Pub Date : 2024-08-09DOI: 10.1038/s41397-024-00344-z
John H. McDermott, Videha Sharma, Glenda M. Beaman, Jessica Keen, William G. Newman, Paul Wilson, Katherine Payne, Stuart Wright
Pharmacogenetic testing in the United Kingdom’s National Health Service (NHS) has historically been reactive in nature, undertaken in the context of single gene-drug relationships in specialist settings. Using a discrete choice experiment we aimed to identify healthcare professional preferences for development of a pharmacogenetic testing service in primary care in the NHS. Respondents, representing two professions groups (general practitioners or pharmacists), completed one of two survey versions, asking them to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or joint pain. Responses from 235 individuals were included. All respondents preferred pharmacogenetic testing over no testing, though preference heterogeneity was identified. Both professional groups, but especially GPs, were highly sensitive to service design, with uptake varying depending on the service offered. This study demonstrates uptake of a pharmacogenetic testing service is impacted by service design and highlights key areas which should be prioritised within future initiatives.
{"title":"Understanding general practitioner and pharmacist preferences for pharmacogenetic testing in primary care: a discrete choice experiment","authors":"John H. McDermott, Videha Sharma, Glenda M. Beaman, Jessica Keen, William G. Newman, Paul Wilson, Katherine Payne, Stuart Wright","doi":"10.1038/s41397-024-00344-z","DOIUrl":"10.1038/s41397-024-00344-z","url":null,"abstract":"Pharmacogenetic testing in the United Kingdom’s National Health Service (NHS) has historically been reactive in nature, undertaken in the context of single gene-drug relationships in specialist settings. Using a discrete choice experiment we aimed to identify healthcare professional preferences for development of a pharmacogenetic testing service in primary care in the NHS. Respondents, representing two professions groups (general practitioners or pharmacists), completed one of two survey versions, asking them to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or joint pain. Responses from 235 individuals were included. All respondents preferred pharmacogenetic testing over no testing, though preference heterogeneity was identified. Both professional groups, but especially GPs, were highly sensitive to service design, with uptake varying depending on the service offered. This study demonstrates uptake of a pharmacogenetic testing service is impacted by service design and highlights key areas which should be prioritised within future initiatives.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 5","pages":"1-7"},"PeriodicalIF":2.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914583","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 : 2024-08-07DOI: 10.1038/s41397-024-00346-x
Houyi Wei, Zhilong Li, Kaiyu Qian, Wenzhi Du, Lingao Ju, Danni Shan, Mengxue Yu, Yayun Fang, Yi Zhang, Yu Xiao, Gang Wang, Xinghuan Wang
This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA.
本研究利用孟德尔随机化（MR）分析和全基因组关联研究（GWAS）数据调查了常用处方药与膀胱癌（BLCA）风险之间的关联。我们的研究结果表明，HMG CoA 还原酶（HMGCR）抑制剂，特别是辛伐他汀，与膀胱癌风险的降低显著相关。我们进一步发现，辛伐他汀能在动物模型中显著抑制BLCA的增殖和上皮-间质转化，转录组数据确定了与这些过程相关的几条通路。HMGCR的高表达与BLCA的发生和发展有关，而某些血脂，如脂蛋白颗粒和极低密度脂蛋白（VLDL）胆固醇，可能会影响BLCA的风险。这些研究结果表明，HMGCR抑制剂，尤其是辛伐他汀，可能是治疗或辅助治疗BLCA的潜在选择。
{"title":"Unveiling the association between HMG-CoA reductase inhibitors and bladder cancer: a comprehensive analysis using Mendelian randomization, animal models, and transcriptomics","authors":"Houyi Wei, Zhilong Li, Kaiyu Qian, Wenzhi Du, Lingao Ju, Danni Shan, Mengxue Yu, Yayun Fang, Yi Zhang, Yu Xiao, Gang Wang, Xinghuan Wang","doi":"10.1038/s41397-024-00346-x","DOIUrl":"10.1038/s41397-024-00346-x","url":null,"abstract":"This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 5","pages":"1-12"},"PeriodicalIF":2.9,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1038/s41397-024-00337-y
Jon E. Sprague, Caroline E. Freiermuth, Joshua Lambert, Robert Braun, Jennifer A. Frey, Daniel J. Bachmann, Jason J. Bischof, Lauren Beaumont, Michael S. Lyons, Michael V. Pantalon, Brittany E. Punches, Rachel Ancona, David F. Kisor
The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) and by sex. From a sample size of 1301 adult patients (>18 years of age) seen in emergency departments of three medical centers in Ohio, six variants were found to be associated with OUD. Two of the variants, rs2740574 (CYP3A4) and rs324029 (DRD3), were included in the analysis having met criteria of at least five subjects for each BGAG, variant carrier status, and OUD status combinations. Variant carriers in the African/Afro-Caribbean BGAG had slightly lower predicted probabilities of OUD. Variant carriers in the European BGAG had slightly higher predicted probabilities of OUD. Relative to sex, all the six variants met evaluation criteria (five subjects for all sex, variant, and OUD status combinations). No statistically significant interactions were found between a given variant, BGAGs and sex. Findings suggest variant testing relative to OUD risk can be applied across BGAGs and sex, however, studies in larger populations are needed.
{"title":"Opioid use disorder risk alleles in self-reported assigned African American/Afro-Caribbean and European biogeographical genetic ancestry groups and in males and females","authors":"Jon E. Sprague, Caroline E. Freiermuth, Joshua Lambert, Robert Braun, Jennifer A. Frey, Daniel J. Bachmann, Jason J. Bischof, Lauren Beaumont, Michael S. Lyons, Michael V. Pantalon, Brittany E. Punches, Rachel Ancona, David F. Kisor","doi":"10.1038/s41397-024-00337-y","DOIUrl":"10.1038/s41397-024-00337-y","url":null,"abstract":"The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) and by sex. From a sample size of 1301 adult patients (>18 years of age) seen in emergency departments of three medical centers in Ohio, six variants were found to be associated with OUD. Two of the variants, rs2740574 (CYP3A4) and rs324029 (DRD3), were included in the analysis having met criteria of at least five subjects for each BGAG, variant carrier status, and OUD status combinations. Variant carriers in the African/Afro-Caribbean BGAG had slightly lower predicted probabilities of OUD. Variant carriers in the European BGAG had slightly higher predicted probabilities of OUD. Relative to sex, all the six variants met evaluation criteria (five subjects for all sex, variant, and OUD status combinations). No statistically significant interactions were found between a given variant, BGAGs and sex. Findings suggest variant testing relative to OUD risk can be applied across BGAGs and sex, however, studies in larger populations are needed.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 4","pages":"1-6"},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876745","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 : 2024-07-12DOI: 10.1038/s41397-024-00342-1
Julia C. F. Quintanilha, William Kevin Kelly, Federico Innocenti
Bevacizumab-induced hypertension poses a therapeutic challenge and identifying biomarkers for hypertension can enhance therapy safety. Lower plasma levels of VEGF-A, angiopoietin-2, and rs6770663 in KCNAB1 were previously associated with increased risk of bevacizumab-induced hypertension. This study investigated whether these factors independently contribute to grade 2–3 bevacizumab-induced hypertension risk in 277 cancer patients (CALGB/Alliance 90401). Multivariable analyses assessed the independent association of each factor and hypertension. Likelihood ratio test (LRT) evaluated the explanatory significance of combining protein levels and rs6770663 in predicting hypertension. Boostrap was employed to assess the mediation effect of protein levels on the rs6770663 association with hypertension. Lower protein levels and rs6770663 were independently associated with increased hypertension risk. Adding rs6770663 to protein levels improved the prediction of hypertension (LRT p = 0.0002), with no mediation effect observed. Protein levels of VEGF-A, angiopoietin-2 and rs6770663 in KCNAB1 are independent risk factors and, when combined, may improve prediction of bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00110214.
{"title":"Contribution of plasma levels of VEGF-A and angiopoietin-2 in addition to a genetic variant in KCNAB1 to predict the risk of bevacizumab-induced hypertension","authors":"Julia C. F. Quintanilha, William Kevin Kelly, Federico Innocenti","doi":"10.1038/s41397-024-00342-1","DOIUrl":"10.1038/s41397-024-00342-1","url":null,"abstract":"Bevacizumab-induced hypertension poses a therapeutic challenge and identifying biomarkers for hypertension can enhance therapy safety. Lower plasma levels of VEGF-A, angiopoietin-2, and rs6770663 in KCNAB1 were previously associated with increased risk of bevacizumab-induced hypertension. This study investigated whether these factors independently contribute to grade 2–3 bevacizumab-induced hypertension risk in 277 cancer patients (CALGB/Alliance 90401). Multivariable analyses assessed the independent association of each factor and hypertension. Likelihood ratio test (LRT) evaluated the explanatory significance of combining protein levels and rs6770663 in predicting hypertension. Boostrap was employed to assess the mediation effect of protein levels on the rs6770663 association with hypertension. Lower protein levels and rs6770663 were independently associated with increased hypertension risk. Adding rs6770663 to protein levels improved the prediction of hypertension (LRT p = 0.0002), with no mediation effect observed. Protein levels of VEGF-A, angiopoietin-2 and rs6770663 in KCNAB1 are independent risk factors and, when combined, may improve prediction of bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00110214.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 4","pages":"1-4"},"PeriodicalIF":2.9,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41397-024-00342-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141592110","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 : 2024-06-29DOI: 10.1038/s41397-024-00343-0
Lily K. Stafford, Xiaohui Tang, Amanda Brandt, Jianzhong Ma, Jose Banchs, J. Andrew Livingston, Michael E. Roth, Alanna C. Morrison, Michelle A. T. Hildebrandt
There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.
{"title":"Risk of anthracycline-induced cardiac dysfunction in adolescent and young adult (AYA) cancer survivors: role of genetic susceptibility loci","authors":"Lily K. Stafford, Xiaohui Tang, Amanda Brandt, Jianzhong Ma, Jose Banchs, J. Andrew Livingston, Michael E. Roth, Alanna C. Morrison, Michelle A. T. Hildebrandt","doi":"10.1038/s41397-024-00343-0","DOIUrl":"10.1038/s41397-024-00343-0","url":null,"abstract":"There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 4","pages":"1-7"},"PeriodicalIF":2.9,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-21DOI: 10.1038/s41397-024-00341-2
Juliana Salazar, Pau Riera, Jordi Gordillo, Albert Altès, Miguel Martínez, Montserrat Serès, Jordina Llaó, Antonio Giordano, Esther Garcia-Planella
Thiopurines, an effective therapy for Crohn’s disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.
硫嘌呤类药物是治疗克罗恩病（CD）的一种有效疗法，但经常会导致不良反应（AEs）。影响硫嘌呤代谢的基因多态性可预测不良反应。这项回顾性研究分析了 TPMT（c.238 G > C、c.460 G > A、c.719 A > G）、ITPA（c.94 C > A、IVS2 + 21 A > C）和 NUDT15（c.415 C > T）多态性。所有患者都接受了硫唑嘌呤治疗（中位剂量为 2.2 毫克/千克），其中 41.2% 的患者出现了 AEs，主要是骨髓毒性（28.1%）。未发现 NUDT15 多态性，7% 的患者存在 TPMT 多态性，31.6% 的患者存在 ITPA 多态性。41.2%的患者因AE导致治疗调整。多变量分析发现，高龄（OR 1.046，p = 0.007）和 ITPA IVS2 + 21 A > C（OR 3.622，p = 0.015）是 AEs 的独立预测因素。IVS2 + 21 A > C 还与骨髓毒性相关（OR 2.863，p = 0.021）。这些研究结果表明，ITPA IVS2 + 21 A > C多态性和高龄可预测TPMT活性中等正常的CD患者在接受硫嘌呤治疗期间出现的AEs。
{"title":"Predictive role of ITPA genetic variants in thiopurine-related myelotoxicity in Crohn’s disease patients","authors":"Juliana Salazar, Pau Riera, Jordi Gordillo, Albert Altès, Miguel Martínez, Montserrat Serès, Jordina Llaó, Antonio Giordano, Esther Garcia-Planella","doi":"10.1038/s41397-024-00341-2","DOIUrl":"10.1038/s41397-024-00341-2","url":null,"abstract":"Thiopurines, an effective therapy for Crohn’s disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 4","pages":"1-6"},"PeriodicalIF":2.9,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-18DOI: 10.1038/s41397-024-00340-3
Adriana Vázquez-Medina, Marion T. Turnbull, Courtney L. James, Jennifer B. Cowart, Elizabeth Lesser, Rickey E. Carter, Owen A. Ross, David A. Miller, James F. Meschia, Aixa De Jesús Espinosa, Richard Weinshilboum, W. David Freeman
Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.
{"title":"Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics","authors":"Adriana Vázquez-Medina, Marion T. Turnbull, Courtney L. James, Jennifer B. Cowart, Elizabeth Lesser, Rickey E. Carter, Owen A. Ross, David A. Miller, James F. Meschia, Aixa De Jesús Espinosa, Richard Weinshilboum, W. David Freeman","doi":"10.1038/s41397-024-00340-3","DOIUrl":"10.1038/s41397-024-00340-3","url":null,"abstract":"Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 4","pages":"1-7"},"PeriodicalIF":2.9,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01DOI: 10.1038/s41397-024-00339-w
Daniel T. Barratt, Pål Klepstad, Ola Dale, Stein Kaasa, Andrew A. Somogyi
The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7–2.3) versus 1.0 (0.5–1.9) μM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20–81) versus 29 (14–60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22–0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02–0.63)) and IL6R rs8192284 carrier (0.55 (0.34–0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2–9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.
{"title":"Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects","authors":"Daniel T. Barratt, Pål Klepstad, Ola Dale, Stein Kaasa, Andrew A. Somogyi","doi":"10.1038/s41397-024-00339-w","DOIUrl":"10.1038/s41397-024-00339-w","url":null,"abstract":"The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7–2.3) versus 1.0 (0.5–1.9) μM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20–81) versus 29 (14–60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22–0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02–0.63)) and IL6R rs8192284 carrier (0.55 (0.34–0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2–9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-8"},"PeriodicalIF":2.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11144121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141187105","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 : 2024-05-27DOI: 10.1038/s41397-024-00338-x
Yitian Zhou, Sebastian Pirmann, Volker M. Lauschke
Lack of efficacy or adverse drug response are common phenomena in pharmacological therapy causing considerable morbidity and mortality. It is estimated that 20–30% of this variability in drug response stems from variations in genes encoding drug targets or factors involved in drug disposition. Leveraging such pharmacogenomic information for the preemptive identification of patients who would benefit from dose adjustments or alternative medications thus constitutes an important frontier of precision medicine. Computational methods can be used to predict the functional effects of variant of unknown significance. However, their performance on pharmacogenomic variant data has been lackluster. To overcome this limitation, we previously developed an ensemble classifier, termed APF, specifically designed for pharmacogenomic variant prediction. Here, we aimed to further improve predictions by leveraging recent key advances in the prediction of protein folding based on deep neural networks. Benchmarking of 28 variant effect predictors on 530 pharmacogenetic missense variants revealed that structural predictions using AlphaMissense were most specific, whereas APF exhibited the most balanced performance. We then developed a new tool, APF2, by optimizing algorithm parametrization of the top performing algorithms for pharmacogenomic variations and aggregating their predictions into a unified ensemble score. Importantly, APF2 provides quantitative variant effect estimates that correlate well with experimental results (R2 = 0.91, p = 0.003) and predicts the functional impact of pharmacogenomic variants with higher accuracy than previous methods, particularly for clinically relevant variations with actionable pharmacogenomic guidelines. We furthermore demonstrate better performance (92% accuracy) on an independent test set of 146 variants across 61 pharmacogenes not used for model training or validation. Application of APF2 to population-scale sequencing data from over 800,000 individuals revealed drastic ethnogeographic differences with important implications for pharmacotherapy. We thus think that APF2 holds the potential to improve the translation of genetic information into pharmacogenetic recommendations, thereby facilitating the use of Next-Generation Sequencing data for stratified medicine.
{"title":"APF2: an improved ensemble method for pharmacogenomic variant effect prediction","authors":"Yitian Zhou, Sebastian Pirmann, Volker M. Lauschke","doi":"10.1038/s41397-024-00338-x","DOIUrl":"10.1038/s41397-024-00338-x","url":null,"abstract":"Lack of efficacy or adverse drug response are common phenomena in pharmacological therapy causing considerable morbidity and mortality. It is estimated that 20–30% of this variability in drug response stems from variations in genes encoding drug targets or factors involved in drug disposition. Leveraging such pharmacogenomic information for the preemptive identification of patients who would benefit from dose adjustments or alternative medications thus constitutes an important frontier of precision medicine. Computational methods can be used to predict the functional effects of variant of unknown significance. However, their performance on pharmacogenomic variant data has been lackluster. To overcome this limitation, we previously developed an ensemble classifier, termed APF, specifically designed for pharmacogenomic variant prediction. Here, we aimed to further improve predictions by leveraging recent key advances in the prediction of protein folding based on deep neural networks. Benchmarking of 28 variant effect predictors on 530 pharmacogenetic missense variants revealed that structural predictions using AlphaMissense were most specific, whereas APF exhibited the most balanced performance. We then developed a new tool, APF2, by optimizing algorithm parametrization of the top performing algorithms for pharmacogenomic variations and aggregating their predictions into a unified ensemble score. Importantly, APF2 provides quantitative variant effect estimates that correlate well with experimental results (R2 = 0.91, p = 0.003) and predicts the functional impact of pharmacogenomic variants with higher accuracy than previous methods, particularly for clinically relevant variations with actionable pharmacogenomic guidelines. We furthermore demonstrate better performance (92% accuracy) on an independent test set of 146 variants across 61 pharmacogenes not used for model training or validation. Application of APF2 to population-scale sequencing data from over 800,000 individuals revealed drastic ethnogeographic differences with important implications for pharmacotherapy. We thus think that APF2 holds the potential to improve the translation of genetic information into pharmacogenetic recommendations, thereby facilitating the use of Next-Generation Sequencing data for stratified medicine.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-11"},"PeriodicalIF":2.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11129946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159216","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 : 2024-05-22DOI: 10.1038/s41397-024-00336-z
Lorenzo Chidiac, Hady Yazbeck, Rami Mahfouz, Nathalie K. Zgheib
Pharmacogenomics (PGx) research and applications are of utmost relevance in Lebanon considering its population genetic diversity. Moreover, as a country with regional leadership in medicine and higher education, Lebanon holds a strong potential in contributing to PGx research and clinical implementation. In this manuscript, we first review and evaluate the available PGx research conducted in Lebanon, then describe the current status of PGx practice in Lebanon while reflecting on the local and regional challenges, and highlighting areas for action, and opportunities to move forward. We specifically expand on the status of PGx at the American University of Beirut Faculty of Medicine and Medical Center as a case study and guide for the further development of local and regional comprehensive PGx research, teaching, and clinical implementation programs. We also delve into the status of PGx knowledge and education, and prospects for further advancement such as with online courses and certificates.
{"title":"Pharmacogenomics in Lebanon: current status, challenges and opportunities","authors":"Lorenzo Chidiac, Hady Yazbeck, Rami Mahfouz, Nathalie K. Zgheib","doi":"10.1038/s41397-024-00336-z","DOIUrl":"10.1038/s41397-024-00336-z","url":null,"abstract":"Pharmacogenomics (PGx) research and applications are of utmost relevance in Lebanon considering its population genetic diversity. Moreover, as a country with regional leadership in medicine and higher education, Lebanon holds a strong potential in contributing to PGx research and clinical implementation. In this manuscript, we first review and evaluate the available PGx research conducted in Lebanon, then describe the current status of PGx practice in Lebanon while reflecting on the local and regional challenges, and highlighting areas for action, and opportunities to move forward. We specifically expand on the status of PGx at the American University of Beirut Faculty of Medicine and Medical Center as a case study and guide for the further development of local and regional comprehensive PGx research, teaching, and clinical implementation programs. We also delve into the status of PGx knowledge and education, and prospects for further advancement such as with online courses and certificates.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"24 3","pages":"1-7"},"PeriodicalIF":2.8,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082098","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}
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