Pharmacogenomics Journal最新文献

{"title":"Influence of genetic biomarkers on cardiac diseases in childhood cancer survivors: a systematic review.","authors":"Naïla Aba, Claire Ducos, Eric Morel, Chiraz El Fayech, Brice Fresneau, Florent de Vathaire, Gwénaël Le Teuff, Nadia Haddy","doi":"10.1038/s41397-025-00369-y","DOIUrl":"10.1038/s41397-025-00369-y","url":null,"abstract":"<p><p>Childhood cancer survivors (CCS) often suffer from cardiac disease (CD) after treatment that included anthracycline and radiotherapy involving the heart. However, the variability in CD occurrence cannot be explained solely by these treatments, suggesting the existence of genetic predisposition. We conducted a systematic review searching on Medline-PubMed and Scopus, to identify studies reporting associations between genetic factors and CD in CCS. We included studies published up to 11 April 2023, with no lower limit, and assessed the quality of genetic associations by the Q-genie tool. As a result, 20 studies were included (15 case-control and five cohorts), revealing several genes and variants associated with cardiomyopathy, among which, SLC28A3-rs7853758, RARG-rs2229774, P2RX7-rs208294 and P2RX7-rs3751143 variants gave the most consistent findings. This review highlights the necessity to establish a set of clinically useful genes and variants to identify patients most at risk of developing cardiomyopathy, and to implement monitoring and prevention strategies.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"15"},"PeriodicalIF":2.9,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144285","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":"KHSRP promotes the malignant behavior and cisplatin resistance of bladder cancer cells through the CLASP2/MAPRE1 axis.","authors":"Ruizhe Wang, Cheng Zhao, Zhenyu Ou, Lingxiao Chen","doi":"10.1038/s41397-025-00374-1","DOIUrl":"https://doi.org/10.1038/s41397-025-00374-1","url":null,"abstract":"<p><p>Bladder cancer (BC) is a highly prevalent form of cancer worldwide, and cisplatin (CDDP) resistance poses a major challenge to patients. Cytoplasmic linker-associated protein 2 (CLASP2) is a member of the microtubule plus-end tracking protein family and is involved in the regulation of microtubule dynamics. In this study, we evaluated the influence of CLASP2 on BC progression and cisplatin resistance. Levels of CLASP2, HNRNPA1, NONO, ZRANB2, FUS, KHSRP and QKI in BC tissues and cells were tested by RT-qPCR. Protein levels of CLASP2 and KHSRP were detected by Western blot. Cell viability and IC50 of cisplatin-treated BC cells were measured by CCK-8. Cell proliferation and apoptosis were determined using colony formation assay and flow cytometry, respectively. RNA immunoprecipitation (RIP) and Co-immunoprecipitation (Co-IP) experiments were adopted to verify target genes of CLASP2. Cellular localization of CLASP2 and MAPRE1 was detected utilizing immunofluorescence staining. The xenograft tumor model was established in BALB/c nude mice. We found that iCLASP2 levels were increased in CDDP-resistant BC tissues and cells. Suppression of CLASP2 impeded BC cell proliferation and alleviated their resistance to CDDP. KHSRP positively influenced the stability of CLASP2 mRNA. There was a protein interaction between CLASP2 and MAPRE1. Silencing KHSRP or MAPRE1 reversed the effect exerted of CLASP2 on BC cells. CLASP2 decreased the sensitivity of BC to CDDP in vivo. Our results imply that CLASP2 contributes to tumorigenesis and cisplatin resistance in BC via targeting MAPRE1, thereby promoting BC progression and providing a new therapeutic target for BC treatment.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"14"},"PeriodicalIF":2.9,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095814","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 interplay between SLC6A4 and HTR1A genetic variants that may lead to antidepressant failure.","authors":"Sandra Hanna, Mark Faiz, Sanjida Ahmed, Cindy Hsieh, Sara Temkit, Cristina Nunez, Feng Zhou","doi":"10.1038/s41397-025-00370-5","DOIUrl":"https://doi.org/10.1038/s41397-025-00370-5","url":null,"abstract":"<p><p>The serotonin transporter (SLC6A4) and the serotonin autoreceptor (HTR1A) are two of the most extensively studied genes in the field of psychiatry, and their variants have been implicated in antidepressant response, specifically with selective serotonin reuptake inhibitors (SSRIs) which are widely regarded as the first-line medications for depression and anxiety. Variants of SLC6A4 and HTR1A have also been studied as risk factors for depression. In this retrospective study, we aim to investigate the relationship between all possible serotonin transporter (SLC6A4) and autoreceptor (HTR1A) variant expression combinations that may have contributed to the therapeutic failure of an SSRI and subsequent disability. In this study, we utilize data from a cohort of 302 European patients diagnosed with depression and/or anxiety who were referred to Personalized Prescribing Inc. (PPI) in 2022 as result of a mental health disability claim to determine whether statistical differences are present in this cohort as compared to general European population allele frequencies. Our data reveals the presence and relevance of significant differences in the presentation of SLC6A4 and HTR1A, specifically in a disability cohort, relative to the average European population. The SLC6A4 gene codes for the serotonin transporter; the SSRI drug target that aims to be blocked to prevent the recycling of serotonin, whereas the HTR1A plays an indirect role as an autoreceptor allowing serotonin levels to be maintained by the SSRI, as well as a direct role in modulating mood through post-synaptic serotonin interaction. This study has revealed statistically significant differences in the expression of these two genes together in increasing the likelihood of drug failure, specifically the presence of one or more G alleles at HTR1A rs6295 in combination with the SLC6A4 SS variant. The most significantly overrepresented combination in this cohort of patients suffering from depression and anxiety that have failed to achieve adequate symptom remission on previous SSRI trials is HTR1A rs6295 GG-SLC6A4 SS which is overrepresented in this study by over 74% at a p-value well below 0.01. Genotyping anti-depressant drug targets may play an important role in optimizing anti-depressant drug response and research developments for future therapies.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"13"},"PeriodicalIF":2.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052347","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":"Implementing CYP2C19-guided clopidogrel therapy: a scoping review of pharmacogenomic testing services.","authors":"Tark J Patel, Eman Wehbe, Stephen Hughes, Asad E Patanwala, Leonard Kritharides, Sean Lal, Sanjay Patel, Sophie L Stocker","doi":"10.1038/s41397-025-00371-4","DOIUrl":"10.1038/s41397-025-00371-4","url":null,"abstract":"<p><p>Pharmacogenomic testing for CYP2C19 helps personalise clopidogrel therapy and reduces the risk of experiencing a secondary myocardial infarction in individuals with impaired CYP2C19 function. Routine testing, however, is uncommon and it is proposed that the key requirements and processes of testing services are poorly understood. This scoping review aimed to explore the literature for CYP2C19 testing services for clopidogrel and identify their commonalities to inform the design and delivery of future services. In total, 37 eligible studies describing services across hospital and community settings were retrieved. Key elements of delivery included a multi-disciplinary approach involving physicians and pharmacists, provision of pre-implementation training and education, and electronic communication of test results. Result integration into clinical decision support systems improved the practical application of pharmacogenomic testing. The identification of the key requirements and processes may be used by institutions looking to design and deliver CYP2C19 testing services to guide clopidogrel therapy.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"12"},"PeriodicalIF":2.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12031670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012576","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":"Association of pharmacodynamic genes with treatment outcomes in major depressive disorder: results from a Sardinian cohort.","authors":"Pasquale Paribello, Mirko Manchia, Marco Pinna, Martina Contu, Davide Orrù, Marco Upali, Sabrina El Kacemi, Ilaria Frau, Federico Suprani, Carolina Corrias, Giulia Somaini, Federica Pinna, Claudia Pisanu, Anna Meloni, Andrea Carta, Claudio Conversano, Francesco Mola, Maria Del Zompo, Lisa Buson, Massimo Gennarelli, Alessandra Minelli, Bernardo Carpiniello, Alessio Squassina","doi":"10.1038/s41397-025-00373-2","DOIUrl":"https://doi.org/10.1038/s41397-025-00373-2","url":null,"abstract":"<p><p>We examined the association of selected candidate pharmacodynamic (PD) genes in MDD with treatment outcomes, defined according to remission thresholds for Hamilton Depression Rating Scale (HDRS) with 6- and 17- items. To this end, we recruited 158 individuals living with MDD followed in an academic community mental health center. We reconstructed their clinical history and tested the association of a selected panel of pharmacodynamic genes with clinical remission. Our multivariate models were corrected for illness duration, substance use, lifetime stressful events, and sex. We found partially concordant associations for candidate biomarkers and clinical remission defined with HDRS-6 and HDRS-17. In the logistic regression model, two polymorphisms were statistically significantly associated with HDRS-17 remission: namely rs10975641 and rs11628713. Our results suggest that polymorphisms in PD genes might influence clinical response in MDD. Interestingly, we showed some degree of concordance of the association depending on the definition of the response.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"10"},"PeriodicalIF":2.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050591","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":"Exploring pharmacogenetic factors influencing hydroxyurea response in tanzanian sickle cell disease patients: a genomic medicine approach.","authors":"Siana Nkya, Collin Nzunda, Emmanuel Saukiwa, Frida Kaywanga, Eliud Buchard, David Solomon, Heavenlight Christopher, Doreen Ngowi, Julieth Johansen, Florence Urio, Josephine Mgaya, Christina Kindole, Mbonea Yonazi, Salman Karim, Mohamed Zahir Alimohamed, Raphael Z Sangeda, Clara Chamba, Collet Dandara, Enrico Novelli, Emile R Chimusa, Julie Makani","doi":"10.1038/s41397-025-00372-3","DOIUrl":"https://doi.org/10.1038/s41397-025-00372-3","url":null,"abstract":"<p><p>In sub-Saharan Africa, sickle cell disease (SCD) remains a significant public health challenge. Despite the discovery of SCD over a century ago, progress in developing and accessing effective treatments has been limited. Hydroxyurea is the primary drug used for managing SCD and associated with improving clinical outcomes. However, up to 30% of patients do not respond to hydroxyurea, likely due to genetic factors. This study involved 148 individuals with SCD investigated the association of hydroxyurea response with genetic variants across 13 loci associated with HbF synthesis and drug metabolism, focusing on MYB, HBB, HBG1, HBG2, BCL11A, KLF10, HAO2, NOS1, ARG2, SAR1A, CYP2C9, and CYP2E1. Significant associations with hydroxyurea response were identified in CYP2C9, CYP2E1, KLF10, BCL11A, ARG2, HBG1, SAR1A, MYB, and NOS1 loci. Furthermore, pathway enrichment and gene-gene interaction analyses provide deeper insights into the genetic mechanisms underlying hydroxyurea treatment response, highlighting potential avenues for personalized therapy in SCD management.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"11"},"PeriodicalIF":2.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042049","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":"Similarity of drug targets to human microbiome metaproteome promotes pharmacological promiscuity.","authors":"Christopher A Beaudoin, Shannon Norget, Ziad Omran, Sharif Hala, Abdullah H Daqeeq, Philip W J Burnet, Tom L Blundell, Andries J van Tonder","doi":"10.1038/s41397-025-00367-0","DOIUrl":"https://doi.org/10.1038/s41397-025-00367-0","url":null,"abstract":"<p><p>Similarity between candidate drug targets and human proteins is commonly assessed to minimize the occurrence of side effects. Although numerous drugs have been found to disrupt the health of the human microbiome, no comprehensive comparison between established drug targets and the human microbiome metaproteome has yet been conducted. Therefore, herein, sequence and structure alignments between human and pathogen drug targets and representative human gut, oral, and vaginal microbiome metaproteomes were performed. Both human and pathogen drug targets were found to be similar in sequence, function, structure, and drug binding capacity to proteins in diverse pathogenic and non-pathogenic bacteria from all three microbiomes. The gut metaproteome was identified as particularly susceptible overall to off-target effects. Certain symptoms, such as infections and immune disorders, may be more common among drugs that non-selectively target host microbiota. These findings suggest that similarities between human microbiome metaproteomes and drug target candidates should be routinely checked.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"9"},"PeriodicalIF":2.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009630","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":"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":"https://doi.org/10.1038/s41397-025-00368-z","url":null,"abstract":"<p><p>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. Graphical extrapolation of some keywords (Drug Discovery; Big Data; Database; Metadata) discussed in this article and their evolution (in terms of absolute items that are available) by time.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"8"},"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}

{"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":"<p><p>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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"7"},"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}

{"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":"<p><p>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.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 1-2","pages":"6"},"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}