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Pharmacogenomics of Clozapine-induced agranulocytosis: a systematic review and meta-analysis 氯氮平诱导的粒细胞缺乏症的药物基因组学:系统回顾和荟萃分析
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-06-16 DOI: 10.1038/s41397-022-00281-9
Farhana Islam, Daniel Hain, David Lewis, Rebecca Law, Lisa C. Brown, Julie-Anne Tanner, Daniel J. Müller
Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20–15.80, pcorrected = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.
尽管氯氮平是治疗耐药性精神分裂症最有效的药物疗法,但它的使用率却很低,而且常常被推迟使用。其中一个原因是出现了一种可能致命的不良反应--氯氮平诱发的粒细胞减少症(CIA)。确定导致 CIA 的基因变异有助于预测患者罹患 CIA 的风险并进行个性化治疗。在此,我们(1)回顾了现有的 CIA 药物基因组学研究,(2)进行了荟萃分析,以确定临床实施的目标。通过系统性文献检索,我们找到了包括接受氯氮平治疗但出现 CIA 的患者和未出现 CIA 的对照组的研究。结果显示,携带HLA-DRB1*04:02等位基因的个体发生CIA的几率高出近6倍(95% CI 2.20-15.80, pcorrected = 0.03),阴性预测值为99.3%。之前未被复制的等位基因 TNFb5、HLA-B*59:01、TNFb4 和 TNFd3 在多重检验校正后显示与 CIA 有显著关联。我们的研究结果表明,基于 HLA-DRB1*04:02 的预测性药物基因组学检测可能有望在临床上应用,但还需要进一步研究。
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引用次数: 6
Exome sequencing allows detection of relevant pharmacogenetic variants in epileptic patients 外显子组测序允许检测癫痫患者的相关药物遗传变异
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-05-19 DOI: 10.1038/s41397-022-00280-w
Simon Verdez, Quentin Thomas, Philippine Garret, Céline Verstuyft, Emilie Tisserant, Antonio Vitobello, Frédéric Tran Mau-Them, Christophe Philippe, Marc Bardou, Maxime Luu, Abderrahmane Bourredjem, Patrick Callier, Christel Thauvin-Robinet, Nicolas Picard, Laurence Faivre, Yannis Duffourd
Beyond the identification of causal genetic variants in the diagnosis of Mendelian disorders, exome sequencing can detect numerous variants with potential relevance for clinical care. Clinical interventions can thus be conducted to improve future health outcomes for patients and their at-risk relatives, such as predicting late-onset genetic disorders accessible to prevention, treatment or identifying differential drug efficacy and safety. To evaluate the interest of such pharmacogenetic information, we designed an “in house” pipeline to determine the status of 122 PharmGKB (Pharmacogenomics Knowledgebase) variant-drug combinations in 31 genes. This pipeline was applied to a cohort of 90 epileptic patients who had previously an exome sequencing (ES) analysis, to determine the frequency of pharmacogenetic variants. We performed a retrospective analysis of drug plasma concentrations and treatment efficacy in patients bearing at least one relevant PharmGKB variant. For PharmGKB level 1A variants, CYP2C9 status for phenytoin prescription was the only relevant information. Nineteen patients were treated with phenytoin, among phenytoin-treated patients, none were poor metabolizers and four were intermediate metabolizers. While being treated with a standard protocol (10–23 mg/kg/30 min loading dose followed by 5 mg/kg/8 h maintenance dose), all identified intermediate metabolizers had toxic plasma concentrations (20 mg/L). In epileptic patients, pangenomic sequencing can provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high plasma levels.
除了在孟德尔疾病诊断中鉴定因果遗传变异外,外显子组测序还能检测出许多与临床治疗潜在相关的变异。因此,可以采取临床干预措施来改善患者及其高危亲属未来的健康状况,如预测可用于预防、治疗或识别不同药物疗效和安全性的晚期遗传性疾病。为了评估此类药物基因信息的意义,我们设计了一个 "内部 "管道,以确定 31 个基因中 122 个 PharmGKB(药物基因组学知识库)变体-药物组合的状态。我们将这一方法应用于曾接受过外显子组测序(ES)分析的 90 例癫痫患者,以确定药物基因变异的频率。我们对至少携带一种相关 PharmGKB 变异的患者的药物血浆浓度和疗效进行了回顾性分析。对于 PharmGKB 1A 级变异,苯妥英处方的 CYP2C9 状态是唯一的相关信息。19名患者接受了苯妥英治疗,在接受苯妥英治疗的患者中,没有人是代谢不良者,4人是中间代谢者。在接受标准方案(10-23 毫克/千克/30 分钟的负荷剂量,然后是 5 毫克/千克/8 小时的维持剂量)治疗时,所有已确定的中等代谢者的血浆浓度都达到了中毒浓度(20 毫克/升)。在癫痫患者中,泛基因组测序可以提供常见药物基因变异的信息,这些信息可能有助于指导治疗药物监测,对于苯妥英,还可以防止因血浆浓度过高而引起的临床中毒。
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引用次数: 1
KDR genetic predictor of toxicities induced by sorafenib and regorafenib 索拉非尼和瑞戈非尼毒性的 KDR 遗传预测因子
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-04-28 DOI: 10.1038/s41397-022-00279-3
Julia C. F. Quintanilha, Susan Geyer, Amy S. Etheridge, Alessandro Racioppi, Kelli Hammond, Daniel J. Crona, Carol E. Peña, Sawyer B. Jacobson, Federica Marmorino, Daniele Rossini, Chiara Cremolini, Hanna K. Sanoff, Ghassan K. Abou-Alfa, Federico Innocenti
No biomarkers are available to predict toxicities induced by VEGFR TKIs. This study aimed to identify markers of toxicities induced by these drugs using a discovery-validation approach. The discovery set included 140 sorafenib-treated cancer patients (TARGET study) genotyped for SNPs in 56 genes. The most significant SNPs associated with grade ≥2 hypertension, diarrhea, dermatologic toxicities, and composite toxicity (any one of the toxicities) were tested for association with grade ≥2 toxicity in a validation set of 201 sorafenib-treated patients (Alliance/CALGB 80802). The validated SNP was tested for association with grade ≥2 toxicity in 107 (LCCC 1029) and 82 (Italian cohort) regorafenib-treated patients. SNP-toxicity associations were evaluated using logistic regression, and a meta-analysis between the studies was performed by inverse variance. Variant rs4864950 in KDR increased the risk of grade ≥2 composite toxicity in TARGET, Alliance/CALGB 80802, and the Italian cohort (meta-analysis p = 6.79 × 10−4, OR = 2.01, 95% CI 1.34–3.01). We identified a predictor of toxicities induced by VEGFR TKIs. NCT00073307 (TARGET), NCT01015833 (Alliance/CALGB 80802), and NCT01298570 (LCCC 1029).
目前还没有生物标志物可用于预测血管内皮生长因子受体 TKI 诱导的毒性。本研究采用发现-验证的方法,旨在确定这些药物诱发毒性的标志物。发现集包括140名索拉非尼治疗的癌症患者(TARGET研究),对56个基因中的SNP进行了基因分型。与≥2级高血压、腹泻、皮肤毒性和复合毒性(任何一种毒性)相关的最重要的SNPs在201名索拉非尼治疗患者(Alliance/CALGB 80802)组成的验证集中进行了与≥2级毒性相关性的测试。在107例(LCCC 1029)和82例(意大利队列)瑞戈非尼治疗患者中测试了已验证的SNP与≥2级毒性的相关性。利用逻辑回归评估了SNP与毒性的相关性,并通过反方差进行了研究间的荟萃分析。在TARGET、Alliance/CALGB 80802和意大利队列中,KDR中的变异体rs4864950增加了≥2级复合毒性的风险(荟萃分析p = 6.79 × 10-4,OR = 2.01,95% CI 1.34-3.01)。我们发现了一种 VEGFR TKIs 诱发毒性的预测因子。NCT00073307(TARGET)、NCT01015833(Alliance/CALGB 80802)和NCT01298570(LCCC 1029)。
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引用次数: 1
Whole-genome sequencing analysis of clozapine-induced myocarditis 氯氮平致心肌炎的全基因组测序分析
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-04-23 DOI: 10.1038/s41397-022-00271-x
Ankita Narang, Paul Lacaze, Kathlyn J. Ronaldson, John J. McNeil, Mahesh Jayaram, Naveen Thomas, Rory Sellmer, David N. Crockford, Robert Stowe, Steven C. Greenway, Christos Pantelis, Chad A. Bousman
One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p < 0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.
在精神分裂症治疗中使用氯氮平的一个限制因素是罕见但可能致命的心肌炎风险。我们之前的全基因组关联研究和人类白细胞抗原分析确定了与氯氮平诱发心肌炎相关的假定位点。然而,细胞色素 P450 基因的 DNA 变异、拷贝数变异和罕见的有害变异的贡献尚未得到研究。我们利用 25 例氯氮平诱发的心肌炎病例和 25 例人口统计学上匹配的氯氮平耐受性对照组的全基因组测序数据,探索了这些尚未探索的 DNA 变异类别。根据罕见变异基因负担分析,我们确定了 15 个基因(MLLT6、CADPS、TACC2、L3MBTL4、NPY、SLC25A21、PARVB、GPR179、ACAD9、NOL8、C5orf33、FAM127A、AFDN、SLC6A11、PXDN)与氯氮平诱发的心肌炎存在名义相关性(p < 0.05)。这些基因中有 13 个在人类心肌组织中表达。尽管这些发现还需要独立的验证,但我们的研究提供了关于罕见基因变异在氯氮平诱发的心肌炎易感性中潜在作用的初步见解。
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引用次数: 1
Point of care CYP2C19 genotyping after percutaneous coronary intervention 经皮冠状动脉介入治疗后的护理点 CYP2C19 基因分型
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-04-21 DOI: 10.1038/s41397-022-00278-4
Linnea M. Baudhuin, Laura J. Train, Shaun G. Goodman, Gary E. Lane, Ryan J. Lennon, Verghese Mathew, Vishakantha Murthy, Tamim M. Nazif, Derek Y. F. So, John P. Sweeney, Alan H. B. Wu, Charanjit S. Rihal, Michael E. Farkouh, Naveen L. Pereira
Loss-of-function CYP2C19 variants are associated with increased cumulative ischemic outcomes warranting CYP2C19 genotyping prior to clopidogrel administration. TAILOR-PCI was an international, multicenter (40 sites), prospective, randomized trial comparing rapid point of care (POC) genotype-guided vs. conventional anti-platelet therapy. The performance of buccal-based rapid CYP2C19 genotyping performed by non-laboratory-trained staff in TAILOR-PCI was assessed. Pre-trial training and evaluation involved rapid genotyping of 373 oral samples, with 99.5% (371/373) concordance with Sanger sequencing. During TAILOR-PCI, 5302 patients undergoing PCI were randomized to POC rapid CYP2C19 *2, *3, and *17 genotyping versus no genotyping. At 12 months post-PCI, TaqMan genotyping determined 99.1% (2,364/2,385) concordance with the POC results, with 90.7–98.8% sensitivity and 99.2–99.6% specificity. In conclusion, non-laboratory personnel can be successfully trained for on-site instrument operation and POC rapid genotyping with analytical accuracy and precision across multiple international centers, thereby supporting POC genotyping in patient-care settings, such as the cardiac catheterization laboratory. Clinical Trial Registration: https://www.clinicalTrials.gov (Identifier: NCT01742117).
功能缺失的 CYP2C19 变异与累积性缺血性结果的增加有关,因此在使用氯吡格雷之前需要进行 CYP2C19 基因分型。TAILOR-PCI是一项国际多中心(40个研究点)前瞻性随机试验,比较了快速护理点(POC)基因型指导与传统抗血小板疗法。在 TAILOR-PCI 中,对非实验室培训人员进行的基于口腔的快速 CYP2C19 基因分型的性能进行了评估。试验前培训和评估包括对 373 份口腔样本进行快速基因分型,与 Sanger 测序的吻合率为 99.5%(371/373)。在TAILOR-PCI期间,5302名接受PCI的患者随机接受了POC快速CYP2C19 *2、*3和*17基因分型与不进行基因分型。PCI术后12个月时,TaqMan基因分型与POC结果的一致性为99.1%(2364/2385),灵敏度为90.7-98.8%,特异性为99.2-99.6%。总之,多个国际中心都能成功培训非实验室人员进行现场仪器操作和 POC 快速基因分型,并保证分析的准确性和精确性,从而为心导管实验室等患者护理场所的 POC 基因分型提供支持。临床试验注册:https://www.clinicalTrials.gov(标识符:NCT01742117)。
{"title":"Point of care CYP2C19 genotyping after percutaneous coronary intervention","authors":"Linnea M. Baudhuin,&nbsp;Laura J. Train,&nbsp;Shaun G. Goodman,&nbsp;Gary E. Lane,&nbsp;Ryan J. Lennon,&nbsp;Verghese Mathew,&nbsp;Vishakantha Murthy,&nbsp;Tamim M. Nazif,&nbsp;Derek Y. F. So,&nbsp;John P. Sweeney,&nbsp;Alan H. B. Wu,&nbsp;Charanjit S. Rihal,&nbsp;Michael E. Farkouh,&nbsp;Naveen L. Pereira","doi":"10.1038/s41397-022-00278-4","DOIUrl":"10.1038/s41397-022-00278-4","url":null,"abstract":"Loss-of-function CYP2C19 variants are associated with increased cumulative ischemic outcomes warranting CYP2C19 genotyping prior to clopidogrel administration. TAILOR-PCI was an international, multicenter (40 sites), prospective, randomized trial comparing rapid point of care (POC) genotype-guided vs. conventional anti-platelet therapy. The performance of buccal-based rapid CYP2C19 genotyping performed by non-laboratory-trained staff in TAILOR-PCI was assessed. Pre-trial training and evaluation involved rapid genotyping of 373 oral samples, with 99.5% (371/373) concordance with Sanger sequencing. During TAILOR-PCI, 5302 patients undergoing PCI were randomized to POC rapid CYP2C19 *2, *3, and *17 genotyping versus no genotyping. At 12 months post-PCI, TaqMan genotyping determined 99.1% (2,364/2,385) concordance with the POC results, with 90.7–98.8% sensitivity and 99.2–99.6% specificity. In conclusion, non-laboratory personnel can be successfully trained for on-site instrument operation and POC rapid genotyping with analytical accuracy and precision across multiple international centers, thereby supporting POC genotyping in patient-care settings, such as the cardiac catheterization laboratory. Clinical Trial Registration: https://www.clinicalTrials.gov (Identifier: NCT01742117).","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9559833","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}
引用次数: 2
Real-world economic evaluation of prospective rapid whole-genome sequencing compared to a matched retrospective cohort of critically ill pediatric patients in the United States 前瞻性快速全基因组测序与美国危重儿科患者匹配回顾性队列的真实世界经济评估
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-04-18 DOI: 10.1038/s41397-022-00277-5
Vakaramoko Diaby, Aram Babcock, Yushi Huang, Richard K. Moussa, Paula S. Espinal, Michelin Janvier, Diana Soler, Apeksha Gupta, Parul Jayakar, Magaly Diaz-Barbosa, Balagangadhar Totapally, Jun Sasaki, Anuj Jayakar, Daria Salyakina
There is an increasing demand for supporting the adoption of rapid whole-genome sequencing (rWGS) by demonstrating its real-world value. We aimed to assess the cost-effectiveness of rWGS in critically ill pediatric patients with diseases of unknown cause. Data were collected prospectively of patients admitted to the Nicklaus Children’s Hospital’s intensive care units from March 2018 to September 2020, with rWGS (N = 65). Comparative data were collected in a matched retrospective cohort with standard diagnostic genetic testing. We determined total costs, diagnostic yield (DY), and incremental cost-effectiveness ratio (ICER) adjusted for selection bias and right censoring. Sensitivity analyses explored the robustness of ICER through bootstrapping. rWGS resulted in a diagnosis in 39.8% while standard testing in 13.5% (p = 0.026). rWGS resulted in a mean saving per person of $100,440 (SE = 26,497, p < 0.001) and a total of $6.53 M for 65 patients. rWGS in critically ill pediatric patients is cost-effective, cost-saving, shortens diagnostic odyssey, and triples the DY of traditional approaches.
通过证明快速全基因组测序(rWGS)的实际价值来支持其应用的需求日益增长。我们旨在评估 rWGS 在病因不明的儿科重症患者中的成本效益。我们前瞻性地收集了2018年3月至2020年9月期间尼克劳斯儿童医院重症监护病房收治的rWGS患者的数据(N = 65)。在一个匹配的回顾性队列中收集了标准诊断基因检测的比较数据。我们确定了总成本、诊断收益 (DY) 和增量成本效益比 (ICER),并对选择偏差和右删减进行了调整。rWGS 为 39.8% 的患者带来了诊断结果,而标准检测仅为 13.5% (p = 0.026)。rWGS 为每人平均节省了 100,440 美元(SE = 26,497, p <0.001),为 65 名患者总共节省了 653 万美元。
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引用次数: 6
Implementation of pharmacogenomic clinical decision support for health systems: a cost-utility analysis 实施药物基因组临床决策支持卫生系统:成本效用分析
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-04-01 DOI: 10.1038/s41397-022-00275-7
Shangqing Jiang, Patrick C. Mathias, Nathaniel Hendrix, Brian H. Shirts, Peter Tarczy-Hornoch, David Veenstra, Daniel Malone, Beth Devine
We constructed a cost-effectiveness model to assess the clinical and economic value of a CDS alert program that provides pharmacogenomic (PGx) testing results, compared to no alert program in acute coronary syndrome (ACS) and atrial fibrillation (AF), from a health system perspective. We defaulted that 20% of 500,000 health-system members between the ages of 55 and 65 received PGx testing for CYP2C19 (ACS-clopidogrel) and CYP2C9, CYP4F2 and VKORC1 (AF-warfarin) annually. Clinical events, costs, and quality-adjusted life years (QALYs) were calculated over 20 years with an annual discount rate of 3%. In total, 3169 alerts would be fired. The CDS alert program would help avoid 16 major clinical events and 6 deaths for ACS; and 2 clinical events and 0.9 deaths for AF. The incremental cost-effectiveness ratio was $39,477/QALY. A PGx-CDS alert program was cost-effective, under a willingness-to-pay threshold of $100,000/QALY gained, compared to no alert program.
从卫生系统的角度来看,我们构建了一个成本效益模型,以评估提供药物基因组学(PGx)检测结果的CDS警报程序与不提供急性冠状动脉综合征(ACS)和心房颤动(AF)警报程序的临床和经济价值。我们假设年龄在55岁到65岁之间的50万健康系统成员中有20%每年接受CYP2C19 (acs -氯吡格雷)和CYP2C9、CYP4F2和VKORC1 (af -华法林)的PGx检测。临床事件、成本和质量调整生命年(QALYs)以每年3%的贴现率计算20年。总共将触发3169个警报。CDS警报程序将有助于避免16个主要临床事件和6例ACS死亡;2例临床事件和0.9例房颤死亡。增量成本-效果比为39,477美元/QALY。与没有预警计划相比,PGx-CDS预警计划在10万美元/QALY的支付意愿阈值下具有成本效益。
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引用次数: 1
Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach 结合家族性高胆固醇血症和他汀类药物基因研究作为药物基因组学实施策略。多学科方法
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-03-31 DOI: 10.1038/s41397-022-00274-8
Luis Ramudo-Cela, Sara Santana-Martínez, Maite García-Ramos, Mariano Bergamino, Diego García-Giustiniani, Paula Vélez-Vieitez, Jose Luis Hernández-Hernández, Carmen García-Ibarbia, Pablo González-Bustos, Patricia Ruíz-Martín, Jaime González-Lozano, Luis Santomé-Collazo, Andrea Grana-Fernandez, Pablo Cabaleiro-Cerviño, Martín Ortíz, Lorenzo Monserrat-Iglesias
The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest. We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection. For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin. This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.
家族性高胆固醇血症的诊断过程经常涉及基因研究。患者接受降脂药物治疗,通常是他汀类药物。虽然已经发布了以基因型为基础的他汀类药物处方为重点的药物基因组学临床实践指南,但其在常规临床实践中的应用仍然非常有限。我们采用了一种新的 NGS 策略,将家族性高胆固醇血症相关基因与临床实践指南以及 EMA 和 FDA 药物标签中描述的降脂药物药物基因组学相关基因组区域相结合。由医生、生物学家和药剂师组成的多学科团队利用知识管理和临床决策支持系统以及治疗选择算法创建临床报告,提供诊断和治疗结果。在 12 个月中,共进行了 483 次家族性高胆固醇血症基因诊断研究,其中 221 人(45.8%)要求进行补充药物基因组学检测。在这 221 名患者中,66.5% 是所研究的药物基因组学途径中可操作变异的携带者:46.6%的患者为一种途径变异携带者,19.0%为两种途径变异携带者,0.9%为三种途径变异携带者。45.7%的患者对阿托伐他汀的反应可能不同于参照人群,45.7%的患者对辛伐他汀和洛伐他汀的反应不同于参照人群,29.0%的患者对氟伐他汀的反应不同于参照人群,6.7%的患者对匹伐他汀的反应不同于参照人群。这种实施方法有助于将药物基因组学研究纳入临床护理实践,既不会增加实验室流程的复杂性,也不会增加额外的步骤,还能改善患者的药物治疗过程。
{"title":"Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach","authors":"Luis Ramudo-Cela,&nbsp;Sara Santana-Martínez,&nbsp;Maite García-Ramos,&nbsp;Mariano Bergamino,&nbsp;Diego García-Giustiniani,&nbsp;Paula Vélez-Vieitez,&nbsp;Jose Luis Hernández-Hernández,&nbsp;Carmen García-Ibarbia,&nbsp;Pablo González-Bustos,&nbsp;Patricia Ruíz-Martín,&nbsp;Jaime González-Lozano,&nbsp;Luis Santomé-Collazo,&nbsp;Andrea Grana-Fernandez,&nbsp;Pablo Cabaleiro-Cerviño,&nbsp;Martín Ortíz,&nbsp;Lorenzo Monserrat-Iglesias","doi":"10.1038/s41397-022-00274-8","DOIUrl":"10.1038/s41397-022-00274-8","url":null,"abstract":"The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest. We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection. For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin. This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47133816","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}
引用次数: 0
Opportunities for personalizing colorectal cancer care: an analysis of SEER-medicare data 个性化大肠癌癌症护理的机会:SEER-Medicare数据分析
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-03-31 DOI: 10.1038/s41397-022-00276-6
Zachary T. Rivers, Helen M. Parsons, Pamala A. Jacobson, Karen M. Kuntz, Joel F. Farley, David J. Stenehjem
United States clinical practice guidelines for metastatic colorectal cancer recommend use of medications impacted by genetic variants but do not recommend testing. We analyzed real-world treatment using a cancer registry and claims dataset to explore pharmacogenomic (PGx) medication treatment patterns and characterize exposure. In a cohort of 6957 patients, most (86.9%) were exposed to at least one chemotherapy medication with PGx guidelines. In a cohort of 2223 patients with retail pharmacy claims available, most (79.2%) were treated with at least one non-chemotherapy (79.2%) medication with PGx guidelines. PGx-associated chemotherapy exposure was associated with age, race/ethnicity, educational attainment, and rurality. PGx-associated non-chemotherapy exposure was associated with medication use and comorbidities. The potential impact of PGx testing is large and policies aimed at increasing PGx testing at diagnosis may impact treatment decisions for patients with metastatic colorectal cancer as most patients are exposed to medications with pharmacogenomics implications during treatment.
美国转移性结直肠癌临床实践指南建议使用受基因变异影响的药物,但不建议进行检测。我们利用癌症登记和理赔数据集分析了真实世界的治疗情况,以探索药物基因组学(PGx)药物治疗模式并描述暴露特征。在一组 6957 例患者中,大多数患者(86.9%)至少接触过一种符合 PGx 指南的化疗药物。在2223名有零售药店报销单的患者队列中,大多数患者(79.2%)接受了至少一种符合PGx指南的非化疗药物治疗(79.2%)。与 PGx 相关的化疗暴露与年龄、种族/民族、教育程度和农村地区有关。PGx相关的非化疗暴露与药物使用和合并症有关。PGx检测的潜在影响很大,旨在增加诊断时PGx检测的政策可能会影响转移性结直肠癌患者的治疗决策,因为大多数患者在治疗期间都会接触到具有药物基因组学影响的药物。
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引用次数: 1
Correction to: Pharmacogenetic interventions to improve outcomes in patients with multimorbidity or prescribed polypharmacy: a systematic review 修正:药物遗传学干预改善多病患者或处方多药患者的预后:一项系统综述
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-03-30 DOI: 10.1038/s41397-022-00273-9
Joseph O’Shea, Mark Ledwidge, Joseph Gallagher, Catherine Keenan, Cristín Ryan
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Pharmacogenomics Journal
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