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The genetic landscape of major drug metabolizing cytochrome P450 genes—an updated analysis of population-scale sequencing data 主要药物代谢细胞色素 P450 基因的遗传格局--对群体规模测序数据的最新分析
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-09-06 DOI: 10.1038/s41397-022-00288-2
Yitian Zhou, Volker M. Lauschke
Genes encoding cytochrome P450 enzymes (CYPs) are extremely polymorphic and multiple CYP variants constitute clinically relevant biomarkers for the guidance of drug selection and dosing. We previously reported the distribution of the most relevant CYP alleles using population-scale sequencing data. Here, we update these findings by making use of the increasing wealth of data, incorporating whole exome and whole genome sequencing data from 141,614 unrelated individuals across 12 human populations. We furthermore extend our previous studies by systematically considering also uncharacterized rare alleles and reveal that they contribute between 1.5% and 17.5% to the overall genetically encoded functional variability. By using established guidelines, we aggregate and translate the available sequencing data into population-specific patterns of metabolizer phenotypes. Combined, the presented data refine the worldwide landscape of ethnogeographic variability in CYP genes and aspire to provide a relevant resource for the optimization of population-specific genotyping strategies and precision public health.
编码细胞色素 P450 酶(CYPs)的基因具有极高的多态性,多种 CYP 变异构成了指导药物选择和剂量的临床相关生物标志物。我们曾利用人群规模的测序数据报告了最相关的 CYP 等位基因的分布情况。在这里,我们利用日益丰富的数据更新了这些发现,纳入了来自 12 个人类群体中 141,614 个无关联个体的全外显子组和全基因组测序数据。此外,我们还系统地考虑了未表征的罕见等位基因,从而进一步扩展了之前的研究,并发现这些等位基因对整体基因编码功能变异的贡献率在 1.5% 到 17.5% 之间。通过使用既定指南,我们汇总了现有测序数据,并将其转化为特定人群的代谢物表型模式。综合上述数据,我们完善了全球范围内 CYP 基因的人种地理变异情况,并希望为优化特定人群基因分型策略和精准公共卫生提供相关资源。
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引用次数: 15
Development of an extensive workflow for comprehensive clinical pharmacogenomic profiling: lessons from a pilot study on 100 whole exome sequencing data 为全面的临床药理基因组学分析开发广泛的工作流程:从 100 个全外显子组测序数据的试点研究中汲取的经验教训
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-08-13 DOI: 10.1038/s41397-022-00286-4
Alireza Tafazoli, Maaike van der Lee, Jesse J. Swen, Anna Zeller, Natalia Wawrusiewicz-Kurylonek, Hailiang Mei, Ruben H. P. Vorderman, Krzysztof Konopko, Andrzej Zankiewicz, Wojciech Miltyk
This pilot study is aimed at implementing an approach for comprehensive clinical pharmacogenomics (PGx) profiling. Fifty patients with cardiovascular diseases and 50 healthy individuals underwent whole-exome sequencing. Data on 1800 PGx genes were extracted and analyzed through deep filtration separately. Theoretical drug induced phenoconversion was assessed for the patients, using sequence2script. In total, 4539 rare variants (including 115 damaging non-synonymous) were identified. Four publicly available PGx bioinformatics algorithms to assign PGx haplotypes were applied to nine selected very important pharmacogenes (VIP) and revealed a 45–70% concordance rate. To ensure availability of the results at point-of-care, actionable variants were stored in a web-hosted database and PGx-cards were developed for quick access and handed to the study subjects. While a comprehensive clinical PGx profile could be successfully extracted from WES data, available tools to interpret these data demonstrated inconsistencies that complicate clinical application.
这项试验性研究旨在实施一种全面的临床药理基因组学(PGx)分析方法。50名心血管疾病患者和50名健康人接受了全外显子组测序。通过深度过滤分别提取和分析了 1800 个 PGx 基因的数据。使用 sequence2script 对患者的理论药物诱导表型转换进行了评估。共鉴定出 4539 个罕见变异(包括 115 个破坏性非同义变异)。将四种公开的 PGx 生物信息学算法分配 PGx 单倍型应用于九种选定的非常重要的药物基因(VIP),结果显示吻合率为 45-70%。为确保在医疗点获得结果,可操作的变体被存储在一个网络托管数据库中,同时还开发了 PGx 卡片,供研究对象快速访问和使用。虽然可以成功地从 WES 数据中提取出全面的临床 PGx 资料,但用于解释这些数据的现有工具显示出不一致性,使临床应用变得复杂。
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引用次数: 3
A blockchain-based framework to support pharmacogenetic data sharing 支持药物基因数据共享的区块链框架
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-07-22 DOI: 10.1038/s41397-022-00285-5
F. Albalwy, J. H. McDermott, W. G. Newman, A. Brass, A. Davies
The successful implementation of pharmacogenetics (PGx) into clinical practice requires patient genomic data to be shared between stakeholders in multiple settings. This creates a number of barriers to widespread adoption of PGx, including privacy concerns related to the storage and movement of identifiable genomic data. Informatic solutions that support secure and equitable data access for genomic data are therefore important to PGx. Here we propose a methodology that uses smart contracts implemented on a blockchain-based framework, PGxChain, to address this issue. The design requirements for PGxChain were identified through a systematic literature review, identifying technical challenges and barriers impeding the clinical implementation of pharmacogenomics. These requirements included security and privacy, accessibility, interoperability, traceability and legal compliance. A proof-of-concept implementation based on Ethereum was then developed that met the design requirements. PGxChain’s performance was examined using Hyperledger Caliper for latency, throughput, and transaction success rate. The findings clearly indicate that blockchain technology offers considerable potential to advance pharmacogenetic data sharing, particularly with regard to PGx data security and privacy, large-scale accessibility of PGx data, PGx data interoperability between multiple health care providers and compliance with data-sharing laws and regulations.
要在临床实践中成功实施药物遗传学 (PGx),患者的基因组数据必须在多种环境下由利益相关者共享。这给 PGx 的广泛应用带来了许多障碍,包括与可识别基因组数据的存储和移动有关的隐私问题。因此,支持安全、公平地访问基因组数据的信息化解决方案对 PGx 非常重要。在此,我们提出一种方法,利用在基于区块链的框架 PGxChain 上实施的智能合约来解决这一问题。PGxChain 的设计要求是通过系统的文献回顾确定的,确定了阻碍药物基因组学临床实施的技术挑战和障碍。这些要求包括安全性和隐私性、可访问性、互操作性、可追溯性和法律合规性。然后,开发了一个基于以太坊的概念验证实现,满足了设计要求。使用 Hyperledger Caliper 对 PGxChain 的延迟、吞吐量和交易成功率进行了性能检测。研究结果清楚地表明,区块链技术在推进药物基因数据共享方面具有相当大的潜力,特别是在 PGx 数据的安全性和隐私性、PGx 数据的大规模可访问性、多个医疗保健提供商之间的 PGx 数据互操作性以及遵守数据共享法律法规方面。
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引用次数: 3
The clinically relevant CYP2C8*3 and CYP2C9*2 haplotype is inherited from Neandertals 与临床相关的 CYP2C8*3 和 CYP2C9*2 单倍型是从尼安德特人那里遗传的
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-07-02 DOI: 10.1038/s41397-022-00284-6
Sigrid Haeggström, Magnus Ingelman-Sundberg, Svante Pääbo, Hugo Zeberg
Genetic variation in genes encoding cytochrome P450 enzymes influences the metabolism of drugs and endogenous compounds. The locus containing the cytochrome genes CYP2C8 and CYP2C9 on chromosome 10 exhibits linkage disequilibrium between the CYP2C8*3 and CYP2C9*2 alleles, forming a haplotype of ~300 kilobases. This haplotype is associated with altered metabolism of several drugs, most notably reduced metabolism of warfarin and phenytoin, leading to toxicity at otherwise therapeutic doses. Here we show that this haplotype is inherited from Neandertals.
编码细胞色素 P450 酶基因的遗传变异会影响药物和内源性化合物的代谢。10 号染色体上含有细胞色素基因 CYP2C8 和 CYP2C9 的基因座显示出 CYP2C8*3 和 CYP2C9*2 等位基因之间的连锁不平衡,形成了约 300 千碱基的单倍型。这种单倍型与几种药物的代谢改变有关,最明显的是华法林和苯妥英的代谢降低,导致药物在达到治疗剂量时产生毒性。在这里,我们证明这种单倍型是从尼安德特人那里遗传下来的。
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引用次数: 2
A machine learning model using SNPs obtained from a genome-wide association study predicts the onset of vincristine-induced peripheral neuropathy 利用从全基因组关联研究中获得的 SNPs 的机器学习模型预测长春新碱诱发的周围神经病变的发病情况
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-06-25 DOI: 10.1038/s41397-022-00282-8
Hiroki Yamada, Rio Ohmori, Naoto Okada, Shingen Nakamura, Kumiko Kagawa, Shiro Fujii, Hirokazu Miki, Keisuke Ishizawa, Masahiro Abe, Youichi Sato
Vincristine treatment may cause peripheral neuropathy. In this study, we identified the genes associated with the development of peripheral neuropathy due to vincristine therapy using a genome-wide association study (GWAS) and constructed a predictive model for the development of peripheral neuropathy using genetic information-based machine learning. The study included 72 patients admitted to the Department of Hematology, Tokushima University Hospital, who received vincristine. Of these, 56 were genotyped using the Illumina Asian Screening Array-24 Kit, and a GWAS for the onset of peripheral neuropathy caused by vincristine was conducted. Using Sanger sequencing for 16 validation samples, the top three single nucleotide polymorphisms (SNPs) associated with the onset of peripheral neuropathy were determined. Machine learning was performed using the statistical software R package “caret”. The 56 GWAS and 16 validation samples were used as the training and test sets, respectively. Predictive models were constructed using random forest, support vector machine, naive Bayes, and neural network algorithms. According to the GWAS, rs2110179, rs7126100, and rs2076549 were associated with the development of peripheral neuropathy on vincristine administration. Machine learning was performed using these three SNPs to construct a prediction model. A high accuracy of 93.8% was obtained with the support vector machine and neural network using rs2110179 and rs2076549. Thus, peripheral neuropathy development due to vincristine therapy can be effectively predicted by a machine learning prediction model using SNPs associated with it.
长春新碱治疗可能会导致周围神经病变。在这项研究中,我们利用全基因组关联研究(GWAS)确定了与长春新碱治疗导致的周围神经病变相关的基因,并利用基于遗传信息的机器学习构建了一个周围神经病变发生的预测模型。研究对象包括德岛大学医院血液科收治的 72 名接受长春新碱治疗的患者。使用 Illumina Asian Screening Array-24 套件对其中 56 例进行了基因分型,并对长春新碱导致的周围神经病变的发病进行了 GWAS 分析。通过对 16 个验证样本进行 Sanger 测序,确定了与外周神经病发病相关的前三个单核苷酸多态性 (SNP)。使用 R 软件包 "caret "进行了机器学习。56 个 GWAS 样本和 16 个验证样本分别作为训练集和测试集。使用随机森林、支持向量机、天真贝叶斯和神经网络算法构建了预测模型。根据 GWAS 的结果,rs2110179、rs7126100 和 rs2076549 与长春新碱用药导致的周围神经病变有关。利用这三个 SNPs 进行机器学习,构建了一个预测模型。使用支持向量机和神经网络对 rs2110179 和 rs2076549 的预测准确率高达 93.8%。因此,利用与长春新碱治疗相关的 SNPs 的机器学习预测模型可以有效地预测长春新碱治疗引起的周围神经病变。
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引用次数: 1
miRNAs as potential diagnostic biomarkers and pharmacogenomic indicators in psychiatric disorders miRNA 作为精神疾病的潜在诊断生物标志物和药物基因组学指标
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-06-20 DOI: 10.1038/s41397-022-00283-7
Evangelia Eirini Tsermpini, Christina I. Kalogirou, George C. Kyriakopoulos, George P. Patrinos, Constantinos Stathopoulos
The heterogeneity of psychiatric disorders and the lack of reliable biomarkers for prediction and treatments follow-up pose difficulties towards recognition and understanding of the molecular basis of psychiatric diseases. However, several studies based on NGS approaches have shown that miRNAs could regulate gene expression during onset and disease progression and could serve as potential diagnostic and pharmacogenomics biomarkers during treatment. We provide herein a detailed overview of circulating miRNAs and their expression profiles as biomarkers in schizophrenia, bipolar disorder and major depressive disorder and their role in response to specific treatments. Bioinformatics analysis of miR-34a, miR-106, miR-134 and miR-132, which are common among SZ, BD and MDD patients, showed brain enrichment and involvement in the modulation of critical signaling pathways, which are often deregulated in psychiatric disorders. We propose that specific miRNAs support accurate diagnosis and effective precision treatment of psychiatric disorders.
精神疾病的异质性以及缺乏可靠的生物标志物进行预测和治疗跟踪,给认识和了解精神疾病的分子基础带来了困难。然而,一些基于 NGS 方法的研究表明,miRNAs 可在发病和疾病进展过程中调控基因表达,并可在治疗过程中作为潜在的诊断和药物基因组学生物标志物。我们在此详细概述了作为精神分裂症、双相情感障碍和重度抑郁障碍生物标志物的循环 miRNA 及其表达谱,以及它们在特定治疗中的作用。生物信息学分析表明,miR-34a、miR-106、miR-134 和 miR-132 在精神分裂症、双相情感障碍和重度抑郁障碍患者中很常见,它们富集于大脑,并参与调节关键信号通路,而这些通路在精神疾病中通常是失调的。我们认为,特异性 miRNA 可支持精神疾病的准确诊断和有效的精准治疗。
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引用次数: 8
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 GENETICS & HEREDITY 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 GENETICS & HEREDITY 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 GENETICS & HEREDITY 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 GENETICS & HEREDITY 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
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Pharmacogenomics Journal
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