NPJ Precis Oncol. 2025 Jun 20;9(1):199. doi: 10.1038/s41698-025-00985-8.

ABSTRACT

CIC::DUX4 translocation-positive sarcomas (CDS) are rare, highly proliferative tumors associated with chemotherapy resistance. Without a clear understanding of the molecular pathways driving CDS, no effective treatment regimens have been developed. Here, we identify protection against DNA damage through upregulation of POLE and DNA repair pathways specific to CDS. These data may explain the high proliferation rate and chemotherapy resistance of these tumors and suggest targeted treatment strategies for CDS.

PMID:40542203 | DOI:10.1038/s41698-025-00985-8

Pediatr Res. 2025 Jun 20. doi: 10.1038/s41390-025-04213-8. Online ahead of print.

NO ABSTRACT

PMID:40542089 | DOI:10.1038/s41390-025-04213-8

Drug Metab Dispos. 2025 May 27;53(7):100105. doi: 10.1016/j.dmd.2025.100105. Online ahead of print.

ABSTRACT

Erythropoietic protoporphyria (EPP) is caused by loss-of-function mutations in ferrochelatase (FECH), leading to the accumulation of its substrate, protoporphyrin IX (PPIX). PPIX is primarily produced in the bone marrow and transported to the liver for excretion. Because PPIX is hydrophobic, its elevated levels can cause bile duct blockage, cholestatic liver injury, and even liver failure. However, the specific transporter responsible for PPIX uptake into hepatocytes remains unclear. The OATP1B1/1B3 transporters, which are expressed in hepatocytes, facilitate the uptake of coproporphyrin III, a structural analog of PPIX. Additionally, OATP1B1/1B3 mediates the uptake of bilirubin, a biomarker of liver injury, from plasma into the liver for excretion. Therefore, we aimed to determine the role of OATP1B1/1B3 in regulating PPIX and bilirubin homeostasis under EPP conditions. A mouse strain carrying a Fech mutation was used as an EPP model. Building on this, we generated a new EPP mouse model with Oatp1a/1b deficiency. Using these EPP mouse models, along with OATP1B1/1B3-overexpressing cells, our study revealed that PPIX is not a substrate of OATP1B1/1B3. Notably, our work found that genetic deficiency or pharmacologic suppression of Oatp1a/1b exacerbates hyperbilirubinemia in EPP mice without worsening liver injury. Mechanistically, Oatp1a/1b deficiency impairs bilirubin uptake from plasma, while Fech deficiency leads to PPIX-mediated bile duct blockage and reduced bilirubin excretion, synergistically exacerbating hyperbilirubinemia. In summary, our work demonstrated that deficiency or suppression of Oatp1a/1b exacerbates hyperbilirubinemia in EPP mouse models, suggesting that assessment of OATP1B1/1B3 function is crucial in EPP patients with EPP with hyperbilirubinemia. SIGNIFICANCE STATEMENT: This work revealed that serum bilirubin levels are not paralleled with liver damage in the erythropoietic protoporphyria mouse models with Oatp1a/1b deficiency. Our findings suggest that assessment of OATP1B1/1B3 function is crucial in patients with erythropoietic protoporphyria with hyperbilirubinemia.

PMID:40540978 | DOI:10.1016/j.dmd.2025.100105

Pharmacogenomics. 2025 Jun 20:1-15. doi: 10.1080/14622416.2025.2509479. Online ahead of print.

ABSTRACT

Tuberculosis is the leading cause of death from a single infectious agent globally, with the highest burden in low-and middle-income countries. Successful treatment requires prolonged administration of multiple drugs. The increasing threat of multidrug-resistant tuberculosis has prompted the development of a robust pipeline for new drugs. While generally safe and well tolerated, adverse drug reactions (ADRs) to TB drugs have a considerable impact on treatment outcomes. Pharmacogenetic testing has been implemented for some diseases to identify at-risk individuals and prevent ADRs. For tuberculosis treatment, the use of pharmacogenetic testing to optimize complex regimens and avoid ADRs is appealing, but there has been minimal implementation. To improve the use of pharmacogenetics, understanding both the pharmacology of relevant drugs and population-specific pathophysiology of ADRs are essential. This review highlights the major treatment-limiting ADRs with TB drugs, the current understanding of drug metabolic pathways, ADR pathophysiology, and known pharmacogenetic risk alleles. We highlight research gaps and barriers to meaningful clinical use and implementation of pharmacogenomic testing to prevent adverse reactions to TB drugs.

PMID:40538374 | DOI:10.1080/14622416.2025.2509479

J Neurol. 2025 Jun 19;272(7):468. doi: 10.1007/s00415-025-13202-0.

ABSTRACT

BACKGROUND: This study aimed to compare the differences in clinical characteristics and response to monoclonal antibodies against CGRP (anti-CGRP mAbs) between patients who habitually used triptans (TRIPTANS group) and patients who were non-current users (NO-TRIPTANS group).

METHODS: In this prospective cohort study, all consecutive outpatients treated with anti-CGRP mAbs for 12 months were included. Clinical data were collected at baseline and monthly: number of headache days (MHDs), the absolute number of analgesics (AMNs), and the number of days with at least one analgesic (AMDs), Headache Impact Test-6 (HIT-6), and Migraine Disability Assessment (MIDAS) questionnaires. The outcomes were to evaluate the differences between TRIPTANS and NO-TRIPTANS groups (users or non-users of triptans in the 6 months before and during anti-CGRP mAb treatment) in MHDs and the other clinical variables during treatment. Response rates were assessed based on reductions in MHDs (≤ 25%, ≥ 50%, ≥ 75%).

RESULTS: A total of 336 patients treated with mAbs were included. At baseline, NO-TRIPTANS group had higher MHDs (24.7 ± 6.7) compared to the TRIPTANS group (21.8 ± 6.9), p < 0.001. Comparative and normalized analyses showed significant and sustained lower MHDs in the TRIPTANS group during treatment. The MIDAS score was also significantly lower in the TRIPTANS group at month-3, 6, 9, 12, and lower AMDs and AMNs compared to NO-TRIPTANS group were seen in most of the time-points. The number of patients with ≥ 50% reduction of MHDs was significantly higher in the TRIPTANS group at months 1 and 12.

CONCLUSIONS: This study showed greater effectiveness of anti-CGRP mAb in habitual triptans users, possibly due to a common and/or synergistic action.

PMID:40536712 | DOI:10.1007/s00415-025-13202-0

Int J Cancer. 2025 Jun 19. doi: 10.1002/ijc.70005. Online ahead of print.

ABSTRACT

DPYD gene variations are associated with severe fluoropyrimidine toxicity, and an initial 50% dose reduction is widely recommended for heterozygous carriers of relevant DPYD variants, including DPYD*2A, DPYD*13, c.2846A>T, and c.1236G>A. However, there is a high variability in DPD activity between DPYD variant carriers, and a proportion of patients may tolerate higher fluoropyrimidine doses. The aim of this retrospective study was to compare fluoropyrimidine toxicity outcomes and tolerated dose intensities between different DPYD variant carriers that received DPYD genotype-guided dosing. We identified DPYD variant carriers that received fluoropyrimidine-based treatment between January 2015 and February 2021 in three Dutch Hospitals. The initial fluoropyrimidine dose was reduced by 25-50% for all heterozygous DPYD variant carriers following the Dutch Pharmacogenetics Working Group guideline. Toxicity outcomes were collected for the first three cycles. From 2112 consecutively DPYD-genotyped patients, 120 patients with DPYD variants were included. The frequency of overall severe toxicity was 21% for wild types, 27% for heterozygous DPYD variant carriers overall, 19% for c.1236G>A carriers, 38% for c.2846A>T carriers, and 44% for DPYD*2A carriers. Median relative dose intensity for cycles 1-3 was 71% for c.1236G>A carriers, 68% for c.2846A>T carriers, and 52% for DPYD*2A carriers. Despite good fluoropyrimidine tolerance in a large proportion of patients, only 13% of patients underwent dose escalation. Novel studies are highly needed to establish the optimal fluoropyrimidine starting dose for heterozygous carriers of c.1236G>A. After initial dose reduction, dose uptitration based on individual tolerance and therapeutic drug monitoring in all DPYD variant heterozygotes is advised to prevent the risk of underdosing.

PMID:40536615 | DOI:10.1002/ijc.70005

J Clin Pharmacol. 2025 Jun 19. doi: 10.1002/jcph.70059. Online ahead of print.

ABSTRACT

Gepirone, an antidepressant drug, is biotransformed into two principal metabolites [1-(2-pyrimidinyl)-piperazine (1-PP) and 3'-OH-gepirone] primarily by CYP3A enzymes. Metabolism of gepirone in the presence of ketoconazole, a potent inhibitor of human CYP3A activity, was studied in vitro in human liver microsomes. The clinical pharmacokinetic interaction of ketoconazole (as a maximal chemical inhibitor of CYP3A isoforms) with single doses of gepirone was evaluated in a Phase 1 study in human volunteers (N = 24). In vitro coincubation of gepirone with increasing concentrations of ketoconazole produced extensive inhibition of 1-PP and 3'-OH-gepirone formation, with IC50 values in the range of 0.026 µM to 0.162 µM. These inhibitory values are substantially lower than clinically encountered systemic concentrations of ketoconazole, thereby predicting extensive in vivo increases in gepirone exposure when coadministered with ketoconazole. In the clinical pharmacokinetic study, ketoconazole produced large increases in gepirone exposure by factors of 5.92- to 7.80-fold. Appearance of 1-PP in the systemic circulation decreased by factors of 0.56 to 0.97, while appearance of 3'-OH-gepirone increased by 1.70- to 2.43-fold. The clinical findings are consistent with the in vitro results, and underlie the labeling recommendation that gepirone not be coadministered with "strong" CYP3A inhibitors.

PMID:40536342 | DOI:10.1002/jcph.70059

Front Pharmacol. 2025 Jun 4;16:1604473. doi: 10.3389/fphar.2025.1604473. eCollection 2025.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is commonly treated with doxorubicin (DOX). However, its effectiveness varies significantly among patients.

AIM: The present study aimed to identify potential genetic variants affecting the response of HCC patients to DOX.

METHODS: 78 patients with HCC who received DOX via transarterial chemoembolization (TACE) technology were selected. DNA was extracted from blood for genome-wide genotyping using the Applied Biosystems™ Axiom™ Precision Medicine Diversity Research™ Array. Genetic data were analysed using Axiom™ Analysis Suite software v5.2.

RESULTS: Six hits in five genes [AK3 (rs378117), TRPM3 (rs1329774 and rs4745058), CDH4 (rs2427043), LINC00504 (rs76228864), and GRIN2D (rs76754767)] were associated with a risk of tumour progression, whereas variants in HPGD (rs45593131) and RC3H2 (rs2792999) were suggested as protective factors. rs8038528 in the PCSK6 gene was categorized as a low-response variant associated with an unsatisfactory reduction in α-fetoprotein (AFP) levels after DOX chemotherapy (P = 6.82 × 10-5). In contrast, three SNPs (rs1998853, rs12440990, and rs4774596) located within two genes (NPAS3 and DMXL2) were identified as predictors of good response rates to the treatment, as AFP levels were reduced by ≥ 20%. Death incidents showed associations with five SNPs that reached p ≤ 5.0 × 10-8; four of these are located within the DENND1B, LOC107986086, TMEM169, and RNF152 genes.

CONCLUSION: These findings support the incorporation of pharmacogenomic testing into clinical practice for HCC therapy, paving the way for customized treatment methods that may improve therapeutic efficacy and patient outcomes. Future research is needed to replicate these genetic connections.

PMID:40535770 | PMC:PMC12174396 | DOI:10.3389/fphar.2025.1604473

Front Genet. 2025 Jun 4;16:1608423. doi: 10.3389/fgene.2025.1608423. eCollection 2025.

ABSTRACT

INTRODUCTION: Genetic variation in genes coding for enzymes metabolising antihypertensive drugs, may affect the efficacy of angiotensin converting enzyme (ACE) inhibitors such as enalapril, potentially leading to resistant hypertension (RHTN). We set out to evaluate the contribution of genetic variation in CES1 and NOS3 genes on susceptibility to RHTN, as well as estimate the frequencies of CES1 copy number variation (CNV) in African and Mixed Ancestry (MA) populations of South Africa.

METHODS: Using a retrospective age, sex and ethnicity matched case-control study design, 379 participants with hypertension belonging to the African and MA ethnic groups were recruited. Cases were participants with RHTN (i.e., blood pressure (BP) ≥140/90 mmHg on ≥3 antihypertensive drugs or BP < 140/90 mmHg on >3 antihypertensive drugs, including a diuretic). Cases were matched to controls with similar characteristics (age (±5 years), sex and ethnicity) in a 1:1 ratio. Controls were participants with hypertension that was under control (BP < 140/90 mmHg on ≤3 antihypertensive drugs). Five polymorphisms in CES1 and NOS3 were characterized using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), quantitative PCR and validated using Sanger sequencing. The additive model of inheritance and multivariable logistic regression were used to determine associations between genotypes and RHTN while adjusting for potential confounding variables.

RESULTS AND DISCUSSION: NOS3 rs3918188A/A (aOR: 0.13; CI: 0.04-0.41; P = 0.0009) genotype and NOS3 rs2070744-rs1798883-rs3918188G-T-A haplotype (OR: 0.54; CI: 0.37-0.78; P = 0.001) appeared to confer protection against RHTN among MA participants only. CES1 rs2244613C>A and CES1 CNV were not significantly associated with RHTN. However, there appeared to be quantitative differences in CES1 CNV profiles across ethnic groups. We speculate that NOS3 rs3918188A allele may affect NOS3 gene expression, potentially leading to increased amounts of the vasodilator, nitric oxide (NO) and favourable outcomes in individuals taking antihypertensives drugs such as enalapril.

CONCLUSION: NOS3 genetic variation seems important in the susceptibility to RHTN among Africans and requires further studies.

PMID:40534840 | PMC:PMC12174097 | DOI:10.3389/fgene.2025.1608423

Nat Genet. 2025 Jun 18. doi: 10.1038/s41588-025-02227-w. Online ahead of print.

ABSTRACT

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

PMID:40533518 | DOI:10.1038/s41588-025-02227-w

Gac Med Mex. 2025;161(1):3-8. doi: 10.24875/GMM.M25000969.

ABSTRACT

Type 2 diabetes (T2DM) is a public health problem and the second leading cause of death in Mexico. More than 20 years after the human genome project was completed, the development of innovative technologies and methodologies to determine the genetic risk factors that predispose an individual to develop this and other pathologies, have made the implementation of genomic medicine as part of clinical practice become a reality. Although in Mexico genomic studies are still in the beginning, these have generated knowledge about the etiopathogenesis of T2DM. In this review, we will address genomic knowledge applications in clinical practice, as well as the advances in the genomics of T2DM in Mexico.

PMID:40532250 | DOI:10.24875/GMM.M25000969

Gac Med Mex. 2025;161(1):94-101. doi: 10.24875/GMM.M25000975.

ABSTRACT

BACKGROUND: Personalized medicine allows the selection of the drug and dose based on the patient's genetic information, which is imperative in the treatment of diabetes and hypercholesterolemia, diseases with high prevalence in Mexico.

OBJECTIVE: To integrate pharmacogenetic and genomic research on antidiabetic and antihypercholesterolemic drugs in Mexican patients.

MATERIAL AND METHODS: We integrated our research, relating it with similar research from national and foreign laboratories.

RESULTS: For antidiabetic pharmacological treatments, variants in the ABCC8 and KCNJ11 genes were consistently associated with the response to sulfonylureas, while variants in the SLC47A1, SLC28A1 and ABCG2 genes explained up to 55% of the variability in the response to metformin. Regarding hypercholesterolemia, atorvastatin treatment is influenced by variants in the genes MTHFR, DRD3, GSTM3, TNFα MDR1, SLCO1BI, ABCB1, CYP2D6, CYP2B6, NAT2 and COMT.

CONCLUSION: Our findings highlight the need to integrate pharmacogenetics into clinical practice to achieve greater therapeu tic success in diabetes and hypercholesterolemia.

PMID:40532247 | DOI:10.24875/GMM.M25000975

Medicine (Baltimore). 2025 Jun 13;104(24):e42868. doi: 10.1097/MD.0000000000042868.

ABSTRACT

Genomics and personalized medicine are transforming cardiology by improving the assessment, diagnosis, and treatment of cardiovascular diseases (CVDs). By understanding the genetic factors underlying CVDs, personalized treatment strategies can be developed to enhance patient outcomes and reduce the burden of cardiovascular conditions. The integration of genomics into clinical practice enables more precise risk assessments, early detection, and targeted interventions. This narrative review examines randomized clinical trials (RCTs) on genotype-guided therapies, pharmacogenomics, and personalized medicine in cardiology. Studies were selected for their contributions to identifying genetic factors influencing CVD risk, evaluating pharmacogenomic data, and exploring personalized treatment approaches. Key outcomes analyzed include treatment efficacy, genetic associations, and clinical implications of genetic insights in cardiovascular care. The findings highlight the identification of genetic variants linked to increased CVD risk and the development of genomic risk scores for personalized risk prediction. Pharmacogenomic studies also revealed genetic determinants of drug response, particularly in cardiovascular treatments. Genetic testing has shown promise in guiding antiplatelet therapy selection, drug dosage optimization, and minimizing adverse effects, thus improving treatment efficacy. Despite the potential of genomics and personalized medicine, challenges such as clinical implementation, cost-effectiveness, and ethical concerns persist. To fully benefit from personalized cardiovascular care, future research should focus on validating genetic markers, refining risk prediction models, and overcoming barriers to widespread adoption. With continued development, these approaches could revolutionize cardiovascular care, providing more effective, individualized treatments and improving patient outcomes.

PMID:40527816 | DOI:10.1097/MD.0000000000042868

Pharmacopsychiatry. 2025 Jun 17. doi: 10.1055/a-2603-0871. Online ahead of print.

ABSTRACT

Traditionally, the aetiology of schizophrenia has been attributed to dopaminergic neurotransmission, but more recent information points to the role of glutamate pathways. Glutamatergic involvement in schizophrenia might be extensible to drug response. The aim of the study was to explore whether the variation in glutamate receptors, transporters and metabolism can influence the outcome of drug treatments.A total of 45 polymorphisms in the genes GRIN1, GRIN2A, GRIN2B, GRIN3A, GRIA1, GRIK2, GRM2, GRM3, GRM5, GRM8, SLC1A1, SLC1A3 and GAD1 were genotyped in 258 patients with schizophrenia. Efficacy and side effects were evaluated with the Positive and Negative Symptoms Scale and the UKU scale, respectively, at baseline and after 12 weeks.The analysis revealed associations between outcomes, including response and adverse effects and genetic variants in several genes (GAD1, GRIA1, GRIN2A, GRIN3A, GRIK2, GRM2, GRM5, GRM8 and SLC1A3). An association of rs1864205 in GRIA1 with autonomic side effects bordered statistical significance after correction for multiple comparisons.Our results suggest that genetic variation in glutamatergic pathways can influence the efficacy and safety of antipsychotic drugs.

PMID:40527340 | DOI:10.1055/a-2603-0871

Alcohol Alcohol. 2025 May 14;60(4):agaf033. doi: 10.1093/alcalc/agaf033.

ABSTRACT

AIMS: Alcohol related cognitive impairment (ARCI) impacts an individual's ability to engage in treatment thus may result in poorer outcomes. We aimed to describe outcomes in a legacy cohort of patients with ARCI, identified in an acute hospital setting.

METHOD: We conducted a retrospective review of a cohort of patients who underwent screening for ARCI between 1 April 2017 and 31 March 2018. Those identified with alternative causes of cognitive impairment were excluded. The Montreal Cognitive Assessment Tool (MoCA©) was utilized to determine presence, and severity, of cognitive impairment. These patients were referred to a multi-disciplinary meeting (MDT) and an out-patient clinic. Mortality was recorded at 3 years. Cox-regression analysis was undertaken and, Kaplan Meier (KM) plots were prepared to visualize the data.

RESULTS: A total of 210 patients met criteria for ARCI screening. Multi-variate analysis found an association between ARCI and mortality at 3 years, Hazard Ratio (HR) 1.732 (p = .019). Co-existent Chronic Liver disease (CLD) increased this association, HR 1.722 (p = .020) but CLD in isolation did not increase mortality risk, HR 1.223 (p = .401). Severe ARCI had the strongest mortality association (p = <.001). Subsequent engagement with the ARCI care pathway improved outcomes, HR .324; (p = .008).

CONCLUSION: ARCI, identified by a simple, bed-side test is significantly associated with early mortality. This relationship is more marked in the presence of liver disease. The more severe the ARCI, the stronger relationship with death by 3 years. The cohort mean age was 52, a decade younger than the expected age at diagnosis of cognitive impairment in the general population.

PMID:40526368 | DOI:10.1093/alcalc/agaf033

Xenobiotica. 2025 Jun 17:1-20. doi: 10.1080/00498254.2025.2519825. Online ahead of print.

ABSTRACT

Valproic acid(VPA) has great individual differences in clinical efficacy, the study aimed to investigate the effects of VPA-related pharmacogenomics on the antiepileptic efficacy of VPA, so as to provide evidence for clinical rational drug use.The patients were followed up for one year, and the number of seizures within one year was used as the evaluation index of efficacy. The target SNPS were genotyped by SNPscan method.A total of 253 patients with epilepsy treated with valproate monotherapy were enrolled in this study, including 125 patients in the valproate-sensitive group and 128 patients in the valproate-resistant group. χ2 test showed that the frequency of C allele of CACNA1H rs3751664 in valproate-sensitive group was significantly higher than that in valproate-resistant group (93.6% vs. 87.5%, P = 0.023), and the difference was still statistically significant after adjusting for confounding factors by logistic regression analysis(P = 0.037). Haplotype analysis showed no association between gene polymorphisms and efficacy of valproic acid.CACNA1C rs1051375 GG and GA genotype patients have a lower risk of drug resistance than AA genotype patients, CACNA1H rs3751664 T allele is a risk factor for VPA monoresistance, while APEH rs3816877 CT genotype patients have a trend of drug resistance during VPA treatment.

PMID:40526024 | DOI:10.1080/00498254.2025.2519825

Eur J Clin Pharmacol. 2025 Jun 16. doi: 10.1007/s00228-025-03864-0. Online ahead of print.

NO ABSTRACT

PMID:40523951 | DOI:10.1007/s00228-025-03864-0

JAACAP Open. 2024 Aug 9;3(2):157-170. doi: 10.1016/j.jaacop.2024.06.002. eCollection 2025 Jun.

ABSTRACT

OBJECTIVE: There has been remarkable progress in recent years in understanding the genetic underpinnings of child psychiatric disorders. Concurrently, genetic testing is becoming increasingly available in the clinic. However, many clinicians report a lack of familiarity with genetics and how genetic testing might inform a clinical evaluation. This review aims to introduce clinicians to cutting-edge research in child psychiatric genetics and discuss the emerging role of genetic tests in clinical practice.

METHOD: This review highlights major findings presented at the Research Institute of the 69th American Academy of Child and Adolescent Psychiatry Annual Meeting.

RESULTS: An overview of critical genetic concepts for clinicians is provided along with a discussion of recent advances in child psychiatric genetics, focusing on autism spectrum disorder, where whole exome sequencing has led to the identification of approximately 250 high-confidence risk genes. The review describes how similar approaches to gene discovery are beginning to shed light on the genetic architecture of early-onset psychosis, Tourette's disorder, obsessive-compulsive disorder, and other disorders. In addition, the practical limitations of pharmacogenetic testing, ethical considerations, and barriers to clinical genetic testing are discussed. Finally, the promise of genetic research for advancing understanding of the pathophysiology of these disorders is illustrated.

CONCLUSION: This review aims to improve clinicians' knowledge of how genetic findings might inform clinical evaluation and management of child psychiatric disorders and the potential for groundbreaking research in the field to shape the development of new treatments.

DIVERSITY & INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group.

PMID:40520982 | PMC:PMC12166933 | DOI:10.1016/j.jaacop.2024.06.002

Genet Med Open. 2025 Mar 22;3:103426. doi: 10.1016/j.gimo.2025.103426. eCollection 2025.

ABSTRACT

PURPOSE: Pharmacogenomic (PGx) testing has proven significant clinical utility in minimizing adverse drug reactions and maximizing therapeutic effects. This report is a proof of concept of the clinical implementation of PGx testing at a tertiary care hospital in Riyadh, Saudi Arabia.

METHODS: In collaboration with different departments, we implemented the PGx testing clinical service into our electronic health record cerner for heart and neurology centers patients. We used the PharmacoScan microarray-based test to perform genotyping.

RESULTS: To date, 512 patients have been tested. 97.5% of all patients have at least 1 gene with altered function. Among those patients, n = 402 (78.5%) had 3 or more genes with altered function (3 genes = 197, 38.5%, 4 genes = 134, 26.2%, 5 genes = 58, 11.3%, and 6 genes = 13, 2.5%).

CONCLUSION: Our work describes the successful implementation of PGx testing in clinical practice and encourages further research on improving patient outcomes. Moreover, we describe the major challenges at each step of our approach, which provides our institute and others with lessons and insights on implementing PGx testing into clinical practice.

PMID:40519746 | PMC:PMC12166389 | DOI:10.1016/j.gimo.2025.103426

Pharmacol Res Perspect. 2025 Jun;13(3):e70135. doi: 10.1002/prp2.70135.

ABSTRACT

In Peru, 33 113 individuals were diagnosed with tuberculosis (TB) in 2023. While TB treatments are generally effective, 3.4% to 13% of cases are associated with significant adverse drug reactions, with drug-induced liver injury (DILI) being the most prevalent. Limited data exist on genetic risk factors for DILI in Latin America; even less is known about these factors in native Peruvian populations. This study aimed to determine the prevalence of TB drug-metabolizing genotypes in these populations. A cross-sectional analysis was conducted using genetic data from 254 participants from the Peruvian Genome Project (PGP) representing three subpopulations: Coast, Andes, and Amazon. Twenty-three genes associated with TB treatment, include isoniazid, rifampin, ethambutol, and pyrazinamide, as identified in the PharmGKB database, were analyzed. Significant differences were observed in genotype frequencies among subpopulations for AGBL4, NAT2, GSTP1, SLCO1B1, NOS, and CYP2B6 genes. The Amazonian population demonstrated a higher risk of DILI due to the increased prevalence of hepatotoxic alleles in AGBL4, GSTP1, and SLCO1B1. In contrast, alleles in the NOS gene indicated a lower risk of hepatotoxicity in the Andean population. However, the high-risk genotypes identified in the study's native Peruvian populations exhibit distinct prevalence patterns compared to those reported in the 1000 Genomes Project. These findings can inform the development of personalized therapeutic strategies to improve TB treatment outcomes among Peru's diverse subpopulations.

PMID:40517315 | DOI:10.1002/prp2.70135