CONCLUSION:Previously reported pharmacogenetic signal involving SLC6A2 did not extend to a more clinically complex population, whereas exploratory serotonergic variation showed a nominal association. Findings inform pharmacogenetic research in late-life depression with comorbid pain.Clinical trial registration identifier is NCT01124188.
BACKGROUND:Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzymatic disorder that is often asymptomatic until exposure to oxidative stress, such as certain medications. Rasburicase, used for tumor lysis syndrome (TLS) prophylaxis, can trigger hemolysis in G6PD-deficient patients. CASE PRESENTATION:We report a nine-year-old Asian boy with acute myeloid leukemia (AML) and hyperleukocytosis who developed severe hemolytic anemia and methemoglobinemia shortly after receiving rasburicase for TLS. Enzymatic testing suggested G6PD deficiency but was unreliable due to hyperleukocytosis. Rasburicase was discontinued, and supportive care with ascorbic acid led to rapid clinical improvement. Subsequent gene-panel analysis using whole exome sequencing (WES) confirmed a pathogenic class B G6PD variant (Viangchan). CONCLUSION:This case highlights the need for caution when administering rasburicase to patients with unknown G6PD status, particularly in individuals from regions or ethnic groups with a high prevalence of G6PD deficiency. Enzymatic testing may become unreliable due to hyperleukocytosis or recent transfusions. Therefore, close monitoring of hemolysis parameters with a low transfusion threshold in acute hemolytic anemia is essential. Genotyping using WES or whole genome sequencing (WGS) provides definitive G6PD variant classification. This enables careful dose adjustments and proactive monitoring for G6PD-related hemolysis caused by high-risk drugs in pediatric oncology.
AIM:The impact of the CYP2C:TG haplotype on CYP2C19-mediated omeprazole metabolism was evaluated. PATIENTS AND METHODS:CYP2C19 enzymatic activity was assessed in 234 volunteers from Nicaragua and Ecuador using the omeprazole/5-hydroxyomeprazole metabolic ratio within a validated CEIBA cocktail protocol. Genotyping included CYP2C19 alleles (*2, *3, *4, *5, *17) and CYP2C:TG defining CYP2C18 variants (rs2860840, rs11188059). Associations among the CYP2C:TG haplotype, CYP2C19 genotype, and metabolic ratio were analyzed using univariate and multivariate models. RESULTS:The CYP2C:TG haplotype was the second most frequent (33.76%) and occurred exclusively with the CYP2C19 *1 allele. No significant association was observed between CYP2C:TG haplotype and the metabolic ratio (p = 0.12). Across predicted metabolizer groups, a trend toward increased CYP2C19 metabolism was observed, although this difference did not reach statistical significance. CONCLUSION:In these admixed Latin American populations, the CYP2C:TG haplotype was not significantly associated with CYP2C19-mediated omeprazole metabolism. This finding does not support clinical implementation of CYP2C:TG haplotype testing for predicting CYP2C19 activity and underscores the need for further research on this haplotype and its potential role in CYP2C19 metabolism across diverse populations in the context of pharmacogenetics.
On November 5-8, 2025, the European Society of Pharmacogenomics and Personalized Therapy (ESPT) organized its 8th biennial congress, this time in Rotterdam, The Netherlands (www.esptcongress.org). The congress aimed to address the current status and future perspectives of pharmacogenomics, share the latest knowledge in this field of precision medicine and showcase the implementation of clinical applications in pharmacogenomics/pharmacogenetics. The 4-day congress consisted of in total 60 lectures given by key-opinion leaders, divided in 11 sessions, and included four national mini-symposia, two poster sessions of in total 160 posters and a discussion forum. The successful event enabled the exchange of information between 514 participants from 42 different countries and 20 industry partners on the current use, future aspects, and challenges of pharmacogenetics and its clinical implementation.
The management of high-bleeding risk (HBR) patients undergoing percutaneous coronary intervention (PCI) for an acute coronary syndrome (ACS) remains a significant challenge, requiring careful balancing of ischemic prevention and bleeding avoidance. Bleeding risk reduction in patients with HBR treated with newer-generation drug-eluting stents includes P2Y12 inhibitor intensity de-escalation, shortening of the dual antiplatelet therapy (DAPT) duration and monotherapy with a P2Y12 inhibitor. Although data for HBR patients are limited, an individualized approach is required. Preference for a short DAPT duration and use of clopidogrel where indicated may reduce bleeding incidence without incurring ischemic risk. Pharmacogenomic testing for CYP2C19 helps personalize antiplatelet therapy in specific patient subgroups. We herein discuss current data and limitations of DAPT strategies in the understudied HBR patient population with ACS undergoing PCI. A literature search of PubMed/MEDLINE and Embase (inception-January 2026) identified randomized trials, meta-analyses, registries, and major guidelines (ESC, ACC/AHA, JCS) on ACS, high-bleeding risk, CYP2C19-guided antiplatelet strategies, de-escalation, and monotherapy. Individualized antiplatelet therapy, genetic characteristics and clinical parameters, should be integrated in the management of such patients. Clopidogrel pharmacogenomics and modern monotherapy or short DAPT strategies promise improved safety and efficacy, with the patient at the center of the therapeutic decision.
Aim Assess the acceptance of genotype-based pharmacist recommendations made within a pharmacogenetics (PGx) clinic. Methods Patients seen by the UF Health PGx clinic between 2017 and 2022 were included in a retrospective chart review. We evaluated CYP2D6/CYP2C19 and three drug classes (opioids, selective serotonin reuptake inhibitors [SSRIs], proton pump inhibitors [PPIs]). Gene-drug pairings were classified as concordant/discordant based on pharmacist recommendations, derived from guidelines. The concordance was compared between baseline, or time that PGx results were available, at 3- and 12-months after the visit. Acceptance of recommendations was inferred by a reduction in discordant gene-drug pairs. Results 201 patients with PGx results were seen at the clinic. There were 101 relevant prescriptions at baseline; of these 50 (50%) were discordant based on CYP2C19/CYP2D6 phenotypes. This decreased to 22 (22%); acceptance rate = 56% at 3-months (28 of 50 recommendations accepted), p-value < 0.05. At baseline, there were 28 SSRIs prescriptions, 18 (64%) were discordant versus 7 (25%) at 3-months; acceptance rate = 61%, p-value < 0.05. Of the 60 PPIs prescriptions at baseline, 25 (42%) were discordant, decreasing to 6 (10%) at 3-months; acceptance rate = 76%, p-value < 0.05. Conclusion We observed a reduction in discordant gene-drug pairs as a result of PGx pharmacist recommendations acceptance.
