J Chemother. 2025 Apr 17:1-7. doi: 10.1080/1120009X.2025.2489837. Online ahead of print.

ABSTRACT

Fluoropyrimidines (FPs) are antineoplastic agents used for the treatment of various solid tumors, especially gastrointestinal cancers. Patients with variations in dihydropyrimidine dehydrogenase gene (DPYD), which can determine the partial or complete deficiency of the dihydropyrimidine dehydrogenase enzyme (DPD), are at an increased risk of developing severe and potentially life-threatening toxicity. Worldwide the introduction of pharmacogenetic testing into clinical practice has been a slow process and in our center the analysis of the DPYD gene has been adopted since April 2020. We evaluated the clinical application of routine DPYD screening and its ability to prevent early-onset of fluoropyrimidine-related toxicity in patients treated at the Oncology Reference Center of Basilicata (IRCCS-CROB), a recognized cancer centre in Southern Italy. From April 2020 to November 2022, 300 patients (male 137; female 163) diagnosed with various types of cancer were subjected to DPYD genotyping, before starting treatment with FPs. In accordance with the current European Medicines Agency (EMA) and the Italian Association of Medical Oncology (AIOM) guidelines patients were tested for four DPYD variants that are associated with reduced DPD activity. FPs dose adjustments in DPYD variant carriers were made following the previously mentioned guidelines. Three hundred patients underwent DPYD testing and thirteen (4.3%) patients were found to be heterozygous variant carriers; ten out of thirteen patients received FP dose reduction as indicated by the guidelines, one out of thirteen patients received alternative treatment, two of the thirteen patients received no treatment at all. The main toxicities observed in patients who received a DPYD genotype-based dose reduction were anemia, neutropenia, nausea and mucositis but events were primarily grade 1 or 2. Our experience confirms the technical feasibility and the usefulness of DPYD genotyping to reduce the risk of severe FPs toxicities.

PMID:40247645 | DOI:10.1080/1120009X.2025.2489837

Clin Pharmacol Ther. 2025 Apr 17. doi: 10.1002/cpt.3681. Online ahead of print.

ABSTRACT

The ESR1 gene is relevant in breast cancer treatments in the pharmacogenetics context. However, Native, African, and mixed populations are known to be underrepresented in genomic studies. This is particularly important given that the difference in variants' frequencies among different populations can lead to population-specific clinical implications. Therefore, this study aims to infer the genomic subcontinental ancestry and allele frequencies of the ESR1 gene variants in 2,427 individuals from 26 populations worldwide from the 1000 Genomes Project and 125 Natives from Peru, whose genomes have not yet been analyzed in the literature regarding this gene. Linear regression with Bonferroni correction analyses was conducted based on ancestry inference and frequencies. Our findings demonstrate subcontinental differentiation of African, Asian, European, and Native populations. Overall, 102 associations (P < 0.01) were found for 68 clinically relevant variants. Particularly, subcontinental associations were observed for variants associated with the Native, Asian, European, and African components. We highlight the findings for the rs9349799 and rs2234693 variants, previously associated with altered responses to breast cancer treatments. rs9349799 was positively associated with the South-Asian component, while rs2234693 was negatively associated with the Coast/Amazonian Native and positively associated with the East-African component. Nearly half of the variants are intronic, highlighting the importance of studying whole genomes rather than just exomes. These results emphasize subcontinental differences' relevance for designing pharmacogenetic panels. Including neglected populations in genomic and pharmacogenomic studies is essential for democratic access to scientific advances and for more egalitarian and effective pharmacogenetic implementation, tailored to each population's specificities.

PMID:40247433 | DOI:10.1002/cpt.3681

Per Med. 2025 Apr 17:1-10. doi: 10.1080/17410541.2025.2493606. Online ahead of print.

ABSTRACT

AIM: In this study, we aimed to reveal the sequence analysis of 69 pharmacogenes in 635 patients and the clinical explanation of variants.

MATERIALS AND METHODS: Genomic DNA was isolated from peripheral blood of patients. Next-Generation Sequence analysis and bioinformatic analysis were performed to identify 69 pharmacogene variants. Variants with clinical annotation were identified.

RESULTS: Analysis of 69 pharmacogenes in a total of 635 patients identified 9485 variants. The number of distinct variants identified in each gene was 1409. Of these 1409 variants, the number of variants registered in PharmGKB was 126. Among the 126 variants registered in PharmGKB, 26 variants were identified that had a direct association with clinical annotation and drug efficacy or toxicity. The most common variant genes were DPYD, CYP2C19, VKORC1,UGT1A1, RYR1 and MTHFR. These 26 variants with clinical annotation were identified in 327 (51%) different individuals.

CONCLUSIONS: Such a high frequency of critical variants (51%) points to the need for pharmacogenetic studies. The results are extremely important in terms of determining the drug dose according to the genomic status of individuals receiving drug therapy and preventing unnecessary health expenditures.

PMID:40247430 | DOI:10.1080/17410541.2025.2493606

Pharmacogenomics J. 2025 Apr 17;25(3):9. doi: 10.1038/s41397-025-00367-0.

ABSTRACT

Similarity between candidate drug targets and human proteins is commonly assessed to minimize the occurrence of side effects. Although numerous drugs have been found to disrupt the health of the human microbiome, no comprehensive comparison between established drug targets and the human microbiome metaproteome has yet been conducted. Therefore, herein, sequence and structure alignments between human and pathogen drug targets and representative human gut, oral, and vaginal microbiome metaproteomes were performed. Both human and pathogen drug targets were found to be similar in sequence, function, structure, and drug binding capacity to proteins in diverse pathogenic and non-pathogenic bacteria from all three microbiomes. The gut metaproteome was identified as particularly susceptible overall to off-target effects. Certain symptoms, such as infections and immune disorders, may be more common among drugs that non-selectively target host microbiota. These findings suggest that similarities between human microbiome metaproteomes and drug target candidates should be routinely checked.

PMID:40246834 | DOI:10.1038/s41397-025-00367-0

Lancet Child Adolesc Health. 2025 May;9(5):315-324. doi: 10.1016/S2352-4642(25)00058-6.

ABSTRACT

BACKGROUND: Many treatments for abdominal pain-related disorders of gut-brain interaction (AP-DGBI) in children have been studied. We aimed to assess the efficacy and safety of all known treatment options for paediatric AP-DGBI.

METHODS: For this systematic review and network meta-analysis, we searched Embase, MEDLINE, and CENTRAL databases from inception to Jan 16, 2025, for published randomised controlled trials. We included trials of any treatment for AP-DGBIs (irritable bowel syndrome, functional abdominal pain-not otherwise specified, and abdominal migraine, excluding functional dyspepsia) in children aged 4-18 years. We excluded randomised controlled trials that solely included children with functional dyspepsia, but we included studies in which children with functional dyspepsia were included alongside children with the other AP-DGBI diagnoses and outcome data could not be separated. Data extraction and quality appraisal were performed in duplicate. The primary outcome for this network meta-analysis was author-defined treatment success. Network meta-analysis methodology was used within a frequentist framework using multivariate meta-analysis and outcomes were assessed using the Grading of Recommendations, Assessment, Development and Evaluation methodology. Clinical relevance of effect sizes was interpreted according to consensus definitions.

FINDINGS: Of 19 337 records identified through the database search, 155 records representing 91 original randomised controlled trials were included in the network meta-analysis: these 91 trials comprised 7226 participants (4119 females and 2673 males). 12 studies assessed dietary treatments (n=730), 25 assessed pharmacological treatments (n=2140), 23 assessed probiotic treatments (n=1762), and 35 assessed psychosocial treatments (n=2952). Two treatments were probably more effective for treatment success than control treatments (moderate certainty): hypnotherapy (risk ratio [RR] 4·99 [95% CI 2·15 to 11·57]; large effect size) and cognitive behavioural therapy (CBT; RR 1·99 [95% CI 1·33 to 2·98]; moderate effect size). All other treatments evaluated for treatment success were either not effective or the data were of very low certainty and thus no conclusions could be made.

INTERPRETATION: Hypnotherapy and CBT show moderate certainty for treatment efficacy with clinically relevant effect sizes. No conclusions can be made about the other therapies and treatment success due to very low evidence certainty. Future randomised controlled trials should focus on improving the evidence certainty for those other therapies with regard to core AP-DGBI outcomes.

FUNDING: None.

PMID:40246358 | DOI:10.1016/S2352-4642(25)00058-6

Pharmacopsychiatry. 2025 Apr 17. doi: 10.1055/a-2560-4028. Online ahead of print.

ABSTRACT

Clozapine is a recommended treatment for psychotic symptoms in patients with Parkinson's disease (PD) and/or dementia. However, the therapeutic reference range for clozapine in these patients has not been established hitherto.The study was performed in three university hospitals in Germany and Switzerland, including clozapine-treated patients with PD and/or dementia. The primary outcome was tolerability based on reports of adverse drug reactions and/or changes in laboratory tests or electrocardiogram and/or clozapine discontinuation. We meta-analyzed demographic and pharmacokinetic parameters in patients tolerating clozapine well versus not. A meta-analytic summary receiver operating characteristic (SROC) to establish the clozapine upper level associated with poor tolerability was estimated.We analyzed a total of 99 patients suffering from PD (56.6%) and/or dementia (49.5%) with a mean age of 70.3±9.5 years and 41.4% females; poor tolerability was reported in 26 of 99 patients (26.3%). When comparing patients with and without poor tolerability, there were no differences in age, body mass index, sex, smoking, or clozapine dose, nor did we find statistically significant differences in clozapine levels (standardized mean difference 0.46, 95% confidence interval - 0.04 to 0.96, p=0.07), and heterogeneity was low (I2=0.0%). Clozapine blood levels above 193 ng/mL were associated with poor tolerability (SROC area-under-curve 0.6, sensitivity 39.7%, specificity 79.9%).One of four patients with PD and/or dementia treated with clozapine did not tolerate clozapine well, which was associated with a trend toward elevated clozapine concentrations. Monitoring drug levels may help to improve tolerability in these patients.

PMID:40245933 | DOI:10.1055/a-2560-4028

J Clin Psychopharmacol. 2025 Apr 18. doi: 10.1097/JCP.0000000000001999. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomic (PGx) testing can help improve response and remission rates for patients with major depressive disorder (MDD) and at least one treatment failure. To investigate real-world outcomes, we examined 1) significant gene-drug interactions (GDIs) and 2) healthcare resource utilization (HRU) in a large US insurance claims dataset.

METHODS: Weighted multigene PGx testing results in adult patients with MDD were linked with deidentified US claims data. The PGx test report organized medications as congruent (no known or moderate GDI) or incongruent (significant GDI). Medication claims data before and after PGx testing was used to categorize patients as no change in congruency, incongruent-to-congruent, or congruent-to-incongruent. HRU (hospitalizations and emergency department visits) was compared in the 180 days before and after PGx testing.

RESULTS: A total of 20,933 patients met inclusion criteria; 16,965 of whom filled medication prescriptions before and after PGx testing. After PGx testing, the proportion of patients filling prescriptions with significant GDIs was reduced (26.1% pretesting vs 15.9% posttesting). All HRU was significantly reduced (P < 0.001) after PGx testing except for nonpsychiatric hospitalizations (P > 0.05). Psychiatric hospitalizations were significantly reduced after PGx testing in the incongruent-to-congruent and no change in congruency categories (P < 0.001), but not in the congruent-to-incongruent category. Conversely, emergency department visits were significantly reduced after PGx testing in all congruency categories (P < 0.005) and did not differ when compared across congruency categories.

CONCLUSIONS: After PGx testing, patients with MDD had decreased prescribing of medications with significant GDI and reduced HRU. PGx testing may have influenced these outcomes, but the retrospective study design limits clarity on its impact.

PMID:40245843 | DOI:10.1097/JCP.0000000000001999

Ann Clin Transl Neurol. 2025 Apr 17. doi: 10.1002/acn3.70053. Online ahead of print.

ABSTRACT

This study assessed whether continued treatment with anti-CGRP monoclonal antibodies (mAbs) is driven more by reductions in monthly migraine days (MMDs) or patients' global impression of change (PGIC), a patient-reported outcome. Among 169 patients treated with anti-CGRP mAbs, 21.3% discontinued due to ineffectiveness. PGIC responders (≥ 5) at month 12 were 69.8%, whereas MMD responders (≥ 50% reduction) were 59.2%. Both were significantly associated with discontinuation (PGIC: χ2 = 33.474, φ = 0.445; MMD: χ2 = 29.884, φ = 0.421; p < 0.0001). PGIC showed a stronger correlation with discontinuation (rpb = 0.541) than MMD reduction (rpb = 0.470). These findings highlight PGIC as strongly associated with treatment response, supporting the need for PROMs in evaluating migraine treatment effectiveness.

PMID:40244898 | DOI:10.1002/acn3.70053

Arterioscler Thromb Vasc Biol. 2025 Apr 17. doi: 10.1161/ATVBAHA.125.319221. Online ahead of print.

ABSTRACT

Advances in genomic technologies have significantly enhanced our understanding of both monogenic and polygenic etiologies of cardiovascular disease. In this review, we explore how the utilization of genomic information is bringing personalized medicine approaches to the forefront of cardiovascular disease management. We discuss how genomic data can resolve diagnostic uncertainty, support cascade screening, and inform treatment strategies. The role that genome-wide association studies have had in identifying thousands of risk variants for polygenic cardiovascular diseases, and how these insights, harnessed through the development of polygenic risk scores, could advance personalized risk prediction beyond traditional clinical algorithms. We detail how pharmacogenomics approaches leverage genotype information to guide drug selection and mitigate adverse events. Finally, we present the paradigm-shifting approach of gene therapy, which holds the promise of being a curative intervention for cardiovascular conditions.

PMID:40244646 | DOI:10.1161/ATVBAHA.125.319221

J Community Genet. 2025 Apr 17. doi: 10.1007/s12687-025-00794-3. Online ahead of print.

NO ABSTRACT

PMID:40244505 | DOI:10.1007/s12687-025-00794-3

Int J Mol Sci. 2025 Mar 27;26(7):3076. doi: 10.3390/ijms26073076.

ABSTRACT

BACKGROUND/OBJECTIVES: Breast cancer is the most prevalent cancer in adult women. Currently, new therapies and protein determinations with prognostic value are under development. Fascin (encoded by the FSCN1 gene) is an actin-binding protein that is critical for the development of cytoplasmic projections that are essential for tumor invasion. DNA topoisomerase 2-alpha (TOP2A) is a nuclear protein crucial for ATP-dependent breakage, passage, and rejoining of double-stranded DNA and cell division. Both proteins are associated with higher proliferation rates and worse prognosis in breast cancer and together can provide comprehensive information on prognosis and treatment response.

METHODS: We simultaneously assessed fascin expression and TOP2A/CEP17 DNA copy number ratios in various histological and molecular subtypes. Additionally, these markers were analyzed along with previously established diagnostic markers and other relevant clinical data.

RESULTS: Our series included 265 patients, four of whom were male, and all of which were diagnosed with breast carcinoma. Of the 265 patients initially included, sufficient material for analysis was available for 175 cases, as some samples were excluded because of insufficient tissue quantity, poor preservation, or lack of hybridization in certain assays. Immunohistochemical (IHC) expression of fascin, both in its aggregated form and by category, showed no association with the TOP2A gene alteration ratio. Fascin expression was significantly associated with histological subtype (p < 0.001), molecular subtype (p < 0.001), hormone receptor (HR) (p < 0.001), BCL2 (p = 0.003), Ki67 (p = 0.002), and histological grade (p < 0.001). TOP2A was significantly associated with molecular subtype (p = 0.041), Ki67 (p = 0.048), and histological grade (p = 0.033). In our study, molecular subtype (p = 0.037) emerged as an independent variable for the complete histological response to neoadjuvant treatment. Multivariate analysis linked pathological stage (p = 0.002) and estrogen receptor (ER) expression (p = 0.004) to overall survival (OS) and disease-free survival (DFS).

CONCLUSIONS: No statistical relationship was evident between fascin expression (IHC) and the TOP2A copy ratio. The results of this study suggested that the mechanisms of increased cell proliferation associated with alterations in fascin and TOP2A are independent.

PMID:40243780 | DOI:10.3390/ijms26073076

Comput Struct Biotechnol J. 2025 Apr 3;27:1440-1448. doi: 10.1016/j.csbj.2025.04.004. eCollection 2025.

ABSTRACT

The generation of omics data sets has become an important approach in modern pharmacological and toxicological research as it can provide mechanistic and quantitative information on a large scale. Analyses of these data frequently revealed a non-linear dose-response relationship underscoring the importance of the modeling process to infer biological exposure limits. A number of tools have been developed for dose-response modeling and various thresholds have been defined as a quantitative representation of the effect of a substance, such as effective concentrations or benchmark doses (BMD). Here we present DoseRider an easy-to-use web application and a companion R package for linear and non-linear dose-response modeling and assessment of BMD at the level of biological pathways or signatures using generalized mixed effect models. This approach allows to analyze custom or provided multi-omics data such as RNA sequencing or metabolomics data and its annotation of a collection of pathways and gene sets from various species. Moreover, we introduce the concept of the trend change doses (TCDs) as a numerical descriptor of effects derived from complex dose-response curves. The usability of DoseRider was demonstrated by analyses of RNA sequencing data of bisphenol AF (BPAF) treatment of a human breast cancer cell line (MCF-7) at 8 different concentrations using gene sets for chemical and genetic perturbations (MSigDB). The BMD for BPAF and a set of genes upregulated by estrogen in breast cancer was 0.2 µM (95 %-CI 0.1-0.5 µM) and the lowest TCD (TCD1) was 0.003 µM (95 %-CI 0.0006-0.01 µM). The comprehensive presentation of the results underlines the suitability of the system for pharmacogenomics, toxicogenomics, and applications beyond.

PMID:40242291 | PMC:PMC12001094 | DOI:10.1016/j.csbj.2025.04.004

Health Care Sci. 2025 Apr 8;4(2):82-93. doi: 10.1002/hcs2.70008. eCollection 2025 Apr.

ABSTRACT

BACKGROUND: Precision medicine (PM) has taken center stage in healthcare since the completion of the genomic project. Developed countries have gradually integrated PM into mainstream patient management. However, Nigeria still grapples with wide acceptance, key translational research and implementation of PM. This study sought to explore the knowledge and attitude of PM among pharmacists as key stakeholders in the healthcare team.

METHODS: A cross-sectional study was conducted in selected tertiary hospitals across the country. A 21-item semi-structured questionnaire was administered by hybrid online and physical methods and the results analyzed with Statistical Package for the Social Sciences Version 25. Descriptive statistics were used to summarize the data. A chi-square test was employed to determine the association of knowledge of PM and the sociodemographic characteristics of the study population.

RESULTS: A total of 167 hospital pharmacists participated in the study. A high proportion of the participants are familiar with artificial intelligence (91.75%), Pharmacogenomics (84.5%), and precision medicine (61%). Overall, 38.9% of the pharmacists had a good knowledge while 13.2% had a poor knowledge of PM and associated terms. The level of knowledge did not correlate significantly with gender (X 2 = 3.21, p = 0.201), age (X 2 = 5, p = 0.27), marital status (X 2 = 3.21, p = 0.201), and professional level (X 2 = 6.85, p = 0.144). The most important value of precision medicine to hospital pharmacists is the ability to minimize the impact of disease through preventive medicine (49%) while a large portion are pursuing and or actively planning to pursue additional education in precision medicine.

CONCLUSIONS: There is a highly positive attitude toward the prospect of PM among hospital pharmacists in Nigeria. Education modules in this field are highly recommended as most do not have a holistic knowledge of terms used in PM. Also, more research aimed at translating PM knowledge into clinical practice is recommended.

PMID:40241984 | PMC:PMC11997455 | DOI:10.1002/hcs2.70008

J Gastrointest Cancer. 2025 Apr 16;56(1):99. doi: 10.1007/s12029-025-01227-7.

ABSTRACT

BACKGROUND: The pathological response in rectal cancer treatment provides insight into the molecular mechanisms, including genetic alterations and signaling pathways that influence tumor behavior and resistance to treatment.

CASE PRESENTATION: This report describes a 34-year-old Iraqi male diagnosed with stage III rectal cancer who achieved a complete pathological response following treatment with oxaliplatin-based chemotherapy. Notably, this outcome was achieved without the administration of chemoradiotherapy or the occurrence of neurotoxicity despite the efficacious cumulative‑dose administration (1700 mg/m2) of oxaliplatin. Genomic analysis revealed the presence of a heterozygous (Ile/Val) genotype in the GSTP1 gene, which may have contributed to the observed treatment response.

CONCLUSIONS: Genetic biomarkers play a crucial role in refining treatment strategies by enabling a more precise selection of patients who may safely forgo radiotherapy, thereby minimizing its associated toxicities. Additionally, molecular profiling can help predict susceptibility to oxaliplatin-induced neurotoxicity, facilitating dose adjustments or alternative therapeutic approaches to enhance treatment tolerance and long-term quality of life. Our findings highlight the importance of molecular profiling in optimizing treatment strategies while minimizing toxicity, especially in situations where radiological assessments suggest residual disease or produce unclear results.

PMID:40240738 | DOI:10.1007/s12029-025-01227-7

EBioMedicine. 2025 Apr 11:105675. doi: 10.1016/j.ebiom.2025.105675. Online ahead of print.

ABSTRACT

BACKGROUND: Epilepsy is one of the most common neurological disorders, affecting over 50 million people worldwide. One-third of people with epilepsy do not respond to currently available anti-seizure medications, constituting one of the most important problems in epilepsy. Little is known about the molecular pathology of drug resistance in epilepsy, in particular, possible underlying genetic factors are largely unknown.

METHODS: We performed a genome-wide association study (GWAS) in two epilepsy cohorts of European ancestry, comparing drug-resistant (N = 4208) to drug-responsive individuals (N = 2618) followed by meta-analyses across the studies. Next, we performed subanalyses split into two broad subtypes: acquired or non-acquired focal and genetic generalized epilepsy.

FINDINGS: Our drug-resistant versus drug-responsive epilepsy GWAS meta-analysis showed no significant loci when combining all epilepsy types. Sub-analyses on individuals with focal epilepsy (FE) identified a significant locus on chromosome 1q42.11-q42.12 (lead SNP: rs35915186, P = 1·51 × 10-8, OR[C] = 0·74). This locus was not associated with any epilepsy subtype in the latest epilepsy GWAS (lowest uncorrected P = 0·009 for FE vs. healthy controls), and drug resistance in FE was not genetically correlated with susceptibility to FE itself. Seven genome-wide significant SNPs within this locus, encompassing the genes CNIH4, WDR26, and CNIH3, were identified to protect against drug-resistant FE. Further transcriptome-wide association studies (TWAS) imply significantly higher expression levels of CNIH3 and WDR26 in drug-resistant FE than in drug-responsive FE. CNIH3 is implicated in AMPA receptor assembly and function, while WDR26 haploinsufficiency is linked to intellectual disability and seizures. These findings suggest that CNIH3 and WDR26 may play a role in mediating drug response in focal epilepsy.

INTERPRETATION: We identified a contribution of common genetic variation to drug-resistant focal epilepsy. These findings provide insights into possible mechanisms underlying drug response variability in epilepsy, offering potential targets for personalised treatment approaches.

FUNDING: This work is part of the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 279062 (EpiPGX) and the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI).

PMID:40240269 | DOI:10.1016/j.ebiom.2025.105675

J Infect Dis. 2025 Apr 17:jiaf195. doi: 10.1093/infdis/jiaf195. Online ahead of print.

ABSTRACT

BACKGROUND: Variability in the pharmacokinetics (PK) of first-line anti-tuberculosis drugs (rifampicin -RIF, isoniazid -INH and pyrazinamide (PZA)) is high and may be influenced by pharmacogenetic polymorphism. We performed a pharmacogenetic substudy in 90 participants with PK data from the HIRIF trial in Peru.

METHODS: Relevant single nucleotide polymorphisms (SNPs) in the NAT2, SLCO1B1, AADAC and AOX1 locii were genotyped using real time PCR.

RESULTS: The proportions of slow, intermediate and fast acetylators predicted by a conventional six-SNP NAT2 panel were 32.5%, 48.2% and 19.2% respectively. A single NAT2 tag SNP (rs1495741) agreed with the panel-predicted phenotype in 91% and was a better predictor of INH AUC. Accounting for discrepancies possibly caused by rare alleles not represented in the panel or that could be unequivocally resolved using observed AUC, sensitivity of the tag SNP was 97.7%. A previously described SNP in SLCO1B1 (rs4149032) was present at an allele frequency of 0.31 and appeared to influence RIF AUC and Cmax at a dose of 20 mg/kg, despite an extreme distribution of alleles across the randomised arms The AADAC SNP (rs1803155) predominated in the study population and was not linked to RIF PK, though an effect could have been missed due to sample size and allele frequency .There was no association between PZA PK and a common SNP in AOX1 (rs55754655).

CONCLUSIONS: A tag SNP approach may offer simpler and cheaper prediction of INH PK. Further exploration of the impact of SLCO1B1 SNPs on RIF PK is required in this and other populations.

PMID:40239986 | DOI:10.1093/infdis/jiaf195

J Appl Lab Med. 2025 Apr 16:jfaf041. doi: 10.1093/jalm/jfaf041. Online ahead of print.

ABSTRACT

BACKGROUND: Clopidogrel is a widely used antiplatelet agent used to prevent adverse events for patients suffering from acute coronary syndromes and ischemic stroke. As a prodrug, clopidogrel must be converted to the active form through the enzyme cytochrome (CYP) P450 2C19 (among other enzymes). Individuals carrying a loss of function (LOF) allele (i.e., *2 and/or *3) have reduced pharmacologic efficacy. Ticagrelor is an alternative antiplatelet medication that is not a prodrug.

METHODS: We reviewed the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE2) Trial demonstrating the inferiority of clopidogrel dual therapy with aspirin vs ticagrelor dual therapy to prevent adverse events among patients suffering from a mild stroke among Chinese patients who carried a CYP2C19 LOF. We also summarized the pharmacogenomic testing policies within Chinese clinical laboratories after publication of this trial, and tabulated the CYP2C19 LOF allele frequencies among ancestries, as a criteria for justifying the expense required for establishing pharmacogenomic testing services for other populations.

RESULTS: The CHANCE2 trial showed that stroke patients carrying a CYP2C19 LOF allele(s) had a reduction of 1.6% for recurrent stroke for those treated with ticagrelor vs clopidogrel. The LOF allele frequency was highest among Pacific Island and Western and Central Asian (e.g., Han Chinese) patients and lowest among European, Latin, and Hispanic Latino patients.

CONCLUSIONS: Pharmacogenomic testing for CYP2C19 variants is more economically justified for laboratories that serve a population enriched with CYP2C19 LOF alleles, than populations exhibiting a lower allele frequency. Within a clinical laboratory offering testing, restricting testing to certain populations is not ethical.

PMID:40238818 | DOI:10.1093/jalm/jfaf041

J Physiol Biochem. 2025 Apr 16. doi: 10.1007/s13105-025-01080-z. Online ahead of print.

ABSTRACT

Cardiovascular diseases (CVDs) constitute a major global health problem, being the leading cause of death. Several risk factors for CVDs have been identified, including tobacco use, unhealthy diet, and physical inactivity. However, the role of genetic factors in CVDs remains unclear. Recent studies suggest that vitamin D deficiency is associated with an increased risk of CVDs. Therefore, the aim of this study is to assess the impact of 13 single nucleotide polymorphisms (SNPs) located in genes involved in vitamin D metabolism (VDR, GC, CYP27B1, CYP2R1, and CYP24A1) on the risk of developing CVDs. A retrospective case-control study was conducted in 766 Caucasian individuals from southern Spain: 383 diagnosed with CVDs and 383 without cardiovascular complications, matched based on age and sex. The 13 SNPs were identified by real-time PCR using TaqMan™ probes at the Virgen de las Nieves University Hospital and the University of Granada. According to statistical analysis the allele G and genotype GG of the SNP CYP2R1 rs10741657 and the allele C and CC genotype of the SNP CYP27B1 rs3782130 are associated with a decreased risk of CVDs and diabetes in three of the five heritage models studied. Thus, it can be concluded that CYP2R1 rs10741657 and CYP27B1 rs3782130 could be used as risk biomarkers for CVDs in the future, although studies with a larger number of participants are needed.

PMID:40237935 | DOI:10.1007/s13105-025-01080-z

Clin Infect Dis. 2025 Apr 16:ciaf198. doi: 10.1093/cid/ciaf198. Online ahead of print.

ABSTRACT

BACKGROUND: TB APPRISE (IMPAACT P1078), a Phase IV randomized, multi-country non-inferiority trial assessing the safety of 28 weeks of isoniazid preventive therapy (IPT) initiated during pregnancy (immediate IPT) versus deferring to week 12 postpartum (deferred IPT) in people living with HIV on antiretroviral therapy, showed higher than expected hepatotoxicity. We investigated the potential roles of antiretrovirals, isoniazid, pharmacogenetics and other factors.

METHODS: Hepatotoxicity was defined as Grade≥3 liver enzyme elevations; or Grade≥2 enzyme elevations with elevated bilirubin or symptomatic hepatitis. We performed Poisson regression of all-cause hepatotoxicity on study arm, antiretroviral regimen, pharmacogenetics of isoniazid and efavirenz metabolism (NAT2, CYP2B6) and other participant characteristics. Adjusted models included study arm and covariates with p<0.25 in unadjusted models. Antiretroviral regimen and pharmacogenetics interactions with study arm were evaluated.

RESULTS: All 945 pregnant participants with follow-up liver function measurements were on antiretrovirals (85% with efavirenz, 13% with nevirapine); 63 (6%) experienced hepatotoxicity events; 29 (6%) in immediate and 34 (7%) in deferred arm; only 5 events (8%) occurred in pregnancy; 49 (78%) occurred between delivery and 24 weeks postpartum. Higher risk of hepatotoxicity was observed with nevirapine use in the immediate arm, but there was no difference by study arm in participants on efavirenz. Slow efavirenz metabolizers had increased risk of hepatotoxicity.

CONCLUSIONS: It is critical to monitor for hepatotoxicity in early postpartum, where there is higher risk compared to antepartum. ARV regimen and pharmacogenetics should also be considered in making decisions on when to initiate IPT in pregnant and postpartum populations.

PMID:40237651 | DOI:10.1093/cid/ciaf198

ACS Med Chem Lett. 2025 Mar 20;16(4):552-559. doi: 10.1021/acsmedchemlett.4c00592. eCollection 2025 Apr 10.

ABSTRACT

The M2 muscarinic acetylcholine receptor (M2R) is a G protein-coupled receptor involved in regulating cardiovascular functions and mediation of central muscarinic effects, such as movement, temperature control, and antinociceptive responses. Molecular probes targeting this receptor are therefore important in exploring its pathophysiological role at a molecular level. Herein, we report the design, synthesis, and evaluation of a new fluorescent probe for M2R based on an anthranilamide ligand. In radioligand binding experiments, the presented Oregon Green 488-labeled conjugate (33) exhibited high M2R affinity (K i = 2.4 nM), a moderate preference for the M2R over the M4 receptor, and excellent to pronounced M2R selectivity compared to the M1, M3, and M5 receptors. The utility of the probe was demonstrated in confocal, two-photon, and stimulated emission depletion nanoscopy (STED) imaging to specifically label the receptors in human embryonic kidney (HEK) 293T cells. These properties suggest that our probe may be utilized in advanced microscopy to study the pharmacology of the M2R.

PMID:40236555 | PMC:PMC11995211 | DOI:10.1021/acsmedchemlett.4c00592