Michigan Hepatotoxicity Clinical Research Network

描述（由申请人提供）： 药物性肝损伤（DILI）是一种罕见的药物不良反应（ADR），对医学界、制药业、监管机构和公众越来越重要。DILI是美国急性肝功能衰竭的主要原因，也是停止开发药物以及从市场上撤回批准药物的主要原因。药物性肝损伤网络（DILIN）成立于2003年，旨在促进对DILI的理解和研究。该回顾性研究收集了58例阿莫西林/克拉维汀、丙戊酸盐、苯妥英、异烟肼所致肝损伤受试者的DNA样本，用于未来的药物遗传学和机制研究。此外，400多名因多种药物和草药产品导致DILI的患者已入组前瞻性研究，其中收集了DNA、血清、血浆、尿液和肝组织样本以及广泛的临床数据。为了建立在不断增长的数据库，生物样本和研究专业知识，提出了一个竞争性的更新与扩大DILIN临床研究中心的数量。该提案的主要目的是继续招募从密歇根肝毒性研究网络招募的具有不同疾病严重程度的真正DILI患者进入密歇根大学的DILIN前瞻性研究。将根据收集的临床数据和生物样本开发因果关系评估工具以及新型诊断和预后生物标志物。本提案的次要目的是对从DILI病例和对照组中采集的DNA样本进行药物遗传学分析。提出全基因组SNP分析和/或靶向基因方法，以帮助阐明宿主药物遗传学在DILI易感性和结局中的作用。建议成立一个具有生物信息学专业知识的遗传分析委员会，以分析和解释药物遗传学数据，并帮助制定额外的假设驱动机制研究。最后，在入组后与DILI病例患者保持长达20年的联系，将允许在DILI患者、家庭成员和对照中进行确证性基因型-表型关联和其他随访研究。这些补充研究可能会导致识别和完善遗传生物标志物，以帮助预防，诊断和管理未来的DILI患者。该提案的第三个目的是与国家医学图书馆合作开发一个权威和全面的LiverTox网站，以帮助教育和协助执业医生，研究人员和公众了解DILI。LiverTox网站不仅将提高全世界对DILI的认识和认识，而且还可能加强DILIN前瞻性研究和其他未来计划的招募。

DESCRIPTION (provided by applicant): Drug induced liver injury (DILI) is an uncommon adverse drug reaction (ADR) of increasing importance to the medical community, pharmaceutical, regulatory agencies, and the general public. DILI is the leading cause of acute liver failure in the United States and the leading reason for discontinuation of drugs in development as well as removal of approved drugs from the marketplace. The Drug Induced Liver Injury Network (DILIN) was established in 2003 to advance understanding and research into DILI. The Retrospective study has collected DNA samples from 58 subjects with liver injury attributed to amoxicillin/clavulanate, valproate, phenytoin, isoniazid for future pharmacogenetic and mechanistic studies. In addition, over 400 patients with DILI due to a multitude of medications and herbal products have been enrolled into the Prospective study wherein DNA, serum, plasma, urine, and liver tissue samples as well as extensive clinical data are collected. To build upon the growing repository of data, biological samples, and research expertise, a competing renewal with expansion of the number of DILIN clinical sites is proposed. The primary aim of this proposal is to continue to enroll bonafide DILI patients with varying disease severity recruited from the Michigan Hepatoxicity Research Network into the DILIN Prospective study at the University of Michigan. A causality assessment instrument as well as novel diagnostic and prognostic biomarkers will be developed from the collected clinical data and biological samples. The secondary aim of this proposal is to conduct pharmacogenetic analyses of DNA samples collected from the DILI cases and controls. Whole genome SNP analyses and/or targeted gene approaches are proposed to help elucidate the contribution of host pharmacogenetics in the susceptibility and outcome of DILI. A Genetic Profiling Committee with bioinformatics expertise is proposed to analyze and interpret the pharmacogenetic data and help formulate additional hypothesis driven mechanistic studies. Finally, maintaining contact with the DILI case patients for up to 20 years after enrollment will allow performance of confirmatory genotype-phenotype association and other follow-up studies in DILI patients, family members, and controls. These supplemental studies may lead to the identification and refinement of genetic biomarkers to assist in the prevention, diagnosis and management of future DILI patients. The third aim of this proposal is to develop an authoritative and comprehensive LiverTox website in conjunction with the National Library of Medicine to help educate and assist practicing physicians, researchers, and the general public on DILI. A LiverTox website will not only improve worldwide knowledge and awareness of DILI but also potentially enhance recruitment for the DILIN Prospective study and other future initiatives.