Pub Date : 2025-11-12DOI: 10.1038/s41397-025-00393-y
Mohammed Khattab, Mohamed Baguneid, George P. Patrinos, Bassam R. Ali, Salahdein Aburuz
Genetic variation in CYP2C19 is linked to variable efficacy in antiplatelet therapies like clopidogrel. Patients with CYP2C19*2 and *3 loss of function alleles show reduced enzyme function, leading to lower active drug levels and higher risks of thromboembolic and cardiovascular events. Point-of-care CYP2C19 testing offers a personalized approach to antiplatelet therapy. We conducted a systematic review of literature assessing point-of-care CYP2C19 testing to individualize antiplatelet therapy in cardiovascular patients compared to standard therapies. The review followed PRISMA guidelines and identified 146 articles, of which 3 randomized controlled trials (RCTs) were comprised. The three studies included 6945 patients; 3483 received genotype-guided therapy, and 3462 received standard care. Efficacy and safety outcomes were compared between groups. Point-of-care genotype-guided therapy improved primary outcomes and lowered bleeding rates compared to conventional therapy. However, the benefit varied, with most trials demonstrating improved efficacy and safety outcomes of various statistical significance levels. Meta-analysis of pooled data (n = 3,424) showed a significant reduction in major adverse cardiovascular events (MACE) with point-of-care genotype-guided therapy (RR = 0.56, 95% CI 0.41–0.76, p = 0.0002; moderate heterogeneity I² = 48%) while bleeding outcomes did not differ significantly (RR = 0.74, 95% CI 0.35–1.56, p = 0.42; I² = 51%). PROSPERO registration (CRD42023378028).
CYP2C19基因变异与氯吡格雷等抗血小板治疗的不同疗效有关。CYP2C19*2和*3功能等位基因缺失的患者表现为酶功能降低，导致活性药物水平降低，血栓栓塞和心血管事件的风险更高。即时检测CYP2C19为抗血小板治疗提供了个性化的方法。我们进行了一项系统的文献综述，评估了与标准治疗相比，即时检测CYP2C19对心血管患者个体化抗血小板治疗的效果。该综述遵循PRISMA指南，共纳入146篇文章，其中包括3项随机对照试验（rct）。三项研究共纳入6945例患者；3483例接受基因型引导治疗，3462例接受标准治疗。比较两组疗效和安全性。与传统治疗相比，即时护理基因型引导治疗改善了主要结果，降低了出血率。然而，益处各不相同，大多数试验显示疗效和安全性结果的改善具有不同的统计学显著性水平。汇总数据的荟萃分析（n = 3,424）显示，即时护理基因型引导治疗显著降低了主要不良心血管事件（MACE） （RR = 0.56, 95% CI 0.41-0.76, p = 0.0002；中度异质性I²= 48%），而出血结局无显著差异（RR = 0.74, 95% CI 0.35-1.56, p = 0.42; I²= 51%）。普洛斯彼罗注册（CRD42023378028）。
{"title":"Comparative analysis of point-of-care bedside cyp2c19-testing guided anti-platelet therapy versus conventional therapies for cardiovascular diseases: a systematic review and meta-analysis","authors":"Mohammed Khattab, Mohamed Baguneid, George P. Patrinos, Bassam R. Ali, Salahdein Aburuz","doi":"10.1038/s41397-025-00393-y","DOIUrl":"10.1038/s41397-025-00393-y","url":null,"abstract":"Genetic variation in CYP2C19 is linked to variable efficacy in antiplatelet therapies like clopidogrel. Patients with CYP2C19*2 and *3 loss of function alleles show reduced enzyme function, leading to lower active drug levels and higher risks of thromboembolic and cardiovascular events. Point-of-care CYP2C19 testing offers a personalized approach to antiplatelet therapy. We conducted a systematic review of literature assessing point-of-care CYP2C19 testing to individualize antiplatelet therapy in cardiovascular patients compared to standard therapies. The review followed PRISMA guidelines and identified 146 articles, of which 3 randomized controlled trials (RCTs) were comprised. The three studies included 6945 patients; 3483 received genotype-guided therapy, and 3462 received standard care. Efficacy and safety outcomes were compared between groups. Point-of-care genotype-guided therapy improved primary outcomes and lowered bleeding rates compared to conventional therapy. However, the benefit varied, with most trials demonstrating improved efficacy and safety outcomes of various statistical significance levels. Meta-analysis of pooled data (n = 3,424) showed a significant reduction in major adverse cardiovascular events (MACE) with point-of-care genotype-guided therapy (RR = 0.56, 95% CI 0.41–0.76, p = 0.0002; moderate heterogeneity I² = 48%) while bleeding outcomes did not differ significantly (RR = 0.74, 95% CI 0.35–1.56, p = 0.42; I² = 51%). PROSPERO registration (CRD42023378028).","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 6","pages":"34-"},"PeriodicalIF":2.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41397-025-00393-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145508075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-12DOI: 10.1038/s41397-025-00392-z
Astrid Johannesson Hjelholt, Tahereh Gholipourshahraki, Zhonghao Bai, Merina Shrestha, Mads Kjolby, Peter Sørensen, Palle Duun Rohde
Type 2 diabetes (T2D) is a complex, polygenic disease with substantial health impact. Despite extensive genome-wide association studies (GWAS) identifying risk loci, therapeutic translation remains limited. We applied a Bayesian Linear Regression (BLR) multi-trait gene set model to prioritize druggable gene sets, integrating GWAS summary statistics with drug-gene interaction data from the Drug Gene Interaction Database (DGIdb). For each drug group, defined at the ATC 4th level, we calculated posterior inclusion probabilities (PIP) to assess relevance. Known antidiabetic agents showed strong associations with T2D, validating the model. Additionally, carboxamide derivatives, fibrates, uric acid inhibitors, and various immunomodulatory and antineoplastic agents demonstrated significant genetic relevance. Gene-level analyses highlighted key T2D-associated genes, including PPARG, KCNQ1, TNF, and GCK. Notably, bezafibrate, a PPAR pan-agonist, demonstrated substantial genetic overlap with T2D loci, supporting its potential in metabolic disease. This study introduces a genetically informed pipeline for drug repurposing based on multi-trait gene set analysis.
{"title":"Leveraging genetic correlations to prioritize drug groups for repurposing in type 2 diabetes","authors":"Astrid Johannesson Hjelholt, Tahereh Gholipourshahraki, Zhonghao Bai, Merina Shrestha, Mads Kjolby, Peter Sørensen, Palle Duun Rohde","doi":"10.1038/s41397-025-00392-z","DOIUrl":"10.1038/s41397-025-00392-z","url":null,"abstract":"Type 2 diabetes (T2D) is a complex, polygenic disease with substantial health impact. Despite extensive genome-wide association studies (GWAS) identifying risk loci, therapeutic translation remains limited. We applied a Bayesian Linear Regression (BLR) multi-trait gene set model to prioritize druggable gene sets, integrating GWAS summary statistics with drug-gene interaction data from the Drug Gene Interaction Database (DGIdb). For each drug group, defined at the ATC 4th level, we calculated posterior inclusion probabilities (PIP) to assess relevance. Known antidiabetic agents showed strong associations with T2D, validating the model. Additionally, carboxamide derivatives, fibrates, uric acid inhibitors, and various immunomodulatory and antineoplastic agents demonstrated significant genetic relevance. Gene-level analyses highlighted key T2D-associated genes, including PPARG, KCNQ1, TNF, and GCK. Notably, bezafibrate, a PPAR pan-agonist, demonstrated substantial genetic overlap with T2D loci, supporting its potential in metabolic disease. This study introduces a genetically informed pipeline for drug repurposing based on multi-trait gene set analysis.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 6","pages":"33-"},"PeriodicalIF":2.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145508039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1038/s41397-025-00391-0
Wei Zhuang, Yi Zeng, Xinping Lin, Haibo Qiu, Wanlong Lin, Min Huang, Xueding Wang
Imatinib is associated with significant toxicities, including myelosuppression, oedema, and hypersensitivity, with considerable interpatient variability. Pharmacokinetic and pharmacogenomic factors contribute, but comprehensive biomarkers are yet to be identified. A retrospective cohort study was conducted on 154 gastrointestinal stromal tumour (GIST) patients receiving imatinib. Steady-state concentrations of imatinib and its metabolite were measured using liquid chromatography-tandem mass spectrometry. Thirty-five genetic polymorphisms in signaling, transporter, and immune genes were genotyped, and multivariate logistic regression was performed, adjusting for clinical covariates. The study found a significant correlation between myelosuppression and imatinib plasma concentration, along with genetic polymorphisms in FLT1, MAPK1, PDGFRB, and SHC1. Peripheral oedema was more prevalent in females and associated with PDGFRB polymorphisms. Hypersensitivity was linked to EGFR and CXCL14 polymorphisms. These findings identify novel pharmacogenetic markers for imatinib-induced toxicities, supporting the potential of personalized treatment strategies through genetic testing and therapeutic drug monitoring. Further validation in larger cohorts is needed.
{"title":"Genetic and pharmacokinetic factors associated with imatinib-induced toxicities in gastrointestinal stromal tumors","authors":"Wei Zhuang, Yi Zeng, Xinping Lin, Haibo Qiu, Wanlong Lin, Min Huang, Xueding Wang","doi":"10.1038/s41397-025-00391-0","DOIUrl":"10.1038/s41397-025-00391-0","url":null,"abstract":"Imatinib is associated with significant toxicities, including myelosuppression, oedema, and hypersensitivity, with considerable interpatient variability. Pharmacokinetic and pharmacogenomic factors contribute, but comprehensive biomarkers are yet to be identified. A retrospective cohort study was conducted on 154 gastrointestinal stromal tumour (GIST) patients receiving imatinib. Steady-state concentrations of imatinib and its metabolite were measured using liquid chromatography-tandem mass spectrometry. Thirty-five genetic polymorphisms in signaling, transporter, and immune genes were genotyped, and multivariate logistic regression was performed, adjusting for clinical covariates. The study found a significant correlation between myelosuppression and imatinib plasma concentration, along with genetic polymorphisms in FLT1, MAPK1, PDGFRB, and SHC1. Peripheral oedema was more prevalent in females and associated with PDGFRB polymorphisms. Hypersensitivity was linked to EGFR and CXCL14 polymorphisms. These findings identify novel pharmacogenetic markers for imatinib-induced toxicities, supporting the potential of personalized treatment strategies through genetic testing and therapeutic drug monitoring. Further validation in larger cohorts is needed.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 6","pages":"32-"},"PeriodicalIF":2.9,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-29DOI: 10.1038/s41397-025-00390-1
Vinh Hoa Pham, Sang-Heon Kim, Young-Koo Jee, Tae-Won Jang, Jinsoo Min, Ho-Sook Kim, Yong-Soon Cho, Jae-Gook Shin
It has been proposed that mitochondrial DNA variations can affect mitochondrial function, increasing the risk of drug-induced liver injury. This study aims to explore the association between mitochondrial DNA (mtDNA) variants and anti-tuberculosis drug-induced liver injury (ATT_DILI) in Korean tuberculosis patients. Whole mitochondrial genomes from 185 patients (61 with ATT_DILI and 124 without liver injury) were sequenced. Comparative analyses examined mtDNA variants, variant counts, and haplogroups between the two groups, adjusted with Bonferroni correction. The m.16189 T > C variant, associated with reduced mtDNA copy number, was more frequent in ATT_DILI cases (39.3%) than in controls (29.0%). Logistic regression suggested a potential association (odds ratio 4.92, 95% confidence interval 1.14–21.23, p = 0.033), though this significance was lost after correction. No significant differences in mtDNA variant counts or haplogroups were observed between groups. While mtDNA variants and haplogroups appear to have a limited role in predicting ATT_DILI risk, the m.16189 T > C variant warrants further investigation.
有人提出线粒体DNA变异可影响线粒体功能，增加药物性肝损伤的风险。本研究旨在探讨韩国结核病患者线粒体DNA （mtDNA）变异与抗结核药物性肝损伤（ATT_DILI）的关系。对185例患者（61例患有ATT_DILI， 124例无肝损伤）的全线粒体基因组进行测序。比较分析检查了两组之间的mtDNA变异、变异计数和单倍群，并进行了Bonferroni校正。与mtDNA拷贝数减少相关的m.16189 T > C变异在ATT_DILI病例中（39.3%）比对照组（29.0%）更常见。Logistic回归提示存在潜在关联（优势比4.92,95%可信区间1.14-21.23,p = 0.033），但校正后该显著性消失。各组间mtDNA变异数或单倍群无显著差异。虽然mtDNA变异和单倍群在预测ATT_DILI风险方面的作用有限，但m.16189 T b> C变异值得进一步研究。
{"title":"Mitochondrial DNA variants and susceptibility to anti-tuberculosis drug-induced liver injury in Korean patients","authors":"Vinh Hoa Pham, Sang-Heon Kim, Young-Koo Jee, Tae-Won Jang, Jinsoo Min, Ho-Sook Kim, Yong-Soon Cho, Jae-Gook Shin","doi":"10.1038/s41397-025-00390-1","DOIUrl":"10.1038/s41397-025-00390-1","url":null,"abstract":"It has been proposed that mitochondrial DNA variations can affect mitochondrial function, increasing the risk of drug-induced liver injury. This study aims to explore the association between mitochondrial DNA (mtDNA) variants and anti-tuberculosis drug-induced liver injury (ATT_DILI) in Korean tuberculosis patients. Whole mitochondrial genomes from 185 patients (61 with ATT_DILI and 124 without liver injury) were sequenced. Comparative analyses examined mtDNA variants, variant counts, and haplogroups between the two groups, adjusted with Bonferroni correction. The m.16189 T > C variant, associated with reduced mtDNA copy number, was more frequent in ATT_DILI cases (39.3%) than in controls (29.0%). Logistic regression suggested a potential association (odds ratio 4.92, 95% confidence interval 1.14–21.23, p = 0.033), though this significance was lost after correction. No significant differences in mtDNA variant counts or haplogroups were observed between groups. While mtDNA variants and haplogroups appear to have a limited role in predicting ATT_DILI risk, the m.16189 T > C variant warrants further investigation.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 6","pages":"31-"},"PeriodicalIF":2.9,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145402060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-28DOI: 10.1038/s41397-025-00389-8
Anna Shteto, Jawad Boulahfa, Adrien Etcheto, Yann Zhong, Martin Kindermans, Frederic Parmentier, Federico Goodsaid
Predictive safety risk biomarkers for drug-induced liver injury (DILI) are critically needed to enhance patient risk stratification and minimize adverse outcomes. This study aims to identify genomic markers associated with increased mortality in toxic liver disease, using the KEM® (Knowledge Extraction and Management) explainable Artificial Intelligence platform. From 225 participants diagnosed with toxic liver disease within the UK Biobank cohort, data were consolidated, including survival outcomes, clinical phenotypes, comorbidities, and 36 394 genomic single nucleotide polymorphisms (SNPs) focusing on liver-related pathways. Fifteen SNPs were found to be significantly associated with increased mortality risk, notably rs73158145 in the PRKAG2 gene. Predictive models built on these selected SNPs achieved a mean accuracy of 85%, outperforming models without pre-selection (68.9% accuracy). Further validation in independent cohorts is planned to confirm the clinical relevance of these biomarkers.
{"title":"Genomic biomarkers of liver toxicity risk from UK Biobank data","authors":"Anna Shteto, Jawad Boulahfa, Adrien Etcheto, Yann Zhong, Martin Kindermans, Frederic Parmentier, Federico Goodsaid","doi":"10.1038/s41397-025-00389-8","DOIUrl":"10.1038/s41397-025-00389-8","url":null,"abstract":"Predictive safety risk biomarkers for drug-induced liver injury (DILI) are critically needed to enhance patient risk stratification and minimize adverse outcomes. This study aims to identify genomic markers associated with increased mortality in toxic liver disease, using the KEM® (Knowledge Extraction and Management) explainable Artificial Intelligence platform. From 225 participants diagnosed with toxic liver disease within the UK Biobank cohort, data were consolidated, including survival outcomes, clinical phenotypes, comorbidities, and 36 394 genomic single nucleotide polymorphisms (SNPs) focusing on liver-related pathways. Fifteen SNPs were found to be significantly associated with increased mortality risk, notably rs73158145 in the PRKAG2 gene. Predictive models built on these selected SNPs achieved a mean accuracy of 85%, outperforming models without pre-selection (68.9% accuracy). Further validation in independent cohorts is planned to confirm the clinical relevance of these biomarkers.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 6","pages":"30-"},"PeriodicalIF":2.9,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145395155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-22DOI: 10.1038/s41397-025-00388-9
Ruby Soueid, Toni J. F. Michael, Pete Yeap, Betty Chaar, Fanfan Zhou, Melanie White-Koning, Stephen Hughes, Rose Cairns, Kellie A. Charles, Sophie L. Stocker
Pharmacogenomic services are commonly pharmacist-led, yet pharmacists report poor knowledge and confidence in application. This study evaluated an experiential teaching approach to enhance students’ confidence and knowledge in pharmacogenomics. Customised modules were delivered to three cohorts of second-year undergraduate pharmacy students. Cohort A received lectures and a tutorial; Cohort B added self-testing; Cohort C (same as B) added a case-based workshop and assignment. Students were predominantly female (64%) and half were younger than 20 years old. Self-perceived confidence, assessed using pre- and post-module surveys, significantly improved across all cohorts, in applying pharmacogenomic skills, recognising pharmacists’ roles and perceptions towards self-testing. Students who self-tested in Cohort C reported greater confidence (e.g., “patient education testing risks”: 26% test vs 0% no test). Knowledge, assessed using examination scores ranged from 70–74% across cohorts, showing no significant differences. Our findings suggest that experiential learning enhances confidence, supporting greater integration of pharmacogenomics into future practice.
{"title":"Evaluation of experiential teaching approaches to enhance pharmacy students’ confidence and knowledge in pharmacogenomics","authors":"Ruby Soueid, Toni J. F. Michael, Pete Yeap, Betty Chaar, Fanfan Zhou, Melanie White-Koning, Stephen Hughes, Rose Cairns, Kellie A. Charles, Sophie L. Stocker","doi":"10.1038/s41397-025-00388-9","DOIUrl":"10.1038/s41397-025-00388-9","url":null,"abstract":"Pharmacogenomic services are commonly pharmacist-led, yet pharmacists report poor knowledge and confidence in application. This study evaluated an experiential teaching approach to enhance students’ confidence and knowledge in pharmacogenomics. Customised modules were delivered to three cohorts of second-year undergraduate pharmacy students. Cohort A received lectures and a tutorial; Cohort B added self-testing; Cohort C (same as B) added a case-based workshop and assignment. Students were predominantly female (64%) and half were younger than 20 years old. Self-perceived confidence, assessed using pre- and post-module surveys, significantly improved across all cohorts, in applying pharmacogenomic skills, recognising pharmacists’ roles and perceptions towards self-testing. Students who self-tested in Cohort C reported greater confidence (e.g., “patient education testing risks”: 26% test vs 0% no test). Knowledge, assessed using examination scores ranged from 70–74% across cohorts, showing no significant differences. Our findings suggest that experiential learning enhances confidence, supporting greater integration of pharmacogenomics into future practice.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 6","pages":"29-"},"PeriodicalIF":2.9,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145350036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1038/s41397-025-00387-w
Yazun Jarrar, Nancy Hakooz, Dina Abu Hashem, Mariam Homsi, Sufyan Ali Ajeen, Maher Al Ghedan, Rania Almasri, Amnah Bdier, Mohammed Alraqad
Pharmacogenomics (PGx) testing aims to identify the most appropriate drug and dose for individual patients based on their genetic profiles. In Jordan, patients with genetic disorders often use multiple medications, some of which have clinical guidelines recommending PGx testing. This study aimed to screen the frequency of clinically relevant PGx biomarkers among a sample of Jordanian patients with genetic disorders. A total of 76 patients (average age 13 ± 14 years; 71% under 13 years old) attending INNOVIA Biobank in Amman between January 2023 and January 2024 participated. Buccal swabs were collected, and DNA was extracted for whole-genome sequencing using Illumina technology. Variant calling and annotation were performed using DRAGEN, Geneyx, and ANNOVAR tools. A PGx panel based on PharmCAT v2.8.3 and Clinical Pharmacogenetics Implementation Consortium v1.30.0, covering 20 pharmacogenes, was applied. In Phase I enzymes, CYP2D6*10 (13.2%) and CYP2C19*1/*17 (18.4%) were most common, while CYP2C9 and CYP3A4 variants were less frequent. In Phase II enzymes, UGT1A180 + 2B appeared in 7.9% and multiple DPYD variants found in heterozygous forms 925%). Among toxicity-related markers, G6PD and HLA-B*57:01 were detected in 3.9 and 2.6%, respectively. Transporter gene variants in SLCO1B1 (15%) and ABCB1 (21.1%) were relatively frequent. For pharmacodynamic genes, VKORC1 −1639G > A (52.6%) and CYP4F2 V433M (40.8%) were most prevalent. Accordingly, over half of the patients had genetic variants affecting warfarin response, with additional impacts seen on antidepressants (45%), clopidogrel (35%), and anticancers (30%). Conclusions, this study demonstrates the presence of key PGx biomarkers among Jordanian patients with genetic diseases and supports the integration of PGx testing to optimize the use of drugs like antidepressants, clopidogrel, and warfarin.
{"title":"Genome-wide screening of pharmacogenomic biomarkers in jordanian patients with genetic disorders","authors":"Yazun Jarrar, Nancy Hakooz, Dina Abu Hashem, Mariam Homsi, Sufyan Ali Ajeen, Maher Al Ghedan, Rania Almasri, Amnah Bdier, Mohammed Alraqad","doi":"10.1038/s41397-025-00387-w","DOIUrl":"10.1038/s41397-025-00387-w","url":null,"abstract":"Pharmacogenomics (PGx) testing aims to identify the most appropriate drug and dose for individual patients based on their genetic profiles. In Jordan, patients with genetic disorders often use multiple medications, some of which have clinical guidelines recommending PGx testing. This study aimed to screen the frequency of clinically relevant PGx biomarkers among a sample of Jordanian patients with genetic disorders. A total of 76 patients (average age 13 ± 14 years; 71% under 13 years old) attending INNOVIA Biobank in Amman between January 2023 and January 2024 participated. Buccal swabs were collected, and DNA was extracted for whole-genome sequencing using Illumina technology. Variant calling and annotation were performed using DRAGEN, Geneyx, and ANNOVAR tools. A PGx panel based on PharmCAT v2.8.3 and Clinical Pharmacogenetics Implementation Consortium v1.30.0, covering 20 pharmacogenes, was applied. In Phase I enzymes, CYP2D6*10 (13.2%) and CYP2C19*1/*17 (18.4%) were most common, while CYP2C9 and CYP3A4 variants were less frequent. In Phase II enzymes, UGT1A180 + 2B appeared in 7.9% and multiple DPYD variants found in heterozygous forms 925%). Among toxicity-related markers, G6PD and HLA-B*57:01 were detected in 3.9 and 2.6%, respectively. Transporter gene variants in SLCO1B1 (15%) and ABCB1 (21.1%) were relatively frequent. For pharmacodynamic genes, VKORC1 −1639G > A (52.6%) and CYP4F2 V433M (40.8%) were most prevalent. Accordingly, over half of the patients had genetic variants affecting warfarin response, with additional impacts seen on antidepressants (45%), clopidogrel (35%), and anticancers (30%). Conclusions, this study demonstrates the presence of key PGx biomarkers among Jordanian patients with genetic diseases and supports the integration of PGx testing to optimize the use of drugs like antidepressants, clopidogrel, and warfarin.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 6","pages":"28-"},"PeriodicalIF":2.9,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-04DOI: 10.1038/s41397-025-00386-x
Wrenda Teeple, Jeffrey A. Shaman, Tootie Tatum, Ben L. Kong, J. Shawn Jones, Sara L. Rogers
{"title":"STRIPE partners in precision medicine: regulatory perspective","authors":"Wrenda Teeple, Jeffrey A. Shaman, Tootie Tatum, Ben L. Kong, J. Shawn Jones, Sara L. Rogers","doi":"10.1038/s41397-025-00386-x","DOIUrl":"10.1038/s41397-025-00386-x","url":null,"abstract":"","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 5","pages":"1-3"},"PeriodicalIF":2.9,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-03DOI: 10.1038/s41397-025-00384-z
William P. Duggan, Mohammedreza Azimi, Lyndsey Flanagan, Graeme P. Sullivan, Ian. S. Reynolds, Joanna Fay, Heiko Dussmann, Tríona Ní Chonghaile, Katherine M. Sheehan, Karin Jirström, Jochen H. M. Prehn, John P. Burke
5–15% of all colorectal cancers (CRCs) are mucinous. Mucinous CRCs are associated with an inhibited response to standard adjuvant and neoadjuvant therapies. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme, which modulates the activity of multiple splicing factors. SRPK1 under-expression is associated with resistance to platinum-based chemotherapeutic agents in multiple tumor types. The objectives of this study were to evaluate SRPK1 expression in mucinous CRC and to explore the potential relationship between differential SRPK1 expression and oxaliplatin resistance in mucinous CRC. Rectal cancer and CRC Tissue Microarrays (TMA) were stained with SRPK1 to compare expression between mucinous and non-mucinous tumors. SRPK1 expression was analyzed in mucinous and non-mucinous CRC cell lines. Cells were treated with oxaliplatin to explore differences in treatment response. Mucinous cells were transfected with an SRPK1 CRISPR/Cas9 lentiviral activation plasmid to investigate the relationship between SRPK1 expression and oxaliplatin resistance. The TMA cohorts included 117 patients with mucinous and 441 patients with non-mucinous CRC. SRPK1 was found to be under-expressed in both the mucinous rectal cancer (P < 0.001) and CRC cohorts (P = 0.003). On univariate analysis, SRPK1 under-expression was found to be associated with worse 5-year OS (P = 0.001). Treatment of mucinous CRC cells with oxaliplatin did not result in a significant increase in cell death (P = 0.149). However overexpression of SRPK1 following transfection with a CRISPR/CAS9 activation plasmid resulted in a significant increase in sensitivity of these cells to oxaliplatin treatment (P = 0.029). SRPK1 is under-expressed in mucinous CRC, and under-expression is associated with worse OS. This may be due to the positive effects of SRPK1 on oxaliplatin sensitivity.
{"title":"Serine-arginine protein kinase 1 (SRPK1) is under-expressed in mucinous colorectal cancer, and may mediate resistance to oxaliplatin","authors":"William P. Duggan, Mohammedreza Azimi, Lyndsey Flanagan, Graeme P. Sullivan, Ian. S. Reynolds, Joanna Fay, Heiko Dussmann, Tríona Ní Chonghaile, Katherine M. Sheehan, Karin Jirström, Jochen H. M. Prehn, John P. Burke","doi":"10.1038/s41397-025-00384-z","DOIUrl":"10.1038/s41397-025-00384-z","url":null,"abstract":"5–15% of all colorectal cancers (CRCs) are mucinous. Mucinous CRCs are associated with an inhibited response to standard adjuvant and neoadjuvant therapies. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme, which modulates the activity of multiple splicing factors. SRPK1 under-expression is associated with resistance to platinum-based chemotherapeutic agents in multiple tumor types. The objectives of this study were to evaluate SRPK1 expression in mucinous CRC and to explore the potential relationship between differential SRPK1 expression and oxaliplatin resistance in mucinous CRC. Rectal cancer and CRC Tissue Microarrays (TMA) were stained with SRPK1 to compare expression between mucinous and non-mucinous tumors. SRPK1 expression was analyzed in mucinous and non-mucinous CRC cell lines. Cells were treated with oxaliplatin to explore differences in treatment response. Mucinous cells were transfected with an SRPK1 CRISPR/Cas9 lentiviral activation plasmid to investigate the relationship between SRPK1 expression and oxaliplatin resistance. The TMA cohorts included 117 patients with mucinous and 441 patients with non-mucinous CRC. SRPK1 was found to be under-expressed in both the mucinous rectal cancer (P < 0.001) and CRC cohorts (P = 0.003). On univariate analysis, SRPK1 under-expression was found to be associated with worse 5-year OS (P = 0.001). Treatment of mucinous CRC cells with oxaliplatin did not result in a significant increase in cell death (P = 0.149). However overexpression of SRPK1 following transfection with a CRISPR/CAS9 activation plasmid resulted in a significant increase in sensitivity of these cells to oxaliplatin treatment (P = 0.029). SRPK1 is under-expressed in mucinous CRC, and under-expression is associated with worse OS. This may be due to the positive effects of SRPK1 on oxaliplatin sensitivity.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 5","pages":"1-10"},"PeriodicalIF":2.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1038/s41397-025-00385-y
Ryley Uber, Vanessa A. Hayduk, Alison Flango, Theron Ward, Leeann Webster, Eric A. Wright
Pharmacogenomics (PGx) test results are returned variably across healthcare settings, which can lead to challenges particularly when results require immediate intervention to avoid adverse consequences. While several return of result models exist in literature, a standard-of-care has not been established. We propose a model to safely return PGx results in the context of scaled and sustained PGx testing: an institutional protocol to integrate new PGx results into patient care.
{"title":"An innovative model for pharmacogenomics critical results identification and intervention","authors":"Ryley Uber, Vanessa A. Hayduk, Alison Flango, Theron Ward, Leeann Webster, Eric A. Wright","doi":"10.1038/s41397-025-00385-y","DOIUrl":"10.1038/s41397-025-00385-y","url":null,"abstract":"Pharmacogenomics (PGx) test results are returned variably across healthcare settings, which can lead to challenges particularly when results require immediate intervention to avoid adverse consequences. While several return of result models exist in literature, a standard-of-care has not been established. We propose a model to safely return PGx results in the context of scaled and sustained PGx testing: an institutional protocol to integrate new PGx results into patient care.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 5","pages":"1-4"},"PeriodicalIF":2.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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