Pub Date : 2025-07-08DOI: 10.1038/s41397-025-00376-z
Mayuri S. Patel, Emily J. Cicali, Frank A. Orlando
This review describes healthcare cost effectiveness/savings for pharmacogenetics (PGx) and relevant clinical outcomes in selected common health conditions. PGx allows targeted drug treatment based on genotype and phenotype. Studies highlight how PGx testing reduces the morbidity and mortality of adverse drug reactions (ADRs) by predicting unexpected drug metabolism due to genetic variation in cytochrome P450 enzymes (CYPs) and drug-drug interactions caused by altered CYP enzyme phenotype. Despite many available PGx testing platforms and PGx-guided treatments, clinical implementation remains challenging and slow due to limited (1) insurance coverage and reimbursement of testing and pharmacist interpretation, (2) outcome data such as evidence showing the benefits of preemptive PGx testing for efficacy or ADR prevention, and (3) promotion of PGx testing among healthcare professionals. Of these, cost is the most significant barrier to patients and the healthcare system. This review describes how PGx testing can be cost effective or cost saving for payors and the healthcare system, especially for depression, cardiovascular disease, and ADRs.
{"title":"Analyzing pharmacogenetics cost effectiveness and savings across common health conditions in the United States","authors":"Mayuri S. Patel, Emily J. Cicali, Frank A. Orlando","doi":"10.1038/s41397-025-00376-z","DOIUrl":"10.1038/s41397-025-00376-z","url":null,"abstract":"This review describes healthcare cost effectiveness/savings for pharmacogenetics (PGx) and relevant clinical outcomes in selected common health conditions. PGx allows targeted drug treatment based on genotype and phenotype. Studies highlight how PGx testing reduces the morbidity and mortality of adverse drug reactions (ADRs) by predicting unexpected drug metabolism due to genetic variation in cytochrome P450 enzymes (CYPs) and drug-drug interactions caused by altered CYP enzyme phenotype. Despite many available PGx testing platforms and PGx-guided treatments, clinical implementation remains challenging and slow due to limited (1) insurance coverage and reimbursement of testing and pharmacist interpretation, (2) outcome data such as evidence showing the benefits of preemptive PGx testing for efficacy or ADR prevention, and (3) promotion of PGx testing among healthcare professionals. Of these, cost is the most significant barrier to patients and the healthcare system. This review describes how PGx testing can be cost effective or cost saving for payors and the healthcare system, especially for depression, cardiovascular disease, and ADRs.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 4","pages":"1-8"},"PeriodicalIF":2.9,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592936","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 : 2025-06-30DOI: 10.1038/s41397-025-00377-y
Ben L. Kong, Benjamin G. Brown, Victoria M. Pratt, Bronwyn Ramey, J. Shawn Jones, Sara L. Rogers
{"title":"STRIPE partners in precision medicine: laboratory perspective","authors":"Ben L. Kong, Benjamin G. Brown, Victoria M. Pratt, Bronwyn Ramey, J. Shawn Jones, Sara L. Rogers","doi":"10.1038/s41397-025-00377-y","DOIUrl":"10.1038/s41397-025-00377-y","url":null,"abstract":"","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 4","pages":"1-3"},"PeriodicalIF":2.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144531141","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 : 2025-06-13DOI: 10.1038/s41397-025-00375-0
Leticia A. Shea
{"title":"CYP2C19 point-of-care testing: where are we now and where should we go?","authors":"Leticia A. Shea","doi":"10.1038/s41397-025-00375-0","DOIUrl":"10.1038/s41397-025-00375-0","url":null,"abstract":"","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 4","pages":"1-5"},"PeriodicalIF":2.9,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295319","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 : 2025-05-24DOI: 10.1038/s41397-025-00369-y
Naïla Aba, Claire Ducos, Eric Morel, Chiraz El Fayech, Brice Fresneau, Florent de Vathaire, Gwénaël Le Teuff, Nadia Haddy
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.
{"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":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"1-12"},"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}
Pub Date : 2025-05-17DOI: 10.1038/s41397-025-00374-1
Ruizhe Wang, Cheng Zhao, Zhenyu Ou, Lingxiao Chen
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.
膀胱癌（BC）是世界范围内高度流行的一种癌症，顺铂（CDDP）耐药性对患者构成了重大挑战。细胞质连接体相关蛋白2 （Cytoplasmic linker-associated protein 2, CLASP2）是微管正端跟踪蛋白家族的一员，参与微管动力学调控。在本研究中，我们评估了CLASP2对BC进展和顺铂耐药的影响。RT-qPCR检测BC组织和细胞中CLASP2、HNRNPA1、NONO、ZRANB2、FUS、KHSRP和QKI的表达水平。Western blot检测CLASP2和KHSRP蛋白水平。CCK-8检测顺铂处理的BC细胞的细胞活力和IC50。采用集落形成法和流式细胞术分别检测细胞增殖和凋亡。采用RNA免疫沉淀（RIP）和共免疫沉淀（Co-IP）实验验证CLASP2的靶基因。利用免疫荧光染色检测CLASP2和MAPRE1的细胞定位。在BALB/c裸鼠身上建立异种移植瘤模型。我们发现iCLASP2水平在抗cddp的BC组织和细胞中升高。抑制CLASP2抑制BC细胞增殖，减轻其对CDDP的抗性。KHSRP正影响CLASP2 mRNA的稳定性。CLASP2和MAPRE1之间存在蛋白相互作用。沉默KHSRP或MAPRE1可逆转CLASP2对BC细胞的作用。CLASP2在体内降低BC对CDDP的敏感性。我们的研究结果提示CLASP2通过靶向MAPRE1参与BC的肿瘤发生和顺铂耐药，从而促进BC的进展，为BC治疗提供新的治疗靶点。
{"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":"10.1038/s41397-025-00374-1","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"1-9"},"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}
Pub Date : 2025-05-07DOI: 10.1038/s41397-025-00370-5
Sandra Hanna, Mark Faiz, Sanjida Ahmed, Cindy Hsieh, Sara Temkit, Cristina Nunez, Feng Zhou
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.
{"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":"10.1038/s41397-025-00370-5","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"1-7"},"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}
Pub Date : 2025-04-25DOI: 10.1038/s41397-025-00371-4
Tark J. Patel, Eman Wehbe, Stephen Hughes, Asad E. Patanwala, Leonard Kritharides, Sean Lal, Sanjay Patel, Sophie L. Stocker
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.
{"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":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"1-14"},"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}
Pub Date : 2025-04-23DOI: 10.1038/s41397-025-00373-2
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
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.
{"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":"10.1038/s41397-025-00373-2","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"1-7"},"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}
Pub Date : 2025-04-23DOI: 10.1038/s41397-025-00372-3
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
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.
{"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":"10.1038/s41397-025-00372-3","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"1-9"},"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}
Pub Date : 2025-04-17DOI: 10.1038/s41397-025-00367-0
Christopher A. Beaudoin, Shannon Norget, Ziad Omran, Sharif Hala, Abdullah H. Daqeeq, Philip W. J. Burnet, Tom L. Blundell, Andries J. van Tonder
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.
{"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":"10.1038/s41397-025-00367-0","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"25 3","pages":"1-11"},"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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：