Pharmacogenomics Journal最新文献

{"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":"<p><p>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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"5"},"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}

{"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":"<p><p>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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 2","pages":"4"},"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}

{"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":"<p><p>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 GABA_A 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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 2","pages":"3"},"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}

{"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":"<p><p>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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 2","pages":"2"},"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}

{"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":"<p><p>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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 2","pages":"1"},"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}

{"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,&nbsp;Anouk J. van Noordenburg,&nbsp;Joëlle Bouwens-Bijsterveld,&nbsp;Maarten A. van Dijk,&nbsp;Janneke M. Stapelbroek,&nbsp;Luc J. J. Derijks,&nbsp;Lennard P. L. Gilissen,&nbsp;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 &lt; 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}

{"title":"Plasma concentrations of venetoclax and Pharmacogenetics correlated with drug efficacy in treatment naive leukemia patients: a retrospective study","authors":"Yue Li,&nbsp;Qing Wan,&nbsp;Jiaqi Wan,&nbsp;Xiong Xiao,&nbsp;Jinfang Hu,&nbsp;Xintong Yang,&nbsp;Fancong Kong,&nbsp;Jieyu Wang,&nbsp;Baoquan Song,&nbsp;Zhentao Li,&nbsp;Fei Li,&nbsp;Simei Ren,&nbsp;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&nbsp;prone to induce higher VEN plasma concentration regardless of whether&nbsp;VEN dosage was&nbsp;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}

{"title":"Polygenic score analyses on antidepressant response in late-life depression, results from the IRL-GRey study","authors":"Samar S. M. Elsheikh,&nbsp;Victoria S. Marshe,&nbsp;Xiaoyu Men,&nbsp;Farhana Islam,&nbsp;Vanessa F. Gonçalves,&nbsp;Guillaume Paré,&nbsp;Daniel Felsky,&nbsp;James L. Kennedy,&nbsp;Benoit H. Mulsant,&nbsp;Charles F. Reynolds 3rd,&nbsp;Eric J. Lenze,&nbsp;Daniel J. Müller","doi":"10.1038/s41397-024-00351-0","DOIUrl":"10.1038/s41397-024-00351-0","url":null,"abstract":"Late-life depression (LLD) is often accompanied by medical comorbidities such as psychiatric disorders and cardiovascular diseases, posing challenges to antidepressant treatment. Recent studies highlighted significant associations between treatment-resistant depression (TRD) and polygenic risk score (PRS) for attention deficit hyperactivity disorder (ADHD) in adults as well as a negative association between antidepressant symptom improvement with both schizophrenia and bipolar. Here, we sought to validate these findings with symptom remission in LLD. We analyzed the Incomplete Response in Late Life Depression: Getting to Remission (IRL-GRey) sample consisting of adults aged 60+ with major depression (N = 342) treated with venlafaxine for 12 weeks. We constructed PRSs for ADHD, depression, schizophrenia, bipolar disorder, neuroticism, general intelligence, antidepressant symptom remission and antidepressant percentage symptom improvement using summary statistics from the Psychiatric Genomics Consortium and the GWAS Catalog. Logistic regression was used to test the association of PRSs with venlafaxine symptom remission and percentage symptom improvement, co-varying for the genomic principal components, age, sex and depressive symptoms severity at baseline. We found a nominal (i.e., p value ≤ 0.05) association between symptom remission and both PRS for ADHD and (OR = 1.36 [1.07, 1.73], p = 0.011) and PRS for bipolar disorder (OR = 0.75 [0.58, 0.97], p = 0.031), as well as between percentage symptom improvement and PRS for general intelligence (beta = 6.81 (SE = 3.122), p = 0.03). However, the ADHD association was in the opposite direction as expected, and both associations did not survive multiple testing corrections. Altogether, these findings suggest that previous findings regarding ADHD PRS and antidepressant response (measured with various outcomes) do not replicate in older adults.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"1-7"},"PeriodicalIF":2.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694027","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}

{"title":"Implementation of pharmacogenetic testing in pediatric oncology: barriers and facilitators assessment at eight Canadian academic health centres","authors":"Jeanette Cooper,&nbsp;Joshua Pratt,&nbsp;Jamie Park,&nbsp;Christine Fahim,&nbsp;Jessica M. Lovnicki,&nbsp;Gabriella S. S. Groeneweg,&nbsp;Bruce Carleton,&nbsp;Sharon Straus","doi":"10.1038/s41397-024-00356-9","DOIUrl":"10.1038/s41397-024-00356-9","url":null,"abstract":"Pharmacogenetic (PGx) testing can enhance drug safety, improve efficacy, and reduce the risk of toxicity. However, the implementation of PGx testing in Canadian pediatric oncology centers has been limited. To address this gap, the aim of this study was to assess the barriers and facilitators to implementing PGx testing for three oncology drugs in eight Canadian pediatric oncology centers and identify strategies that could be used to support PGx testing implementation. We used semi-structured interviews to identify barriers and facilitators to PGx testing and identified evidence-based strategies for PGx testing implementation through a mapping process that utilized the Theoretical Domains Framework, the Consolidated Framework for Implementation Research and the Behavior Change Wheel. We identified 38 facilitators and 26 barriers to implementation of PGx testing and mapped these to&nbsp;6 implementation strategies.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"1-17"},"PeriodicalIF":2.9,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677829","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}

{"title":"Correction to: A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform","authors":"Y Choi,&nbsp;F Jiang,&nbsp;H An,&nbsp;H J Park,&nbsp;J H Choi,&nbsp;H Lee","doi":"10.1038/s41397-024-00354-x","DOIUrl":"10.1038/s41397-024-00354-x","url":null,"abstract":"","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"1-3"},"PeriodicalIF":2.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41397-024-00354-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669796","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}