Zhonghua Xin Xue Guan Bing Za Zhi. 2025 May 24;53(5):557-562. doi: 10.3760/cma.j.cn112148-20250320-00210.

ABSTRACT

心脏K+、Na+和Ca2+通道在心肌电生理过程中起关键作用，相关基因突变导致离子通道功能异常，是长QT综合征、Brugada综合征、短QT综合征及儿茶酚胺敏感性多形性室性心动过速等多种心脏离子通道病的病理基础。药物遗传学通过分析个体基因型如何影响药物反应和疗效，为个体化治疗提供指导。该文综述了心脏离子通道基因变异与上述疾病发病机制的关联，并深入探讨了不同心脏离子通道突变中药物的疗效差异，旨在推动该领域药物遗传学研究的深入与临床应用。.

PMID:40389349 | DOI:10.3760/cma.j.cn112148-20250320-00210

J Adv Res. 2025 May 17:S2090-1232(25)00347-9. doi: 10.1016/j.jare.2025.05.033. Online ahead of print.

ABSTRACT

INTRODUCTION: Platinum-based drugs, the most widely used chemotherapeutic drugs in clinical oncology, have long faced the problem of drug resistance, which is urgently in need of resolution. Identifying biomarkers of drug resistance may help reduce platinum resistance and improve therapeutic efficacy.

OBJECTIVES: This study aims to identify potential biomarkers associated with the development of cisplatin resistance in non-small cell lung cancer (NSCLC) and explore mechanisms to overcome chemoresistance.

METHODS: NSCLC cisplatin resistance cell lines were constructed, and transcriptome sequencing was performed. Results were validated using Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Molecular docking, proteomics sequencing, and in vitro and in vivo experiments were conducted to evaluate the role of Heme Oxygenase 1 (HMOX1) in cisplatin resistance.

RESULTS: NSCLC cisplatin resistance cell lines, GEO and TCGA data identified HMOX1, downstream of Nrf2, as a key drug resistance gene induced by cisplatin. Activation of the Nrf2/HO-1 pathway was found to induce ferroptosis resistance, a critical mechanism of cisplatin resistance. Candidate compounds SB 202190 and Nordihydroguaiaretic acid (NDGA) effectively reactivated ferroptosis by inhibiting HO-1, thereby increasing cisplatin sensitivity.

CONCLUSION: The Nrf2/HMOX1 pathway is a significant contributor to cisplatin resistance in NSCLC. Targeting HO-1 with SB 202190 and NDGA presents a promising strategy to overcome resistance and improve chemotherapy outcomes.

PMID:40389113 | DOI:10.1016/j.jare.2025.05.033

J Mol Diagn. 2025 May 17:S1525-1578(25)00115-1. doi: 10.1016/j.jmoldx.2025.04.006. Online ahead of print.

NO ABSTRACT

PMID:40389062 | DOI:10.1016/j.jmoldx.2025.04.006

Clin Pharmacol Ther. 2025 Jun;117(6):1562-1576. doi: 10.1002/cpt.3675.

ABSTRACT

Over the last three decades, transporters have become increasingly recognized for their important roles in clinical pharmacology. As gatekeepers of drug absorption, disposition and targeting, transporters in the intestine, liver, kidney and blood brain barrier have been the subject of many clinical pharmacology studies. A seminal work published in 2001 was among the first studies to shift the focus of pharmacogenomic research from drug metabolizing enzymes to drug transporters, demonstrating that pharmacogenomic factors in genes in addition to drug metabolizing enzymes, and in particular, in transporter genes, could play an important role in interindividual variation in pharmacokinetics of drugs.

PMID:40388108 | DOI:10.1002/cpt.3675

Minerva Med. 2025 Apr;116(2):89-93. doi: 10.23736/S0026-4806.20.06488-5.

ABSTRACT

BACKGROUND: In acute respiratory distress syndrome (ARDS) obesity is associated with lower mortality but the mechanism(s) have not been elucidated.

METHODS: We aimed at assessing plasma biomarker levels interleukin-8 (IL-8), matrix metalloproteinase-7 (MMP-7), Toll-like receptor 2 (TLR-2), tumor necrosis factor-α (TNF-α) and procalcitonin (PCT) at baseline and 3 days later in 20 consecutive moderate-severe ARDS consecutively admitted to our Center.

RESULTS: Our population includes 20 consecutive mechanically ventilated patients with moderate-to severe ARDS. The incidence of obesity was 40% (8/20). No differences were detectable between obese and normal patients in baseline characteristics. In particular, ICU mortality was comparable between the two subgroups. No differences were detectable between the two subgroups at baseline and after 72 hours in biomarker plasma levels. When examining the behavior of each biomarker, obese patients showed a significant increase in MMP7 and TLR-2 values at 72 hours in respect to baseline, differently from normal patients.

CONCLUSIONS: Our data strongly suggest that obese patients with moderate to severe ARDS have an altered inflammatory response to acute lung injury, since a significant increase in MMP-7 and TLR-2 was detectable at 72 hours only in these patients. Further investigations are needed to confirm our results in larger cohorts.

PMID:40387315 | DOI:10.23736/S0026-4806.20.06488-5

Int J Med Sci. 2025 Apr 28;22(10):2434-2445. doi: 10.7150/ijms.114402. eCollection 2025.

ABSTRACT

Aim and background: Vaccines are a cornerstone of modern medicine, significantly reducing morbidity and mortality worldwide. Their administration in infants requires consideration of physiological maturity. Cytochrome P450 (CYP450) enzymes, crucial for drug metabolism, are underdeveloped at birth and mature over the first two to three years of life. While vaccines are not directly metabolized by CYP450 enzymes, emerging evidence suggests that certain excipients-such as polysorbate 80 and gelatin-could interact with CYP450 pathways, particularly in genetically susceptible infants. This study integrates pharmacogenetics and epidemiology to examine how CYP450 immaturity and variability may influence vaccine excipient metabolism, immune activation, and infant health outcomes. Methods: A systematic review of peer-reviewed literature, pharmacogenetic data, and epidemiological studies was conducted to assess CYP450 enzyme activity in infants, potential metabolic interactions with vaccine excipients, and temporal associations between vaccination and sudden infant death syndrome (SIDS). Gaps in postmortem investigations were also evaluated for their impact to identify metabolic vulnerabilities. Results: CYP450 enzymes exhibit developmental immaturity in infants and genetic polymorphisms-particularly in CYP2D6 and CYP3A5-may affect vaccine excipient clearance. While epidemiological evidence shows temporal clustering of some SIDS cases post-vaccination, causality remains unproven. Inflammation-induced suppression of CYP450 enzymes raise questions about potential metabolic vulnerabilities, which current postmortem protocols often fail to capture. Conclusion: This study highlights the need for further research into the influence of CYP450 variability on vaccine-related outcomes. Incorporating genetic and metabolic profiling into postmortem protocols may improve our understanding of metabolic contributions to SIDS and refine vaccine safety assessments. Clinical significance: Developmental immaturity and genetic variability in CYP450 enzymes may affect vaccine excipient metabolism and interact with immune activation. This interplay could influence metabolic vulnerabilities in infants, particularly with inflammation-induced CYP450 suppression. Genetic and metabolic profiling before vaccination could identify at-risk infants, while postmortem analysis may enhance SIDS understanding and vaccine safety assessments.

PMID:40386062 | PMC:PMC12080585 | DOI:10.7150/ijms.114402

Obesity (Silver Spring). 2025 May 19. doi: 10.1002/oby.24300. Online ahead of print.

ABSTRACT

OBJECTIVE: The objective of this study is to identify whether the glucagon-like peptide-1 receptor (GLP1R) gene variant rs6923761G→A has an influence on semaglutide response in individuals with severe obesity.

METHODS: From March 2023 to July 2024, we prospectively genotyped 112 patients treated with semaglutide 2.4 mg weekly. All patients had been treated over 4 months for grade 3 obesity (BMI ≥ 40 kg/m2).

RESULTS: The frequency of the rs6923761 AA variant was 9 out of 112 patients (8%), GA was 42 out of 112 (37.5%), and GG was 61 out of 112 (54.5%). The mean weight loss kinetics was 1.64% (SD 0.78%) per month in homozygotes of variant A in comparison with a mean weight loss of 1.04% (SD 0.79%) per month in carriers of at least one G variant (p = 0.03). Multivariate analysis demonstrated that rs6923761G→A and sex were independent predictors of weight loss. The rate of weight loss in women homozygous for the A allele was more than double that observed in men carrying the G allele: mean (SD) 1.89% (0.75%) per month versus 0.7% (0.7%) per month (p = 0.0009). No woman homozygous for the A allele was a nonresponder, compared with 56% (21 out of 37) of the men carrying the G allele.

CONCLUSIONS: The rs6923761G→A gene variant and sex profoundly affect weight loss in response to semaglutide in patients with severe obesity.

PMID:40384505 | DOI:10.1002/oby.24300

Pharmacogenomics J. 2025 May 17;25(3):14. doi: 10.1038/s41397-025-00374-1.

ABSTRACT

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

PMID:40382315 | DOI:10.1038/s41397-025-00374-1

Gastroenterology. 2025 May 15:S0016-5085(25)00755-3. doi: 10.1053/j.gastro.2025.04.025. Online ahead of print.

ABSTRACT

There is a large heterogeneity among individuals in their therapeutic responses to the same drug and in the occurrence of adverse events. A key factor increasingly recognized to contribute to this variability is the gut microbiome. The gut microbiome can be regarded as a second genome, holding significant metabolic capacity. Consequently, the field of pharmacomicrobiomics has emerged as a natural extension of pharmacogenomics for studying variations in drug responses. Pharmacomicrobiomics explores the interaction of microbiome variation with drug response and disposition. The interaction between microbes and drugs is, however, complex and bidirectional. While drugs can directly alter microbial growth or influence gut microbiome composition and functionality, the gut microbiome also modulates drug responses directly through enzymatic activities and indirectly via host-mediated immune and metabolic mechanisms. Here we review recent studies that demonstrate the interaction between drugs and the gut microbiome, focusing on cancer immunotherapy and immunomodulation in the context of inflammatory bowel disease and solid organ transplantation. Since the gut microbiome is modifiable, pharmacomicrobiomics presents promising opportunities for optimizing therapeutic outcomes, with recent clinical trials highlighting fecal microbiota transplantation as a strategy to enhance the efficacy of immune checkpoint blockade. We also shed light on the future perspectives for patients arising from this field. While multiple lines of evidence already demonstrate that the gut microbiome interacts with drugs, and vice versa, thereby affecting treatment efficacy and safety, well-designed clinical studies and integrated in vivo and ex vivo models are necessary to obtain consistent results, improve clinical translation and further unlock the gut microbiome's potential to improve drug responses.

PMID:40381958 | DOI:10.1053/j.gastro.2025.04.025

Curr Probl Cardiol. 2025 May 15:103076. doi: 10.1016/j.cpcardiol.2025.103076. Online ahead of print.

ABSTRACT

Dilated cardiomyopathy (DCM) is a prevalent cardiac disorder affecting 1 in 250-500 individuals, characterized by ventricular dilation and impaired systolic function, leading to heart failure and increased mortality, including sudden cardiac death. DCM arises from genetic and environmental factors, such as drug-induced, inflammatory, and viral causes, resulting in diverse yet overlapping phenotypes. Advances in precision medicine are revolutionizing DCM management by leveraging genetic and molecular profiling for tailored diagnostic and therapeutic approaches. This review highlights comprehensive diagnostic evaluations, genetic discoveries, and multi-omics approaches integrating genomic, transcriptomic, proteomic, and metabolomic data to enhance understanding of DCM pathophysiology. Innovative risk stratification methods, including machine learning, are improving predictions of disease progression. Despite these advancements, the current one-size-fits-all management strategy contributes to persistently high morbidity and mortality. Emerging targeted therapies, such as CRISPR/Cas9 genome editing, aetiology-specific interventions, and pharmacogenomics, are reshaping treatment paradigms. Precision medicine holds promise for optimizing DCM diagnosis, treatment, and outcomes, aiming to reduce the burden of this debilitating condition.

PMID:40381754 | DOI:10.1016/j.cpcardiol.2025.103076

Pharmacol Res. 2025 May 14:107779. doi: 10.1016/j.phrs.2025.107779. Online ahead of print.

ABSTRACT

Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are so-called xenobiotic nuclear receptors that play pivotal roles in xenobiotic metabolism and detoxification. Both receptors, highly expressed in the liver and intestine, also have endobiotic functions by regulating the homeostasis of endogenous chemicals. While their hepatic functions are well-documented, the functional roles of PXR and CAR in the gastrointestinal tract are less understood. This review highlights the intestinal functions of PXR and CAR, focusing on their involvement in colon cancer, host-microbiome interactions, inflammation, and gut barrier integrity. PXR exhibits dual roles in colon cancer, acting either as a tumor suppressor by inducing cell-cycle arrest or as a promoter of cancer aggressiveness through activating the FGF19 signaling. CAR, on the other hand, regulates intestinal barrier integrity and immune responses, particularly in the context of inflammatory bowel disease (IBD). Both PXR and CAR interact with gut microbiota, modulating microbial composition and the production of metabolites, such as indole-3-propionic acid (IPA) that influences the gut barrier function and inflammation. Activation of PXR also mitigates intestinal inflammation by antagonizing the NF-κB signaling, while CAR activation affects bile acid metabolism and T-cell homeostasis. These findings underscore the complex and context-dependent roles of PXR and CAR in the intestinal tracts, offering potential therapeutic targets for gastrointestinal diseases.

PMID:40378938 | DOI:10.1016/j.phrs.2025.107779

Cell Genom. 2025 May 13:100878. doi: 10.1016/j.xgen.2025.100878. Online ahead of print.

ABSTRACT

Emerging evidence suggests that MYC interacts with RNAs. Here, we performed an integrative characterization of MYC as an RNA-binding protein in six cell lines. We found that MYC binds to a myriad of RNAs with high affinity for guanosine-rich RNAs. Global and specific depletion of RNAs reduces MYC chromatin occupancy. Mechanistically, two highly conserved sequences, amino acids 355-357 KRR and 364-367 RQRR, within the basic region of MYC are necessary for its RNA binding. Notably, alanine substitution of KRR abolishes MYC's RNA-binding ability both in vitro and in vivo, without affecting its ability to bind E-box DNA as part of the MYC:MAX dimer in vitro. The loss of RNA-binding function decreases MYC chromatin binding in vivo and attenuates its ability to promote gene expression, cell-cycle progression, and proliferation. Our study lays a foundation for future investigation into the role of RNAs in MYC-mediated transcriptional activation and oncogenic functions.

PMID:40378850 | DOI:10.1016/j.xgen.2025.100878

Nucleic Acids Res. 2025 May 16:gkaf414. doi: 10.1093/nar/gkaf414. Online ahead of print.

ABSTRACT

We present the CellHit web server (https://cellhit.bioinfolab.sns.it/), a web-based platform designed to predict and analyze cancer patients' responsiveness to drugs using transcriptomic data. By leveraging extensive pharmacogenomics datasets from the Genomics of Drug Sensitivity in Cancer v1 and v2 (GDSC) and Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) and transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas Program (TCGA). CellHit integrates a computational pipeline for preprocessing, gene imputation, and robust alignment between patient and cell line transcriptomic data with pre-trained SOTA models for drug sensitivity prediction. The pipeline employs batch correction, enhanced Celligner methodology, and Parametric UMAP for stable and actionable alignment. The intuitive interface requires no programming expertise, offering interactive visualizations, including low-dimensional embeddings and drug sensitivity heatmaps for the input transcriptomic samples. Results feature contextual metadata, SHAP-based feature importance, and transcriptomic neighbors from reference datasets, simplifying interpretation and hypothesis generation. CellHit provides precomputed predictions across TCGA samples and offers the ability to run custom analyses online on input samples, democratizing precision oncology by enabling rapid, interpretable predictions accessible the research community.

PMID:40377071 | DOI:10.1093/nar/gkaf414

Front Pharmacol. 2025 May 1;16:1559399. doi: 10.3389/fphar.2025.1559399. eCollection 2025.

ABSTRACT

BACKGROUND: Pharmacogenomic (PGx) variants can significantly impact drug response, but limited data exists on their prevalence in Middle Eastern populations. This study aimed to investigate the inheritance of certain markers in candidate pharmacogenes among healthy Saudis.

METHODS: DNA samples from 95 unrelated healthy Saudi participants were genotyped using the Affymetrix Axiom Precision Medicine Diversity Array. Thirty-eight variants in 15 pharmacogenes were analyzed based on their clinical relevance and lack of previous reporting in Saudi populations.

RESULTS: Twenty-six of the 37 tested markers were undetected in the cohort. The selected variants in six genes [DPYD (rs1801268), CACNA1S (rs772226819), EGFR (rs121434568), RYR1 (rs193922816), CYP2B6 (rs3826711), and MT-RNR1 (rs267606617, rs267606618, rs267606619)] were found to be non-existing among Saudis. In contrast, 11 variants and alleles in nine pharmacogenes were detected at varying frequencies. Notable findings included high frequencies of variants in ATIC [rs4673993, minor allele frequency (MAF) = 0.71)] and SLC19A1 (rs1051266, MAF = 0.48) affecting methotrexate efficacy. Three alleles were identified in CYP3A4, including a common (CYP3A4 rs2242480) and two rare alleles (*3 and *22). Another three markers [rs16969968 in CHRNA5, rs11881222 in IFNL3 (IL28B), and SLCO1B1*14] were found to be highly distributed among the participants (MAF = 0.35, 0.30, and 0.14, respectively). Conversely, three rare markers: CYP2A6*2, NAT2*14, and rs115545701 in CFTR, were identified at low-frequency levels (MAF = 0.021, 0.011, 0.005, respectively). Statistically significant differences in allele frequencies were observed for eight variants between Saudi and African populations, five variants compared to East Asians, and two variants compared to Europeans.

CONCLUSION: This study provides novel insights into the distribution of clinically relevant PGx variants in the Saudi population. The findings have implications for personalizing treatments for various conditions, including rheumatoid arthritis, cystic fibrosis, and hepatitis C. These data contribute to the development of population-specific PGx testing panels and treatment guidelines.

PMID:40376268 | PMC:PMC12078325 | DOI:10.3389/fphar.2025.1559399

Pharmacogenomics. 2025 May 16:1-7. doi: 10.1080/14622416.2025.2502316. Online ahead of print.

ABSTRACT

AIMS: To study the availability, perceived necessity, barriers, and preferred formats for pharmacogenomics (PGx) education disseminated to healthcare professionals by professional societies.

MATERIALS & METHODS: A web-based survey of professional organizations affiliated with the Inter-Society Coordinating Committee for Practitioner Education in Genomics (ISCC-PEG), a U.S.-based initiative coordinated by the National Human Genome Research Institute, targeted representatives who could reflect their organization's educational stance.

RESULTS: Of the 34 unique responses analyzed, most organizations provided general and genomic education (94.1% and 82.4%, respectively), and 70.6% offered PGx-specific education. Most (61.8%) indicated they either needed major additions to the education they provide or had no PGx education resources. Key barriers included a lack of PGx focus within organizations (78.1%) and challenges in maintaining an up-to-date curriculum (75.0%). Preferred educational formats were live webinars (84.4%), hybrid courses (78.1%), and self-study modules (78.1%).

CONCLUSIONS: Our study identifies gaps in PGx education across professional organizations and underscores the need for resources to advance clinician competence in PGx. While some PGx education is available, many organizations require additional resources and support. Enhancing PGx education through targeted initiatives by organizations like ISCC-PEG may improve clinician competence and the integration of PGx into clinical practice.

PMID:40375817 | DOI:10.1080/14622416.2025.2502316

Nat Chem Biol. 2025 May 15. doi: 10.1038/s41589-025-01896-2. Online ahead of print.

ABSTRACT

Allosteric modulation of receptor responses to endogenous agonists has therapeutic value, maintaining ligand profiles, reducing side effects and restoring mutant responses. Adhesion G-protein-coupled receptors (aGPCRs), with large N termini, are ideal for allosteric modulator development. We designed a nanobody strategy targeting ADGRG2 N-terminal fragments and got a specific nanobody Nb23-bi, which promoted dehydroepiandrosterone (DHEA)-induced ADGRG2 activation and reversed mutant-induced dysfunctions. By combining structural characterization, crosslinking mass spectrometry, mutational analysis and molecular dynamics simulations, we clarified the allosteric mechanism of how the Nb23-bi modulates conformational changes in the DHEA-binding pocket. Animal studies showed that Nb23-bi promoted the response of DHEA in alleviating testicular inflammation and reversing mutant defects. In summary, we developed an allosteric nanobody of ADGRG2 and gained insights into its functions in reversing disease-associated dysfunctions. Our study may serve as a template for developing allosteric modulators of other aGPCRs for biological and therapeutic purposes.

PMID:40374856 | DOI:10.1038/s41589-025-01896-2

Int J Biol Macromol. 2025 May 13:144190. doi: 10.1016/j.ijbiomac.2025.144190. Online ahead of print.

ABSTRACT

Platycodon grandiflorum (PG) is a traditional medicinal herb with a history of >2000 years, exhibiting various biological activities. However, its anti-lung cancer potential remains largely unexplored. This study aimed to extract Platycodon grandiflorum polysaccharides (PGP) using an environmentally friendly natural deep eutectic solvent (NADES) system and evaluate their anti-lung cancer activity. An NADES system composed of choline chloride and oxalic acid (1:3 M ratio) was selected based on carbohydrate yield. The extraction conditions were optimized using Box-Behnken design (BBD). The structural characterization of PGP was performed using ultraviolet spectroscopy, fourier transform infrared (FT-IR) spectroscopy, and high-performance liquid chromatography (HPLC), revealing that PGP are glucans with a molecular weight of 7.036 kDa and a glucose content of 92.8 %. Biological assays demonstrated that PGP promoted ferroptosis in H1299 cells through mitochondrial dysfunction, lipid peroxidation (LPO), and overproduction of reactive oxygen species (ROS). Also, PGP inhibited cell migration by modulating epithelial-mesenchymal transition(EMT)-related protein expression. These findings provide novel insights into the pharmacological basis of PG and support its potential application in lung cancer therapy.

PMID:40373906 | DOI:10.1016/j.ijbiomac.2025.144190

NPJ Drug Discov. 2025;2(1):8. doi: 10.1038/s44386-025-00011-8. Epub 2025 May 12.

ABSTRACT

G-protein-coupled receptors (GPCRs) have proven to be the most successful target class for drug discovery but their complicated signal transduction pathways cause difficulties for drug development. Recently, ligands have been identified that engage an intracellular binding site which promotes pathway biased signal in cooperation with orthosteric ligands. Here, we explore the topic of biased signaling and intracellular modulators to understand their application for precision pharmacology of Class A or Rhodopsin-Like GPCRs.

PMID:40371403 | PMC:PMC12069105 | DOI:10.1038/s44386-025-00011-8

Front Pharmacol. 2025 Apr 30;16:1547142. doi: 10.3389/fphar.2025.1547142. eCollection 2025.

ABSTRACT

BACKGROUND: Limited data are available on factors that affect warfarin dose requirement in Saudi patients. Saudis are among the underrepresented ethnic groups in warfarin pharmacogenetics research. The present study investigated the frequency of CYP2C9*2 and*3, CYP4F2 (G1347A) and VKORC1 -1639G>A genotypes and their impact on warfarin dose requirement in a cohort of Saudi patients requiring anticoagulation therapy.

METHODS: 193 patients on chronic warfarin therapy and with stable anticoagulation took part in the study. Genotyping for VKORC1 1639G>A, CYP4F2 G1347A, CYP2C9*2 430C>T and CYP2C9*3 1075A>C were performed using TaqMan genotyping assays. Analysis of variance was carried out to determine the association between CYP2C9, CYP4F2, and VKORC1 genotype and warfarin dose requirement in two groups based on target INR range. Backward linear regression analysis identified genetic and clinical factors influencing doe requirements.

RESULTS: Patients with CYP2C9 and VKORC1 polymorphisms required significantly lower warfarin doses compared to wild-type patients. Carriers of two mutant alleles required lower doses than those with one mutant allele. In contrast, CYP4F2 polymorphisms did not influence warfarin dose. Age and genetic variants in CYP2C9 and VKORC1 were negatively correlated with dose requirements, while body surface area (BSA) was positively correlated.

CONCLUSION: Saudi patients with polymorphisms in CYP2C9 and VKORC1 required lower warfarin doses than those with the wild-type allele. CYP4F2 polymorphism had no effect on warfarin dose requirement. Integrating patient clinical factors, including age and BSA, and genetic polymorphisms in CYP2C9 and VKORC1 provides the best estimation of factors contributing to warfarin dose in the Saudi patient population.

PMID:40371326 | PMC:PMC12075942 | DOI:10.3389/fphar.2025.1547142

Front Genet. 2025 Apr 30;16:1435416. doi: 10.3389/fgene.2025.1435416. eCollection 2025.

ABSTRACT

Long-read sequencing (LRS) was introduced as the third generation of next-generation sequencing technologies with a high accuracy rate in genomic variant identification for some of its platforms. Due to the structural complexity of many pharmacogenes, the presence of rare variants, and the limitations of genotyping and short-read sequencing approaches in detecting pharmacovariants, LRS methods are likely to become increasingly utilized in the near future. In this review, we aim to provide a comprehensive discussion of current and future applications of long-read genotyping methods by introducing the opportunities and advantages as well as the challenges and disadvantages of state-of-the-art LRS platforms for the implementation of pharmacogenomic tests in clinical and research settings. New approaches to data processing, as well as the challenges and pitfalls of performing such tests in daily practice, will be explored in detail. We provide references to resources for those who are interested or intend to employ LRS in pharmacogenomics screening, both in clinical and research settings.

PMID:40370700 | PMC:PMC12075302 | DOI:10.3389/fgene.2025.1435416