Pub Date : 2025-04-09DOI: 10.1038/s41397-025-00368-z
Arife Uzundurukan, Mark Nelson, Christopher Teske, Mohamed Shahidul Islam, Elzagheid Mohamed, John Victor Christy, Holli-Joi Martin, Eugene Muratov, Samantha Glover, Domenico Fuoco
This review offers an overview of advanced in silico methods crucial for drug discovery, emphasizing their integration with data science, and investigates the effectiveness of data science, machine learning, and artificial intelligence via a thorough meta-analysis of existing technologies. This meta-analysis aims to rank these technologies based on their applications and accessibility of knowledge. Initially, a search strategy yielded 900 papers, which were then refined into two subsets: the top 300 most-cited papers since 2000 and papers selected for systematic review based on high impact. From these, 97 articles were identified for discussion, categorized by their influence on society. The focus remains on the qualitative impact of these disciplines rather than solely on metrics like new drug approvals. Ultimately, the review underscores the role of big data in enhancing our comprehension of drug candidate trajectories from development to commercialization, utilizing information stored in publicly available databases to chemical space.
{"title":"Meta-analysis and review of in silico methods in drug discovery – part 1: technological evolution and trends from big data to chemical space","authors":"Arife Uzundurukan, Mark Nelson, Christopher Teske, Mohamed Shahidul Islam, Elzagheid Mohamed, John Victor Christy, Holli-Joi Martin, Eugene Muratov, Samantha Glover, Domenico Fuoco","doi":"10.1038/s41397-025-00368-z","DOIUrl":"10.1038/s41397-025-00368-z","url":null,"abstract":"This review offers an overview of advanced in silico methods crucial for drug discovery, emphasizing their integration with data science, and investigates the effectiveness of data science, machine learning, and artificial intelligence via a thorough meta-analysis of existing technologies. This meta-analysis aims to rank these technologies based on their applications and accessibility of knowledge. Initially, a search strategy yielded 900 papers, which were then refined into two subsets: the top 300 most-cited papers since 2000 and papers selected for systematic review based on high impact. From these, 97 articles were identified for discussion, categorized by their influence on society. The focus remains on the qualitative impact of these disciplines rather than solely on metrics like new drug approvals. Ultimately, the review underscores the role of big data in enhancing our comprehension of drug candidate trajectories from development to commercialization, utilizing information stored in publicly available databases to chemical space.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"1-13"},"PeriodicalIF":2.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055576","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 : 2025-03-12DOI: 10.1038/s41397-025-00366-1
Fiona FJ Ng, Rashmi Verma, Levana Sani, Astrid Irwanto, Michael Lee, Angeline Wee, Shih Kiat Chng, Melvyn Wong, Alexandre Chan
In view of the limited data related to preemptive pharmacogenomics (PGx) testing in the primary care setting, we designed a study to assess the feasibility of implementing preemptive PGx services at outpatient clinics, with the aim to assess the practicality and challenges of implementing preemptive PGx testing within primary care, and its impact on clinical workflows and patient care. This prospective study was conducted between October 2022 and August 2023 at five outpatient clinics located in Singapore. Patients aged 21 to 65 with a reported history or risk of developing any of the target chronic conditions or any patients receiving one of the 29 PGx-associated medications were recruited. Patients’ buccal samples were processed using a multi-gene qPCR-based panel of 21 allele variants of five pharmacogenes. Surveys were administered to study participants and clinicians to assess their perceptions and outcomes related to PGx testing. Among the 222 patients, 95% had at least one clinically actionable variant. Of these patients, 113 reported taking at least one of the 29 studied drugs, with 21.2% of them receiving at least one clinically actionable recommendation based on their PGx results. A total of 150 patients (67.6%) participated in the post-test follow-up survey. Among them, 70% expressed feeling relieved and happy upon receiving their test reports and reported increased confidence in taking their prescribed medication. Furthermore, clinicians identified the necessity for clearer legal regulations regarding PGx testing and insurance coverage to enhance future adoption of PGx testing. Given a high prevalence of clinically actionable variants in almost all tested patients, this study underscores the feasibility and clinical benefits of preemptive PGx testing in primary care clinics in Singapore. Clinical Trial Registration: This study is registered with ClinicalTrials.gov, identifier NCT05504135, with the registration date of August 17, 2022.
{"title":"A feasibility study on implementing pre-emptive pharmacogenomics testing in outpatient clinics in Singapore (IMPT study)","authors":"Fiona FJ Ng, Rashmi Verma, Levana Sani, Astrid Irwanto, Michael Lee, Angeline Wee, Shih Kiat Chng, Melvyn Wong, Alexandre Chan","doi":"10.1038/s41397-025-00366-1","DOIUrl":"10.1038/s41397-025-00366-1","url":null,"abstract":"In view of the limited data related to preemptive pharmacogenomics (PGx) testing in the primary care setting, we designed a study to assess the feasibility of implementing preemptive PGx services at outpatient clinics, with the aim to assess the practicality and challenges of implementing preemptive PGx testing within primary care, and its impact on clinical workflows and patient care. This prospective study was conducted between October 2022 and August 2023 at five outpatient clinics located in Singapore. Patients aged 21 to 65 with a reported history or risk of developing any of the target chronic conditions or any patients receiving one of the 29 PGx-associated medications were recruited. Patients’ buccal samples were processed using a multi-gene qPCR-based panel of 21 allele variants of five pharmacogenes. Surveys were administered to study participants and clinicians to assess their perceptions and outcomes related to PGx testing. Among the 222 patients, 95% had at least one clinically actionable variant. Of these patients, 113 reported taking at least one of the 29 studied drugs, with 21.2% of them receiving at least one clinically actionable recommendation based on their PGx results. A total of 150 patients (67.6%) participated in the post-test follow-up survey. Among them, 70% expressed feeling relieved and happy upon receiving their test reports and reported increased confidence in taking their prescribed medication. Furthermore, clinicians identified the necessity for clearer legal regulations regarding PGx testing and insurance coverage to enhance future adoption of PGx testing. Given a high prevalence of clinically actionable variants in almost all tested patients, this study underscores the feasibility and clinical benefits of preemptive PGx testing in primary care clinics in Singapore. Clinical Trial Registration: This study is registered with ClinicalTrials.gov, identifier NCT05504135, with the registration date of August 17, 2022.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"1-11"},"PeriodicalIF":2.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617792","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 : 2025-03-10DOI: 10.1038/s41397-025-00365-2
Vasileios Fragoulakis, Margarita-Ioanna Koufaki, Gregor Mlinšek, Tanja Blagus, Jasna Klen, George P. Patrinos, Vita Dolžan, Christina Mitropoulou
Tacrolimus (TAC) is one of the most widely prescribed maintenance immunosuppressant drugs in solid organ transplantation. Kidney transplantation is often the preferred treatment for patients with the kidney failure and is complemented with TAC treatment. TAC treatment is often associated with adverse drug events, which can be reduced by pharmacogenomic (PGx)-guided prescription. We conducted a cost-utility analysis to assess the cost-effectiveness of PGx-guided TAC treatment versus the conventional scheme in patients who recently underwent kidney transplantation in Slovenia. Clinical data were collected from the PREPARE study. The effectiveness of the treatment was determined by mean survival and utility values and Incremental Cost-Effectiveness Ratio was also calculated. Costs of PGx-guided treatment was comparable to conventional treatment but shared reduced risk for severe ADEs and 43% improved quality of life. PGx-guided arm showed a mean of 0.956 Quality-Adjusted Life Years (QALYs) (95% CI: 0.900–1.014) compared to 0.862 QALYs (95%CI: 0.801–0.918) in the other arm. Probabilistic sensitivity analyses confirmed the results’ robustness. In conclusion, PGx-guided treatment represents a cost-effective option for the TAC treatment of kidney-transplanted patients in the Slovenian healthcare setting.
{"title":"Cost-utility analysis of pharmacogenomics-guided tacrolimus treatment of Slovenian patients undergoing kidney transplantation in the U-PGx PREPARE study","authors":"Vasileios Fragoulakis, Margarita-Ioanna Koufaki, Gregor Mlinšek, Tanja Blagus, Jasna Klen, George P. Patrinos, Vita Dolžan, Christina Mitropoulou","doi":"10.1038/s41397-025-00365-2","DOIUrl":"10.1038/s41397-025-00365-2","url":null,"abstract":"Tacrolimus (TAC) is one of the most widely prescribed maintenance immunosuppressant drugs in solid organ transplantation. Kidney transplantation is often the preferred treatment for patients with the kidney failure and is complemented with TAC treatment. TAC treatment is often associated with adverse drug events, which can be reduced by pharmacogenomic (PGx)-guided prescription. We conducted a cost-utility analysis to assess the cost-effectiveness of PGx-guided TAC treatment versus the conventional scheme in patients who recently underwent kidney transplantation in Slovenia. Clinical data were collected from the PREPARE study. The effectiveness of the treatment was determined by mean survival and utility values and Incremental Cost-Effectiveness Ratio was also calculated. Costs of PGx-guided treatment was comparable to conventional treatment but shared reduced risk for severe ADEs and 43% improved quality of life. PGx-guided arm showed a mean of 0.956 Quality-Adjusted Life Years (QALYs) (95% CI: 0.900–1.014) compared to 0.862 QALYs (95%CI: 0.801–0.918) in the other arm. Probabilistic sensitivity analyses confirmed the results’ robustness. In conclusion, PGx-guided treatment represents a cost-effective option for the TAC treatment of kidney-transplanted patients in the Slovenian healthcare setting.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"1-8"},"PeriodicalIF":2.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598175","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 : 2025-03-05DOI: 10.1038/s41397-025-00364-3
Adith S. Arun, David Liarakos, Gaurav Mendiratta, Jacob Kim, George Goshua, Peter Olson, Edward C. Stites
Reliable estimates for the number of cancer patients with a specific mutation can help quantify the size of the population that could potentially benefit from a targeted therapy. We adapt our previously developed approach for estimating gene-level mutation abundances to estimate mutation-specific (e.g., KRAS G12C) abundances by combining United States cancer epidemiology and genomic data. We demonstrate the approach by obtaining population-level estimates for all acquired somatic missense mutations that create a de novo cysteine residue. We find that approximately 14% of non-epidemiological informed estimates are more than twice the epidemiological informed estimate. Non-epidemiologically informed pan-cancer estimation of mutation rates may not be representative of the number of cancer patients with a specific mutation. Our study suggests that epidemiological and genomic information should be combined when estimating the population level abundance of specific pathogenic mutations.
{"title":"Integrating epidemiology and genomics data to estimate the prevalence of acquired cysteine drug targets in the U.S. cancer patient population","authors":"Adith S. Arun, David Liarakos, Gaurav Mendiratta, Jacob Kim, George Goshua, Peter Olson, Edward C. Stites","doi":"10.1038/s41397-025-00364-3","DOIUrl":"10.1038/s41397-025-00364-3","url":null,"abstract":"Reliable estimates for the number of cancer patients with a specific mutation can help quantify the size of the population that could potentially benefit from a targeted therapy. We adapt our previously developed approach for estimating gene-level mutation abundances to estimate mutation-specific (e.g., KRAS G12C) abundances by combining United States cancer epidemiology and genomic data. We demonstrate the approach by obtaining population-level estimates for all acquired somatic missense mutations that create a de novo cysteine residue. We find that approximately 14% of non-epidemiological informed estimates are more than twice the epidemiological informed estimate. Non-epidemiologically informed pan-cancer estimation of mutation rates may not be representative of the number of cancer patients with a specific mutation. Our study suggests that epidemiological and genomic information should be combined when estimating the population level abundance of specific pathogenic mutations.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"1-7"},"PeriodicalIF":2.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568871","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 : 2025-02-25DOI: 10.1038/s41397-025-00363-4
Graziella D’ Agostino Ribeiro Naldi, Ariane Boccoli Minari, Thales D. M. Pereira, Victor Fossaluza, Nicholas Wagner Eugenio, Marcelo Alves Ferreira, Guilherme H. Gregório, Lucas Nacif, Luiz Augusto Carneiro D Albuquerque, Ricardo di Lazzaro Filho, Eduardo Luiz Rachid Cançado, Suzane Kioko Ono
Liver transplantation is the only curative option for patients with advanced stages of liver disease, with tacrolimus used as the immunosuppressive drug of choice. Genetic variability can interfere with drug response, potentially leading to overexposure or underexposure. This study aims to investigate the association of CYP3A4 (rs2740574, rs2242480, rs35599367), CYP3A5 (rs776746, rs10264272), POR (rs1057868) and ABCB1 (rs1128503, rs2229109, rs9282564) gene polymorphisms with infection, acute rejection, and renal failure. The logistic regression model found an influence of CYP3A5 (rs776746) and POR28 (rs1057868) on the development of acute rejection after liver transplantation (p = 0.028). It also found an association between carriers of the variant allele of the POR*28 gene and infection.
{"title":"CYP3A5 and POR gene polymorphisms as predictors of infection and graft rejection in post-liver transplant patients treated with tacrolimus - a cohort study","authors":"Graziella D’ Agostino Ribeiro Naldi, Ariane Boccoli Minari, Thales D. M. Pereira, Victor Fossaluza, Nicholas Wagner Eugenio, Marcelo Alves Ferreira, Guilherme H. Gregório, Lucas Nacif, Luiz Augusto Carneiro D Albuquerque, Ricardo di Lazzaro Filho, Eduardo Luiz Rachid Cançado, Suzane Kioko Ono","doi":"10.1038/s41397-025-00363-4","DOIUrl":"10.1038/s41397-025-00363-4","url":null,"abstract":"Liver transplantation is the only curative option for patients with advanced stages of liver disease, with tacrolimus used as the immunosuppressive drug of choice. Genetic variability can interfere with drug response, potentially leading to overexposure or underexposure. This study aims to investigate the association of CYP3A4 (rs2740574, rs2242480, rs35599367), CYP3A5 (rs776746, rs10264272), POR (rs1057868) and ABCB1 (rs1128503, rs2229109, rs9282564) gene polymorphisms with infection, acute rejection, and renal failure. The logistic regression model found an influence of CYP3A5 (rs776746) and POR28 (rs1057868) on the development of acute rejection after liver transplantation (p = 0.028). It also found an association between carriers of the variant allele of the POR*28 gene and infection.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"1-9"},"PeriodicalIF":2.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143494840","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 : 2025-02-20DOI: 10.1038/s41397-024-00360-z
Akane Yoshikawa, Jiang Li, Ney Alliey-Rodriguez, Herbert Y. Meltzer
Prediction of treatment response by genetic biomarkers has potential for clinical use and contributes to the understanding of pathophysiology and drug mechanism of action. The purpose of this study is to detect genetic biomarkers possibly associated with response to lurasidone, during the first four weeks of treatment. One-hundred and seventy-one acutely psychotic patients from two placebo-controlled clinical trials of lurasidone were included. Genetic associations with changes in Positive and Negative Syndrome Scale total score at weeks one, two, and four were examined. Genotyping was done with the Affymetrix 6.0 microarray and associations were computed using PLINK regression model. Although genome-wide significance was not reached with a limited sample size, signals of potential interest for further studies were with genes important for neurogenesis. Possible week one marker, rs6459950 (p = 7.05 × 10−7), was close to the sonic hedgehog gene (SHH), involved in neuronal differentiation and neurogenesis. Possible week two marker, rs7435958, was a SNP of GABRB1, encoding the GABAA Receptor β1. Notably, possible week four signals included a SNP within PTCH1, a specific receptor for the SHH, the possible week one marker. Pathway analysis supported the possibility that neurogenesis might be involved in early antipsychotic response. Tissue enrichment analysis suggested that potential signals were enriched in anterior cingulate cortex, reported to be relevant in antipsychotic action. This is the first study to examine genes possibly associated with very early response to lurasidone. Further replication studies in larger sample size should be required.
{"title":"Genetic markers of early response to lurasidone in acute schizophrenia","authors":"Akane Yoshikawa, Jiang Li, Ney Alliey-Rodriguez, Herbert Y. Meltzer","doi":"10.1038/s41397-024-00360-z","DOIUrl":"10.1038/s41397-024-00360-z","url":null,"abstract":"Prediction of treatment response by genetic biomarkers has potential for clinical use and contributes to the understanding of pathophysiology and drug mechanism of action. The purpose of this study is to detect genetic biomarkers possibly associated with response to lurasidone, during the first four weeks of treatment. One-hundred and seventy-one acutely psychotic patients from two placebo-controlled clinical trials of lurasidone were included. Genetic associations with changes in Positive and Negative Syndrome Scale total score at weeks one, two, and four were examined. Genotyping was done with the Affymetrix 6.0 microarray and associations were computed using PLINK regression model. Although genome-wide significance was not reached with a limited sample size, signals of potential interest for further studies were with genes important for neurogenesis. Possible week one marker, rs6459950 (p = 7.05 × 10−7), was close to the sonic hedgehog gene (SHH), involved in neuronal differentiation and neurogenesis. Possible week two marker, rs7435958, was a SNP of GABRB1, encoding the GABAA Receptor β1. Notably, possible week four signals included a SNP within PTCH1, a specific receptor for the SHH, the possible week one marker. Pathway analysis supported the possibility that neurogenesis might be involved in early antipsychotic response. Tissue enrichment analysis suggested that potential signals were enriched in anterior cingulate cortex, reported to be relevant in antipsychotic action. This is the first study to examine genes possibly associated with very early response to lurasidone. Further replication studies in larger sample size should be required.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"1-9"},"PeriodicalIF":2.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11842270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470255","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 : 2025-02-19DOI: 10.1038/s41397-025-00361-6
Tuan Xu, Deborah K. Ngan, Wei Zheng, Ruili Huang
The pathogenesis of cancer is complicated, and different types of cancer often exhibit different gene mutations resulting in different omics profiles. The purpose of this study was to systematically identify cancer-specific biological pathways and potential cancer-targeting drugs. We collectively analyzed the transcriptomics and proteomics data from 16 common types of human cancer to study the mechanism of carcinogenesis and seek potential treatment. Statistical approaches were applied to identify significant molecular targets and pathways related to each cancer type. Potential anti-cancer drugs were subsequently retrieved that can target these pathways. The number of significant pathways linked to each cancer type ranged from four (stomach cancer) to 112 (acute myeloid leukemia), and the number of therapeutic drugs that can target these cancer related pathways, ranged from one (ovarian cancer) to 97 (acute myeloid leukemia and non-small-cell lung carcinoma). As a validation of our method, some of these drugs are FDA approved therapies for their corresponding cancer type. Our findings provide a rich source of testable hypotheses that can be applied to deconvolute the complex underlying mechanisms of human cancer and used to prioritize and repurpose drugs as anti-cancer therapies.
{"title":"Systematic identification of cancer pathways and potential drugs for intervention through multi-omics analysis","authors":"Tuan Xu, Deborah K. Ngan, Wei Zheng, Ruili Huang","doi":"10.1038/s41397-025-00361-6","DOIUrl":"10.1038/s41397-025-00361-6","url":null,"abstract":"The pathogenesis of cancer is complicated, and different types of cancer often exhibit different gene mutations resulting in different omics profiles. The purpose of this study was to systematically identify cancer-specific biological pathways and potential cancer-targeting drugs. We collectively analyzed the transcriptomics and proteomics data from 16 common types of human cancer to study the mechanism of carcinogenesis and seek potential treatment. Statistical approaches were applied to identify significant molecular targets and pathways related to each cancer type. Potential anti-cancer drugs were subsequently retrieved that can target these pathways. The number of significant pathways linked to each cancer type ranged from four (stomach cancer) to 112 (acute myeloid leukemia), and the number of therapeutic drugs that can target these cancer related pathways, ranged from one (ovarian cancer) to 97 (acute myeloid leukemia and non-small-cell lung carcinoma). As a validation of our method, some of these drugs are FDA approved therapies for their corresponding cancer type. Our findings provide a rich source of testable hypotheses that can be applied to deconvolute the complex underlying mechanisms of human cancer and used to prioritize and repurpose drugs as anti-cancer therapies.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"1-9"},"PeriodicalIF":2.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460712","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 : 2025-02-18DOI: 10.1038/s41397-025-00362-5
Lisanne E. N. Manson, Jacqueline D. H. Anholts, Jos J. M. Drabbels, Jesse J. Swen, Dave L. Roelen, Henk-Jan Guchelaar
Patients carrying specific HLA risk alleles are at higher risk for developing drug hypersensitivity reactions, yet pre-therapeutic screening is uncommon. We examined whether patients with a history of drug allergies have more HLA risk alleles to assess whether these patients are potential candidates for pre-therapeutic HLA screening. We performed a case-control study with patients who had a self-reported history of drug allergy (N = 94) and patients without such a history (N = 185). HLA regions were sequenced by use of Alloseq Tx for HLA-A -B, -C, -DP, -DQ and -DR genotypes. A logistic regression was performed to investigate whether the number of HLA risk alleles differed between cases and controls. Sequencing data of 279 patients were available for this analysis. There was no statistically significant difference in the mean number of unique HLA risk alleles between the cases and controls (5.31 vs 5.31, p = 0.9397). Therefore, patients with a self-reported history of drug allergy do not form a suitable group for pre-therapeutic screening for HLA risk alleles to prevent future drug allergies.
携带特定HLA风险等位基因的患者发生药物过敏反应的风险较高，但治疗前筛查并不常见。我们研究了有药物过敏史的患者是否有更多的HLA风险等位基因，以评估这些患者是否有可能进行治疗前HLA筛查。我们对自我报告有药物过敏史的患者（N = 94）和无药物过敏史的患者（N = 185）进行了病例对照研究。采用Alloseq Tx对HLA- a -B、-C、-DP、-DQ和-DR基因型进行区域测序。采用逻辑回归分析研究HLA风险等位基因数量在病例和对照组之间是否存在差异。279例患者的测序数据可用于该分析。两组患者HLA独特风险等位基因的平均数目比较，差异无统计学意义（5.31比5.31,p = 0.9397）。因此，自我报告有药物过敏史的患者不适合进行治疗前HLA风险等位基因筛查以预防未来的药物过敏。
{"title":"The association between the number of HLA risk alleles and drug allergy and its implications for HLA screening – a case-control study","authors":"Lisanne E. N. Manson, Jacqueline D. H. Anholts, Jos J. M. Drabbels, Jesse J. Swen, Dave L. Roelen, Henk-Jan Guchelaar","doi":"10.1038/s41397-025-00362-5","DOIUrl":"10.1038/s41397-025-00362-5","url":null,"abstract":"Patients carrying specific HLA risk alleles are at higher risk for developing drug hypersensitivity reactions, yet pre-therapeutic screening is uncommon. We examined whether patients with a history of drug allergies have more HLA risk alleles to assess whether these patients are potential candidates for pre-therapeutic HLA screening. We performed a case-control study with patients who had a self-reported history of drug allergy (N = 94) and patients without such a history (N = 185). HLA regions were sequenced by use of Alloseq Tx for HLA-A -B, -C, -DP, -DQ and -DR genotypes. A logistic regression was performed to investigate whether the number of HLA risk alleles differed between cases and controls. Sequencing data of 279 patients were available for this analysis. There was no statistically significant difference in the mean number of unique HLA risk alleles between the cases and controls (5.31 vs 5.31, p = 0.9397). Therefore, patients with a self-reported history of drug allergy do not form a suitable group for pre-therapeutic screening for HLA risk alleles to prevent future drug allergies.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"1-6"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450795","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 : 2024-11-23DOI: 10.1038/s41397-024-00358-7
Maarten J. Deenen, Anouk J. van Noordenburg, Joëlle Bouwens-Bijsterveld, Maarten A. van Dijk, Janneke M. Stapelbroek, Luc J. J. Derijks, Lennard P. L. Gilissen, Birgit A. L. M. Deiman
Thiopurine drugs are cornerstone treatment for patients with inflammatory bowel disease (IBD). The most common adverse drug reaction is thiopurine-induced myelosuppression (TIM), that may partly be explained by the genetic polymorphism NUDT15*3. The aim of this retrospective study was to determine the NUDT15*3 polymorphism frequency and its association with TIM in an IBD patient population in the Netherlands. DNA from patients previously genotyped for TPMT was genotyped for NUDT15*3. In IBD patients treated with thiopurines association tests with TIM were conducted. Out of 988 included patients, 13 (1.3%) were heterozygous for NUDT15*3. Of all patients, 606 had IBD and received thiopurine treatment. In these patients, 8/606 (1.3%) were heterozygous polymorphic for NUDT15*3 of which 50.0% developed TIM compared to 2.3% in the wild type patients (p < 0.001). The study results show a clinically relevant prevalence of NUDT15*3 in the Dutch patient population. Its strong association with TIM suggests pre-therapeutic genotyping potentially clinically utile.
{"title":"Genetic association analysis and frequency of NUDT15*3 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease in a large Dutch cohort","authors":"Maarten J. Deenen, Anouk J. van Noordenburg, Joëlle Bouwens-Bijsterveld, Maarten A. van Dijk, Janneke M. Stapelbroek, Luc J. J. Derijks, Lennard P. L. Gilissen, Birgit A. L. M. Deiman","doi":"10.1038/s41397-024-00358-7","DOIUrl":"10.1038/s41397-024-00358-7","url":null,"abstract":"Thiopurine drugs are cornerstone treatment for patients with inflammatory bowel disease (IBD). The most common adverse drug reaction is thiopurine-induced myelosuppression (TIM), that may partly be explained by the genetic polymorphism NUDT15*3. The aim of this retrospective study was to determine the NUDT15*3 polymorphism frequency and its association with TIM in an IBD patient population in the Netherlands. DNA from patients previously genotyped for TPMT was genotyped for NUDT15*3. In IBD patients treated with thiopurines association tests with TIM were conducted. Out of 988 included patients, 13 (1.3%) were heterozygous for NUDT15*3. Of all patients, 606 had IBD and received thiopurine treatment. In these patients, 8/606 (1.3%) were heterozygous polymorphic for NUDT15*3 of which 50.0% developed TIM compared to 2.3% in the wild type patients (p < 0.001). The study results show a clinically relevant prevalence of NUDT15*3 in the Dutch patient population. Its strong association with TIM suggests pre-therapeutic genotyping potentially clinically utile.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"1-7"},"PeriodicalIF":2.9,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696241","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}
Venetoclax (VEN) was the only Bcl-2 inhibitor approved yet and showed large differences in clinical efficacy. The aim of the study was to explore the relationships between the plasma concentration and efficacy of VEN, and identify potential influencing factors. A retrospective cohort study was conducted and a total of 76 trough (C0h) and 91 6 h post-dose plasma concentration (C6h) blood concentrations of VEN were collected in 54 patients. C6h/D concentration of VEN was found to be significantly correlated with treatment efficacy (p = 0.006) in leukemia patients with good or intermediate prognosis stratification. A ROC curve was then established and the cut-off value was calculated as 0.2868 μg/ml (AUC = 0.7097, p = 0.1081). Besides, patients co-administered with triazoles or carrying CYP3A5 rs776746 AA/AG genotypes were prone to induce higher VEN plasma concentration regardless of whether VEN dosage was reduced or not. Through LASSO-logistic regression and nomogram analysis, chemotherapy regimens and neutrophil percentages were identified as the critical elements that may predict drug response. Above all, in addition to identify prognostic stratification, AML patients taken with VEN were suggested to test plasma concentration routinely so as to achieve desired efficacy, especially when co-administered with triazoles or carried with CYP3A5 rs776746 AA/AG.
Venetoclax（VEN）是目前唯一获批的Bcl-2抑制剂，其临床疗效差异很大。该研究旨在探讨VEN的血浆浓度与疗效之间的关系，并找出潜在的影响因素。研究采用回顾性队列研究方法，共收集了54名患者的76份谷浓度（C0h）和91份给药后6小时血浆浓度（C6h）。研究发现，在预后分层为良好或中等的白血病患者中，VEN的C6h/D浓度与治疗效果明显相关（p = 0.006）。随后建立了 ROC 曲线，并计算出临界值为 0.2868 μg/ml（AUC = 0.7097，p = 0.1081）。此外，合用三唑类药物或携带 CYP3A5 rs776746 AA/AG 基因型的患者，无论是否减少 VEN 的剂量，均易诱发 VEN 血浆浓度升高。通过LASSO-逻辑回归和提名图分析，化疗方案和中性粒细胞百分比被确定为可能预测药物反应的关键因素。此外，除了确定预后分层外，还建议使用 VEN 的急性髓细胞白血病患者定期检测血浆浓度，以达到预期疗效，尤其是与三唑类药物合用或携带 CYP3A5 rs776746 AA/AG 时。
{"title":"Plasma concentrations of venetoclax and Pharmacogenetics correlated with drug efficacy in treatment naive leukemia patients: a retrospective study","authors":"Yue Li, Qing Wan, Jiaqi Wan, Xiong Xiao, Jinfang Hu, Xintong Yang, Fancong Kong, Jieyu Wang, Baoquan Song, Zhentao Li, Fei Li, Simei Ren, Hongwei Peng","doi":"10.1038/s41397-024-00359-6","DOIUrl":"10.1038/s41397-024-00359-6","url":null,"abstract":"Venetoclax (VEN) was the only Bcl-2 inhibitor approved yet and showed large differences in clinical efficacy. The aim of the study was to explore the relationships between the plasma concentration and efficacy of VEN, and identify potential influencing factors. A retrospective cohort study was conducted and a total of 76 trough (C0h) and 91 6 h post-dose plasma concentration (C6h) blood concentrations of VEN were collected in 54 patients. C6h/D concentration of VEN was found to be significantly correlated with treatment efficacy (p = 0.006) in leukemia patients with good or intermediate prognosis stratification. A ROC curve was then established and the cut-off value was calculated as 0.2868 μg/ml (AUC = 0.7097, p = 0.1081). Besides, patients co-administered with triazoles or carrying CYP3A5 rs776746 AA/AG genotypes were prone to induce higher VEN plasma concentration regardless of whether VEN dosage was reduced or not. Through LASSO-logistic regression and nomogram analysis, chemotherapy regimens and neutrophil percentages were identified as the critical elements that may predict drug response. Above all, in addition to identify prognostic stratification, AML patients taken with VEN were suggested to test plasma concentration routinely so as to achieve desired efficacy, especially when co-administered with triazoles or carried with CYP3A5 rs776746 AA/AG.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"1-10"},"PeriodicalIF":2.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694025","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}
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