Pharmacogenomics Journal最新文献

{"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":"https://doi.org/10.1038/s41397-024-00358-7","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"39"},"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, 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":"https://doi.org/10.1038/s41397-024-00359-6","url":null,"abstract":"<p><p>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 (C_0h) and 91 6 h post-dose plasma concentration (C_6h) blood concentrations of VEN were collected in 54 patients. C_6h/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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"37"},"PeriodicalIF":2.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Victoria S Marshe, Xiaoyu Men, Farhana Islam, Vanessa F Gonçalves, Guillaume Paré, Daniel Felsky, James L Kennedy, Benoit H Mulsant, Charles F Reynolds, Eric J Lenze, Daniel J Müller","doi":"10.1038/s41397-024-00351-0","DOIUrl":"https://doi.org/10.1038/s41397-024-00351-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"38"},"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, Joshua Pratt, Jamie Park, Christine Fahim, Jessica M Lovnicki, Gabriella S S Groeneweg, Bruce Carleton, Sharon Straus","doi":"10.1038/s41397-024-00356-9","DOIUrl":"https://doi.org/10.1038/s41397-024-00356-9","url":null,"abstract":"<p><p>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 6 implementation strategies.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"36"},"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 DMET^TM Plus platform.","authors":"Y Choi, F Jiang, H An, H J Park, J H Choi, 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":"35"},"PeriodicalIF":2.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMEM158, as plasma cfRNA marker, promotes proliferation and doxorubicin resistance in ovarian cancer.","authors":"Xiaolin Zhu, Tongchao Liu, Xuexue Yin","doi":"10.1038/s41397-024-00357-8","DOIUrl":"10.1038/s41397-024-00357-8","url":null,"abstract":"<p><p>The current study aimed to identify the potential biomarker for the diagnosis of ovarian cancer within plasma cell-free RNA (cfRNA) species and to characterize their oncogenic properties. cfRNAs were isolated from the peripheral blood of ovarian cancer patients and sequenced using an NGS platform. Principal component analysis (PCA) was performed using Salmon software. Gene ontology (GO) analysis was conducted with clusterProfiler. The relative abundance of TMEM158 transcripts was determined by real-time PCR. Cell viability and proliferation was monitored using the MTT and cell counting assays, respectively. The protein levels of TMEM158 and ABCG2 were quantified by immunoblotting. We observed a clear separation of cfRNAs between ovarian cancer patients and healthy individuals. Additionally, we identified TMEM158 as the most significantly differential gene in both peripheral blood and tumor tissues. Overexpression of TMEM158 stimulated cell viability and promoted cell proliferation in ovarian cancer cells. Notably, the aberrant upregulation of TMEM158 was closely associated with doxorubicin resistance in ovarian cancer. Mechanistically, we demonstrated that TMEM158 positively regulates ABCG2 expression, which consequently contributes to drug resistance. In summary, we identified cfRNA TMEM158 as a potential diagnostic biomarker for ovarian cancer and elucidated the critical involvement of TMEM158-ABCG2 signaling axis in the development of doxorubicin resistance.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"34"},"PeriodicalIF":2.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632771","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":"The ZNF263/CPT1B axis regulates fatty acid β-oxidation to affect cisplatin resistance in lung adenocarcinoma.","authors":"Renhe Yan, Caibin Zheng, Suting Qian, Kezhi Li, Xiangsheng Kong, Shunhang Liao","doi":"10.1038/s41397-024-00355-w","DOIUrl":"https://doi.org/10.1038/s41397-024-00355-w","url":null,"abstract":"<p><p>Cisplatin is widely used as a conventional chemotherapy drug for lung adenocarcinoma (LUAD) patients. However, the chemical resistance greatly limits its therapeutic potential. The study aimed to uncover the specific role and new mechanisms of CPT1B in the cisplatin resistance of LUAD. Bioinformatics analysis was utilized to analyze the expression level and enriched pathway of CPT1B in LUAD. The expression of CPT1B in LUAD cells was determined by utilizing quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB). The cisplatin resistance in LUAD was measured with IC₅₀ values obtained from the CCK-8 assay. We used the corresponding reagent kit and WB analysis to determine the levels of triglycerides, cholesterol, phospholipids, fatty acid β-oxidation (FAO) rate, and expression of lipid metabolism-related proteins. Finally, the regulation relationship between CPT1B and ZNF263 was confirmed through bioinformatics analysis, dual-luciferase, and chromatin immunoprecipitation assays. The present investigation revealed that CPT1B was upregulated in LUAD, participating in fatty acid metabolism pathways. In vitro studies have shown that upregulation of CPT1B promoted cisplatin resistance in LUAD cells. This promotion effect induced by the high expression of CPT1B on cisplatin resistance in LUAD was weakened after the addition of the FAO inhibitor Etomoxir. Mechanistically, ZNF263 was capable of binding to the promoter of CPT1B to activate its transcription, thereby enhancing FAO and promoting cisplatin resistance in LUAD cells. In summary, ZNF263 enhances cisplatin resistance in LUAD cells by upregulating CPT1B expression. This study enriches the molecular mechanisms of LUAD chemotherapy resistance and provides new directions for exploring therapeutic targets for LUAD.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"33"},"PeriodicalIF":2.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583442","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":"Cost analysis of CYP2C19 genetic testing in percutaneous coronary intervention patients.","authors":"Samuel Huxley, James Moriarty, Mark A Hlatky, Ryan Lennon, Kent Bailey, Malcolm Bell, Nancy Geller, Amir Lerman, Verghese Mathew, Yves Rosenberg, Michael Farkouh, Charanjit Rihal, Bijan Borah, Naveen L Pereira","doi":"10.1038/s41397-024-00353-y","DOIUrl":"https://doi.org/10.1038/s41397-024-00353-y","url":null,"abstract":"<p><p>CYP2C19 loss of function (LOF) carriers undergoing percutaneous coronary intervention (PCI) have an increased risk of ischemic events when treated with clopidogrel. PCI patients in TAILOR-PCI were randomized to clopidogrel or genotype-guided (GG) therapy in which LOF carriers received ticagrelor and non-carriers clopidogrel. Direct medical costs associated with a GG approach have not been described before. TAILOR-PCI participants for whom direct medical costs were available for the duration from the date of PCI to one-year post PCI were included. Primary cost estimates were obtained from the Mayo Clinic Cost Data Warehouse. There were no differences in direct medical costs between the GG and clopidogrel groups (mean $20,682 versus $19,747, p = 0.11) however total costs were greater in the GG group (mean $21,245 versus $19,891, p = 0.02) which was primarily driven by ticagrelor costs. In conclusion the increased expense of a GG strategy post PCI as compared to clopidogrel for all is primarily driven by the cost of ticagrelor.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"32"},"PeriodicalIF":2.9,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395293","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":"Effects and interaction of single nucleotide polymorphisms at the pharmacokinetic/pharmacodynamic site: insights from the Rotterdam study into metformin clinical response and dose titration.","authors":"Soroush Mohammadi Jouabadi, Payam Peymani, Mitra Nekouei Shahraki, Jeroen G J van Rooij, Linda Broer, Anton J M Roks, Bruno H Stricker, Fariba Ahmadizar","doi":"10.1038/s41397-024-00352-z","DOIUrl":"https://doi.org/10.1038/s41397-024-00352-z","url":null,"abstract":"<p><p>Our study investigated the impact of genetic variations on metformin glycemic response in a cohort from the Rotterdam Study, comprising 14,926 individuals followed for up to 27 years. Among 1285 metformin users of European ancestry, using linear mixed models, we analyzed the association of single nucleotide polymorphisms (SNPs) and a Polygenic Risk Score (PRS) with glycemic response, measured by changes in metformin dosage or HbA1c levels. While individual genetic variants showed no significant association, rs622342 on SLC2A1 correlated with increased glycemic response only in metformin monotherapy patients (β = -2.09, P-value < 0.001). The collective effect of variants, as represented by PRS, weakly correlated with changes in metformin dosage (β = 0.023, P-value = 0.027). Synergistic interaction was observed between rs7124355 and rs8192675. Our findings suggest that while higher PRS correlates with increased metformin dosage, its modest effect size limits clinical utility, emphasizing the need for future research in diverse populations to refine genetic risk models.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 6","pages":"31"},"PeriodicalIF":2.9,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395294","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":"Clinical and economic outcomes of a pharmacogenomics-enriched comprehensive medication management program in a self-insured employee population","authors":"Maren S. Fragala,&nbsp;Murray Keogh,&nbsp;Steven E. Goldberg,&nbsp;Raymond A. Lorenz,&nbsp;Jeffrey A. Shaman","doi":"10.1038/s41397-024-00350-1","DOIUrl":"10.1038/s41397-024-00350-1","url":null,"abstract":"Clinical and economic outcomes from a pharmacogenomics-enriched comprehensive medication management program were evaluated over 26 months in a self-insured U.S. employee population (n = 452 participants; n = 1500 controls) using propensity matched pre-post design with adjusted negative binomial and linear regression models. After adjusting for baseline covariates, program participation was associated with 39% fewer inpatient (p = 0.05) and 39% fewer emergency department (p = 0.002) visits, and with 21% more outpatient visits (p &lt; 0.001) in the follow-up period compared to the control group. Results show pharmacogenomics-enriched comprehensive medication management can favorably impact healthcare utilization in a self-insured employer population by reducing emergency department and inpatient visits and can offer the potential for cost savings. Self-insured employers may consider implementing pharmacogenomics-enriched comprehensive medication management to improve the healthcare of their employees.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 5","pages":"1-6"},"PeriodicalIF":2.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367382","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}