J Affect Disord. 2025 Apr 3:S0165-0327(25)00564-6. doi: 10.1016/j.jad.2025.04.012. Online ahead of print.

ABSTRACT

BACKGROUND: Treatment-resistant depression (TRD) affects one-third of major depressive disorder (MDD) patients. Previous pharmacogenetic studies suggest genetic variation may influence medication response but findings are heterogeneous. We conducted a comprehensive genetic investigation using proxy TRD phenotypes (TRDp) that mirror the treatment options of MDD from UK Biobank primary care records.

METHODS: Among 15,125 White British MDD patients, we identified TRDp with medication changes (switching or receiving multiple antidepressants [AD]); augmentation therapy (antipsychotics; mood stabilizers; valproate; lithium); or electroconvulsive therapy (ECT). Hospitalized TRDp patients (HOSP-TRDp) were also identified. We conducted genome-wide association analysis, estimated SNP-heritability (hg2), and assessed the genetic burden for nine psychiatric diseases using polygenic risk scores (PRS).

RESULTS: TRDp patients were more often female, unemployed, less educated, and had higher BMI, with hospitalization rates twice as high as non-TRDp. While no credible risk variants emerged, heritability analysis showed significant genetic influence on TRDp (liability hg2 21-24 %), particularly for HOSP-TRDp (28-31 %). TRDp classified by AD changes and augmentation carried an elevated yet varied polygenic burden for MDD, ADHD, BD, and SCZ. Higher BD PRS increased the likelihood of receiving ECT, lithium, and valproate by 1.27-1.80 fold. Patients in the top 10 % PRS relative to the average had a 12-36 % and 24-51 % higher risk of TRDp and HOSP-TRDp, respectively.

CONCLUSIONS: Our findings support a significant polygenic basis for TRD, highlighting genetic and phenotypic distinctions from non-TRD. We demonstrate that different TRDp endpoints are enriched with various spectra of psychiatric genetic liability, offering insights into pharmacogenomics and TRD's complex genetic architecture.

PMID:40187433 | DOI:10.1016/j.jad.2025.04.012

Cell Rep Med. 2025 Apr 2:102053. doi: 10.1016/j.xcrm.2025.102053. Online ahead of print.

ABSTRACT

Application of machine learning (ML) on cancer-specific pharmacogenomic datasets shows immense promise for identifying predictive response biomarkers to enable personalized treatment. We introduce CAN-Scan, a precision oncology platform, which applies ML on next-generation pharmacogenomic datasets generated from a freeze-viable biobank of patient-derived primary cell lines (PDCs). These PDCs are screened against 84 Food and Drug Administration (FDA)-approved drugs at clinically relevant doses (Cmax), focusing on colorectal cancer (CRC) as a model system. CAN-Scan uncovers prognostic biomarkers and alternative treatment strategies, particularly for patients unresponsive to first-line chemotherapy. Specifically, it identifies gene expression signatures linked to resistance against 5-fluorouracil (5-FU)-based drugs and a focal copy-number gain on chromosome 7q, harboring critical resistance-associated genes. CAN-Scan-derived response signatures accurately predict clinical outcomes across four independent, ethnically diverse CRC cohorts. Notably, drug-specific ML models reveal regorafenib and vemurafenib as alternative treatments for BRAF-expressing, 5-FU-insensitive CRC. Altogether, this approach demonstrates significant potential in improving biomarker discovery and guiding personalized treatments.

PMID:40187357 | DOI:10.1016/j.xcrm.2025.102053

Int Immunopharmacol. 2025 Apr 4;154:114554. doi: 10.1016/j.intimp.2025.114554. Online ahead of print.

ABSTRACT

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly concerning global health issue characterized by pronounced hepatic steatosis and liver fibrosis. Hepatic monocyte-derived macrophages (MDMs) are crucial in the pathogenesis of liver fibrosis under MASLD. Nevertheless, the precise functions of MDMs and the underlying mechanisms governing their differentiation remain inadequately elucidated. In this study, we revealed an orchestrator of this process: Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB), one of the characteristic genes of MDMs. Notably, myeloid-specific Gpnmb-knockout contributed to the retention of resident Kupffer cells (KCs) and rerouted monocyte differentiation towards a monocyte-derived macrophage subset that occupies the Kupffer cell niche (MoKC subset, resembling resident KCs), thereby impeding the formation of hepatic lipid-associated macrophages (LAMs). This transition has a profound impact, manifested in significantly reduced steatosis and modestly decreased liver fibrosis in myeloid-specific Gpnmb-knockout mice. In conclusion, our research clarifies the complex interactions between Gpnmb and MDMs and underscores the therapeutic potential of targeting Gpnmb within MDMs to manage MASLD.

PMID:40186908 | DOI:10.1016/j.intimp.2025.114554

Front Pharmacol. 2025 Mar 20;16:1574010. doi: 10.3389/fphar.2025.1574010. eCollection 2025.

ABSTRACT

BACKGROUND/OBJECTIVES: This article reviews some key emerging pharmacogenomic topics in oncology pharmacy practice.

METHODS: Publications selected to review were mainly sourced from the new drug approvals by the Food and Drug Administration and the new regimens listed in the National Comprehensive Cancer Network.

RESULTS: Key pharmacogenomic topics were presented, including genetic alterations influencing drug metabolism, drug efficacy, and changes in therapeutic targeting; Relevant clinical updates and advancements were summarized to provide an in-depth understanding.

CONCLUSION: The abundance of pharmacogenomic measures builds a solid foundation and heralds a paradigm shift toward individualized patient care.

PMID:40183077 | PMC:PMC11965669 | DOI:10.3389/fphar.2025.1574010

South Afr J HIV Med. 2025 Mar 18;26(1):1661. doi: 10.4102/sajhivmed.v26i1.1661. eCollection 2025.

ABSTRACT

BACKGROUND: CYP2B6 slow metabolisers have higher efavirenz concentrations, which are further increased by isoniazid inhibiting efavirenz's accessory metabolic pathway.

OBJECTIVES: We investigated the association between CYP2B6 genotype and toxicity in people living with HIV (PLWH) on isoniazid and efavirenz.

METHOD: We enrolled participants from the efavirenz arm of the ADVANCE trial (reference no.: NCT03122262), who received isoniazid and consented to genotyping. We compared efavirenz concentrations on and off isoniazid, stratified by CYP2B6 genotype. We explored associations between the CYP2B6 genotype and efavirenz concentrations on isoniazid; and changes over 24 weeks in lipids, alanine aminotransferase (ALT), fasting plasma glucose (FPG), sleep quality, and Modified Mini Screen (MMS) scores.

RESULTS: A total of 168 participants, median age 31 years, 57% female, had classifiable CYP2B6 genotypes. Efavirenz concentrations on isoniazid were higher (pseudo-median difference 0.49 µg/mL (95% confidence interval [CI] [0.19-0.91]) and associated with increases in total and high-density lipoprotein (HDL)-cholesterol. CYP2B6 slow metabolisers had higher efavirenz concentrations on isoniazid than extensive metabolisers (β = 1.66 [95% CI 0.98-2.34]). CYP2B6 slow metabolisers had greater increases in total (β = 0.44 mmol/L [95% CI 0.01-0.86]) and HDL-cholesterol (β = 0.39 mmol/L [95% CI 0.21-0.57]) than extensive metabolisers. There were no associations between efavirenz concentrations or CYP2B6 genotype, and change in ALT, FPG, low-density lipoprotein (LDL)-cholesterol, triglycerides, sleep quality, or MMS scores.

CONCLUSION: CYP2B6 slow metabolisers on isoniazid and efavirenz had greater efavirenz concentrations and increases in total and HDL-cholesterol. We found no association between CYP2B6 genotype or efavirenz concentrations and sleep or psychiatric symptoms.

PMID:40182085 | PMC:PMC11966721 | DOI:10.4102/sajhivmed.v26i1.1661

BMJ Open. 2025 Apr 2;15(4):e088543. doi: 10.1136/bmjopen-2024-088543.

ABSTRACT

INTRODUCTION: Childhood tuberculous meningitis (TBM) is a devastating disease. The long-standing WHO recommendation for treatment is 2 months of intensive phase with isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), followed by 10 months of isoniazid and rifampicin. In 2022, WHO released a conditional recommendation that 6 months of intensified antituberculosis therapy (ATT) could be used as an alternative for drug-susceptible TBM. However, this has never been evaluated in a randomised clinical trial. Trials evaluating ATT shortening regimens using high-dose rifampicin and drugs with better central nervous system penetration alongside adjuvant anti-inflammatory therapy are needed to improve outcomes.

METHODS AND ANALYSIS: The Shortened Intensive Therapy for Children with Tuberculous Meningitis (SURE) trial is a phase 3, randomised, partially blinded, factorial trial being conducted in Asia (India and Vietnam) and Africa (Uganda, Zambia and Zimbabwe). It is coordinated by the Medical Research Council Clinical Trial Unit at University College London (MRCCTU at UCL). 400 children (aged 29 days to <18 years) with clinically diagnosed TBM will be randomised, using a factorial design, to either a 24-week intensified regimen (isoniazid (20 mg/kg), rifampicin (30 mg/kg), pyrazinamide (40 mg/kg) and levofloxacin (20 mg/kg)) or the standard 48-week ATT regimen and 8 weeks of high-dose aspirin or placebo. The primary outcome for the first randomisation is all-cause mortality, and for the second randomisation is the paediatric modified Rankin Scale (mRS), both at 48 weeks. Nested substudies include pharmacokinetics, pharmacogenetics, pathophysiology, diagnostics and prognostic biomarkers, in-depth neurodevelopmental outcomes, MRI and health economics.

ETHICS AND DISSEMINATION: Local ethics committees at all participating study sites and respective regulators approved the SURE protocol. Ethics approval was also obtained from UCL, UK (14935/001). Informed consent from parents/carers and assent from age-appropriate children are required for all participants. Results will be published in international peer-reviewed journals, and appropriate media will be used to summarise results for patients and their families and policymakers.

TRIAL REGISTRATION: ISRCTN40829906 (registered 13 November 2018).

PMID:40180374 | DOI:10.1136/bmjopen-2024-088543

Am J Pharm Educ. 2025 Apr 1:101397. doi: 10.1016/j.ajpe.2025.101397. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe the creation of a curated, shared repository of pharmacogenomics cases for pharmacy educators and lessons learned during the process.

METHODS: The 2019-2020 American Association of Colleges of Pharmacy Pharmacogenomics Special Interest Group (PGx SIG) formed an ad-hoc committee charged with creating a pharmacogenomics patient case repository for educational use. Following a needs assessment, a standardized case framework was developed using the Pharmacists' Patient Care Process. A guidance document was also created for case authors. The maintenance of the repository and the involvement of students is also described.

RESULTS: A total of 44 pharmacogenomics cases were accepted at various levels of difficulty, including 17 introductory cases, 18 intermediate cases, and 9 advanced cases. These cases cover 9 therapeutic areas and are freely available in an online network and information sharing platform (i.e., AACP Connect). Over the last 36 months, cases have been downloaded 427 times.

CONCLUSION: The AACP Pharmacogenomics SIG successfully created a shared repository of educational pharmacogenomics cases using a standardized framework. This approach can serve as a model for other Sections, SIGs or educators who desire to develop their own case repository in another field of study. Future work will measure direct outcomes of this available resource in the academic setting.

PMID:40180241 | DOI:10.1016/j.ajpe.2025.101397

EBioMedicine. 2025 Apr 2;115:105676. doi: 10.1016/j.ebiom.2025.105676. Online ahead of print.

ABSTRACT

BACKGROUND: Disruption of circadian rest-activity is prevalent in patients with bipolar disorder (BD). Lithium's impact on circadian rhythms has been documented in cell lines, animal models, and pharmacogenomics studies in patients with BD. However, the causal relationship between such disruption and BD remains unclear.

METHODS: We investigated the early effects of lithium on circadian rest-activity in an exploratory analysis of a randomised, placebo-controlled, double-blind six-week study on patients with BD. Participants were assigned to receive either lithium or a placebo in a 1:1 ratio. Circadian activity was monitored using actigraphy, and daily affect was assessed through ecological momentary assessment. A computational model was used to quantify different types of activity variability, and the impact of lithium on activity level, activity onset time and their variability were analysed using linear mixed models.

FINDINGS: Of the thirty-five participants who began treatment, 19 received lithium and 16 received a placebo. Lithium significantly altered circadian rest-activity patterns, including reducing daytime activity levels (after 4 weeks, below as well: Cohen's d = -0.19, p = 0.002, linear mixed model, ibid.), advancing the onset of daytime activity (Cohen's d = -0.14, p = 0.018), and increasing the volatility of both daytime activity level (Cohen's d = 0.10, p = 0.002) and its onset time (Cohen's d = 0.13, p < 0.001), independent of affective symptoms changes.

INTERPRETATION: This study establishes a causal link between lithium treatment and reduced circadian activity with advanced circadian phase, potentially via temporarily increasing their volatility (flexibility). Significant circadian changes were detected within one week of starting lithium, highlighting their potential as an early biomarker for treatment response.

FUNDING: This research was supported by the Wellcome Trust Strategic Award (CONBRIO: Collaborative Oxford Network for Bipolar Research to Improve Outcomes, reference No. 102,616/Z), NIHR Oxford Health Biomedical Research Centre and the NIHR Oxford cognitive health Clinical Research Facility.

PMID:40179662 | DOI:10.1016/j.ebiom.2025.105676

Acta Pharm Sin B. 2025 Feb;15(2):963-972. doi: 10.1016/j.apsb.2024.11.002. Epub 2024 Nov 7.

ABSTRACT

One of the leading therapies for acute lymphoblastic leukemia (ALL) is the chemotherapeutic agent PEGylated E. coli-derived-l-asparaginase (PEG-ASNase). Due to the high risk of dose-limiting liver injury, characterized by clinically elevated levels of hepatic transaminases, PEG-ASNase therapy is generally avoided in adult patients. Our preclinical investigations have indicated that PEG-ASNase-induced liver injury is associated with the release of free fatty acids (FFAs) from white adipose tissue (WAT), suggesting potential lipotoxic effects. However, it remains uncertain whether PEG-ASNase directly induces hepatotoxicity or sensitizes hepatocytes to FFA-induced toxicity. Our results show that PEG-ASNase treatment results in hepatocyte apoptosis and lipid peroxidation. Ex vivo and in vitro studies in mouse and human WAT suggest that PEG-ASNase induces the expression of adipose triglyceride lipase (ATGL), activates the lipase, and stimulates adipose tissue lipolysis, suggesting that the FFAs from WAT may contribute to the observed liver injury. Moreover, treatment with PEG-ASNase sensitizes hepatocytes to FFA-induced lipotoxicity. Mechanistically, our RNA-sequencing (RNA-seq) analyses reveal that PEG-ASNase-induced sensitization to lipotoxicity is accompanied by the induction of Cyp2e1. We demonstrated that this sensitization effect is attenuated by both pharmacological and genetic inhibition of Cyp2e1. Our findings suggest that PEG-ASNase therapy induces WAT lipolysis and sensitizes hepatocytes to hepatic lipotoxicity in a Cyp2e1-dependent manner.

PMID:40177540 | PMC:PMC11959929 | DOI:10.1016/j.apsb.2024.11.002

Front Pharmacol. 2025 Mar 19;16:1538432. doi: 10.3389/fphar.2025.1538432. eCollection 2025.

ABSTRACT

BACKGROUND: Tacrolimus, an approved first-line calcineurin inhibitor, is widely prescribed in organ transplantation to prevent allograft rejection. Its narrow therapeutic index requires precise management to achieve optimal dosing and to minimize adverse drug events (ADEs) while ensuring its therapeutic efficacy. Among several factors, genetic differences contribute significantly to the inter-individual and inter-ethnic variability in pharmacokinetics (PK) of tacrolimus in kidney transplant recipients. As a result, investigating the role of genetic variation in Greek transplant recipients becomes crucial to optimizing therapeutic strategies and enhancing the efficacy of immunosuppressive treatment.

HYPOTHESIS: Genetic variants which are known to influence the activity of enzymes or drug-transporters critical to tacrolimus pharmacokinetics, may significantly affect the required kidney post-transplant tacrolimus daily dose.

AIM: To assess the correlation of ABCB1 genetic variants (rs1128503, rs2229109) and CYP3A4 (rs2242480, rs4986910) with tacrolimus dose-adjusted trough concentration (C0/D), in Greek kidney transplant recipients.

METHODS: Ninety-four unrelated Greek kidney transplant recipients were included in this study from the Department of Nephrology and Kidney Transplantation of the University General Hospital of Patras. Patients' dose-adjusted trough levels were measured at five distinct time points after transplantation and analyzed in relation to the possible influence of CYP3A4 and correlated with the abovementioned ABCB1 genetic variants using standard genotyping analysis and Sanger sequencing.

RESULTS: The genetic variants rs1128503, rs2229109, rs2242480, rs4986910 did not show any significant association with the daily dosing requirements of tacrolimus for at least 1 year, in Greek patients who have undergone kidney transplant.

CONCLUSION: It remains uncertain whether these genetic variants influence the assessment of the appropriate tacrolimus dosing 1 year after transplantation in Greek kidney transplant recipients.

PMID:40176889 | PMC:PMC11962430 | DOI:10.3389/fphar.2025.1538432

Curr Rev Clin Exp Pharmacol. 2025 Mar 28. doi: 10.2174/0127724328356429250315163111. Online ahead of print.

ABSTRACT

INTRODUCTION: Statin-induced myopathy (SIM) is a prevalent adverse event impacting treatment adherence. Despite extensive exploration of genotypes, conflicting evidence obscures their role in SIM incidence, prompting this network meta-analysis.

METHODS: Observational studies meeting eligibility criteria (patients on any statin with reported SNPs and SIM details) were systematically reviewed. Severe SIM was defined as creatine kinase elevations exceeding 10 times the upper limit of normal. Mixed treatment comparison pooled estimates were generated from direct and indirect pooled estimates, represented by odds ratios (OR) with 95% confidence intervals (CI), and validated via bootstrap analysis.

RESULTS: Thirty-four studies (26,152 participants) examining genotypes spanning drug transporters, metabolizing enzymes, reactive oxygen species production, and myopathy-related genes were analyzed. Significant associations were observed with drug transporters (OR: 1.4; 95% CI: 1.04, 1.5). Notably, solute carrier organic anion transporter 1B1 (SLCO1B1) (rs4149056) exhibited a moderate association with SIM (OR: 2.1; 95% CI: 1.7, 2.6), validated by bootstrap analysis (OR: 2.1; 95% CI: 1.7, 2.8). Similar associations were found for severe SIM with SLCO1B1 (rs4149056) (OR: 3.8; 95% CI: 1.4, 10.4) and ATP Binding Cassette Subfamily B Member 1 (ABCB1) (rs2373588) (OR: 2.8; 95% CI: 1.4, 5.4). Intraclass differences in genetic predictor risks were noted among statins.

CONCLUSION: Our meta-analysis underscores the significant association of SLCO1B1 with SIM, supporting its clinical utility. Further research is warranted to clarify additional genetic predictors. These findings endorse current guidelines advocating for SLCO1B1 genotyping in statin therapy decisions.

PMID:40176697 | DOI:10.2174/0127724328356429250315163111

Mol Divers. 2025 Apr 2. doi: 10.1007/s11030-025-11135-4. Online ahead of print.

ABSTRACT

The process of various virus entry into host cells, including SARS-CoV-2, is mediated by clathrin-mediated endocytosis (CME). AP-2 plays a crucial role in this process by recognizing membrane receptors and binding with clathrin, facilitating the formation of clathrin-coated vesicles and promoting CME. AAK1 catalyzes the phosphorylation of AP2M1 subunit at Thr156. Therefore, suppressing AAK1 activity can hinder virus invasion by blocking CME. indicating that AAK1 could be a potential target for developing novel antiviral drugs against SARS-CoV-2. In this study, we present a series of novel AAK1 inhibitors based on previously reported AAK1 inhibitors. Drug design was carried out by fusing the 1H-indazole scaffold of SGC-AAK1-1 with pharmacophore groups of compound 6, and further optimized with the assistance of molecular docking. Among the 42 compounds novelly synthesized, compounds 9i, 9s, 11f and 11l exhibited comparable antiviral activity against SARS-CoV-2 infection compared to reference compound 6 at the concentration of 3 μM. Particularly, 11f showed almost no cytotoxicity at all tested concentrations. Additionally, 11f exhibited favorable predictive pharmacokinetic properties. These findings support the potential of 11f as a lead compound for developing antiviral drugs targeting SARS-CoV-2 infection, as well as potentially other viruses which are dependent on the CME process to enter host cells. In summary, we have expanded the structural types of AAK1 inhibitors and successfully obtained effective AAK1 inhibitors with antiviral capabilities.

PMID:40175846 | DOI:10.1007/s11030-025-11135-4

Am J Hum Genet. 2025 Mar 24:S0002-9297(25)00102-8. doi: 10.1016/j.ajhg.2025.03.003. Online ahead of print.

ABSTRACT

Pharmacogenomic (PGx) information is essential for precision medicine, enabling drug prescriptions to be personalized according to an individual's genetic background. Almost all individuals will carry a genetic marker that affects their drug response, so the ideal drug prescription for these individuals will differ from the population-level guidelines. Currently, PGx information is often not available at first prescription, reducing its effectiveness. In the Netherlands, pharmacogenetic information is most often obtained using dedicated single-gene assays, making it expensive and time consuming to generate complete multi-gene PGx profiles. We therefore hypothesized that we could also use genome-wide oligonucleotide genotyping arrays to generate comprehensive PGx information (PGx passports), thereby decreasing the cost and time required for PGx testing and lowering the barrier to generating PGx information prior to first prescription. Taking advantage of existing genetic data generated in two biobanks, we developed and validated Asterix, a low-cost, clinical-grade PGx passport pipeline for 12 PGx genes. In these biobanks, we performed and clinically validated genetic variant calling and statistical phasing and imputation. In addition, we developed and validated a CYP2D6 copy-number-variant-calling tool, forgoing the need to use separate PCR-based copy-number detection. Ultimately, we returned 1,227 PGx passports to biobank participants via a layperson-friendly app, improving knowledge of PGx among citizens. Our study demonstrates the feasibility of a low-cost, clinical-grade PGx passport pipeline that could be readily implemented in clinical settings to enhance personalized healthcare, ensuring that patients receive the most effective and safe drug therapy based on their unique genetic makeup.

PMID:40174590 | DOI:10.1016/j.ajhg.2025.03.003

Allergy. 2025 Apr 2. doi: 10.1111/all.16544. Online ahead of print.

NO ABSTRACT

PMID:40171941 | DOI:10.1111/all.16544

Ann Hum Genet. 2025 Apr 2:e12596. doi: 10.1111/ahg.12596. Online ahead of print.

ABSTRACT

Pharmacological responses can vary significantly among patients from different ethnogeographic backgrounds. This variability can, at least in part, be attributed to population-specific genetic patterns in genes involved in drug absorption, distribution, metabolism, and excretion, as well as in genes associated with drug-induced toxicity. Identification of such ethnogeographic variability is thus crucial for the optimization of precise population-specific drug treatments. In this review, we summarize the current knowledge about the clinically actionable pharmacogenetic diversity of genes involved in drug metabolism (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, TPMT, NUDT15, UGT1A1, and NAT2), drug-induced hypersensitivity reactions (HLA-A and HLA-B), and drug-induced acute hemolytic anemia (G6PD). We highlight risk populations with distinct allele frequencies and discuss implications for the customization of treatment. Subsequently, we discuss key challenges and opportunities in population pharmacogenomics, including the importance of considering distinct allele frequency patterns in indigenous or founder populations, interpreting pharmacogenomic response in admixed populations, addressing the investigation bias of the pharmacogenomic literature, and difficulties in including rare and population-specific variants into drug response predictions. The information provided here underscores the critical role of population pharmacogenomics in refining pharmacological treatment strategies and aspires to provide further guidance to maximize the benefits of precision medicine across populations.

PMID:40171627 | DOI:10.1111/ahg.12596

Front Pharmacol. 2025 Mar 18;16:1577547. doi: 10.3389/fphar.2025.1577547. eCollection 2025.

NO ABSTRACT

PMID:40170722 | PMC:PMC11959060 | DOI:10.3389/fphar.2025.1577547

Ann Lab Med. 2025 Apr 2. doi: 10.3343/alm.2024.0652. Online ahead of print.

ABSTRACT

Pharmacogenomics is a rapidly evolving field with a strong foundation in basic science dating back to 1960. Pharmacogenomic findings have been translated into clinical care through collaborative efforts of clinical practitioners, pharmacists, clinical laboratories, and research groups. The methods used have transitioned from targeted genotyping of relatively few variants in individual genes to multiplexed multi-gene panels, and sequencing-based methods are likely on the horizon; however, no system exists for classifying and reporting rare variants identified via sequencing-based approaches. Laboratory testing in pharmacogenomics is complex for several genes, including cytochrome P450 2D6 (CYP2D6), HLA-A, and HLA-B, owing to a high degree of polymorphisms, homology with other genes, and copy-number variation. These loci require specialized methods and familiarity with each gene, which may persist during the transition to next-generation sequencing. Increasing implementation across laboratories and clinical facilities has required cooperative efforts to develop standard testing targets, nomenclature, and reporting practices and guidelines for applying the results clinically. Beyond standardization, harmonization between pharmacogenomics and the broader field of genomic medicine may be essential for facilitating further adoption and realizing the full potential of personalized medicine. In this review, we describe the evolution of clinical laboratory testing for pharmacogenomics, including standardization efforts and the anticipated transition from targeted genotyping to sequencing-based pharmacogenomics. We speculate on potential upcoming developments, including pharmacoepigenetics, improved understanding of the impact of non-coding variants, use of large-scale functional genomics to characterize rare variants, and a renewed interest in polygenic risk or combinatorial approaches, which will drive the progression of the field.

PMID:40170583 | DOI:10.3343/alm.2024.0652

Front Pharmacol. 2025 Mar 17;16:1553536. doi: 10.3389/fphar.2025.1553536. eCollection 2025.

ABSTRACT

BACKGROUND: Pharmacogenomics offers a possibility of anticipating drug response based on individuals' genetic profiles and represents a step toward implementation of personalized treatment through routine genetic testing. Development of highthroughput sequencing technologies aided identification and interpretation of variants in many pharmacogenes simultaneously. Nonetheless, the integration of pharmacogenomics into clinical practice is arduous, partly due to insufficient knowledge of ethnic pharmacogenetic data. The aim of our study was to assemble the most comprehensive pharmacogenomics landscape of the Serbian population so far.

METHODS: We used genomic data of 881 individuals from Serbia obtained by clinical and whole exome sequencing. Raw sequencing files were processed using an in-house pipeline for alignment and variant calling. For annotation of pharmacogenetics star alleles and determination of phenotypes, we used the PharmCAT and Stargazer tools. Star allele and phenotype frequencies were calculated and compared to worldwide and European populations. Population differentiation was presented through calculation of Wright's fixation index.

RESULTS: Our results showed that population differentiation was the highest between the Serbian and the worldwide population. In the Serbian population, the most relevant pharmacogenes in terms of star allele frequencies and actionable phenotypes were CYP2B6, NAT2, SLCO1B1, UGT1A1 and VKORC1, that had significantly different distribution compared to other European populations.

CONCLUSION: In conclusion, significant differences in frequencies of pharmacogenetic phenotypes that influence response to several drug categories including statins and antidepressants indicate that inclusion of data relevant for drug response to genetic reports would be beneficial in the Serbian population. Implementation of pharmacogenetic testing could be achieved through analysis of clinical and whole exome sequencing data.

PMID:40166472 | PMC:PMC11955590 | DOI:10.3389/fphar.2025.1553536

Front Med (Lausanne). 2025 Mar 17;12:1535099. doi: 10.3389/fmed.2025.1535099. eCollection 2025.

ABSTRACT

INTRODUCTION: Gaucher disease (GD), a lysosomal storage disorder, results from the accumulation of glycosphingolipids due to deficient lysosomal glucocerebrosidase activity. This pathological accumulation triggers immune activation, which paradoxically induces UDPglucose ceramide glucosyltransferase (UGCG), further exacerbating the metabolic defect. Eliglustat, a highly specific inhibitor of UGCG, functions as a substrate reduction therapy (SRT) and has demonstrated efficacy in reversing GD manifestations in clinical trials and real-world settings. Despite its established safety profile, preclinical studies have shown that supratherapeutic concentrations of eliglustat can inhibit ion channels involved in cardiac electrophysiology. However, pharmacogenomic-guided dosing ensures therapeutic efficacy while maintaining a wide safety margin, minimizing such risks. Nevertheless, lingering concerns regarding cardiac safety have persisted, particularly in patients with preexisting cardiac comorbidities.

METHODS: We report a single-center experience of eliglustat use in 13 patients with type 1 Gaucher disease (GD1) and concurrent cardiac comorbidities. Patients underwent standard cardiac evaluations, including electrocardiogram (EKG) with QTc interval assessment and echocardiogram. Eliglustat dosing was guided by CYP2D6 metabolizer status, and potential drug-drug interactions (DDIs) were carefully monitored.

RESULTS: Cardiac comorbidities included prior myocardial infarction (n = 2), aortic stenosis (n = 2), atrial fibrillation (n = 2), Wolff-Parkinson-White syndrome (n = 1), pericarditis (n = 1), premature ventricular complexes (n = 2), severe pulmonary arterial hypertension with right heart strain (n = 1), mitral annular calcification with diastolic dysfunction (n = 1), and mildly prolonged QTc interval (n = 1). No patients experienced arrhythmia, QTc prolongation, or arrhythmia-related symptoms. Treatment discontinuation was not required. All patients achieved expected therapeutic outcomes, as evidenced by serial reductions in glucosylsphingosine (GlcSph) levels and other disease indicators.

CONCLUSION: This study represents the first real-world clinical evidence evaluating Eliglustat's cardiac safety in a high-risk GD1 population. Unlike prior theoretical concerns derived from in vitro ion channel studies, our findings demonstrate that Eliglustat does not induce clinically significant cardiac events when administered according to pharmacogenomic guidelines. The misinformation regarding Eliglustat's cardiotoxicity, largely driven by speculative interpretations rather than clinical data, is effectively countered by our findings, which show no significant QT prolongation or arrhythmias over a median treatment duration of 8 years.

PMID:40166071 | PMC:PMC11956841 | DOI:10.3389/fmed.2025.1535099

Am J Chin Med. 2025 Mar 29:1-30. doi: 10.1142/S0192415X25500223. Online ahead of print.

ABSTRACT

Bile acid metabolism mediated by gut microbiota is significantly related to immunity regulation that plays an important role in the development and treatment of inflammatory bowel disease (IBD). Our previous study has demonstrated that Panax notoginseng saponins (PNS) alleviate colitis due to the regulation of T helper 17/Regulatory T cells (Th17/Treg) balance via gut microbiota. However, the effects and mechanism of PNS on colitis pertinent to bile acid metabolism mediated by gut microbiota remain elusive. This study aims to investigate the anti-colitis mechanism of PNS by regulating the Th17/Treg balance pertinent to gut microbiota-bile acid metabolism. Results showed that PNS significantly decreased the relative abundance of Allobaculum, Dubosiella, Muribaculum, and Alistipes, and up-regulated the relative contents of conjugated bile acids, such as TCA and TCDCA. Fecal microbiota transplantation (FMT) showed that the gut microbiota remodeled by PNS had a regulatory effect on bile acid metabolism, and up-regulated the relative contents of TCA and TCDCA, which alleviated IBD and promoted Treg cell expression in vivo and in vitro. Taken together, PNS could reshape the profiling of gut microbiota to generate more TCA and TCDCA, which improve the balance of Th17/Treg to exert anti-IBD effects.

PMID:40165428 | DOI:10.1142/S0192415X25500223