Alcoholic Hepatitis Consortia: an intramural/extramural collaboration to unravel genetic determinants

项目摘要/摘要--补编 NIAAA认识到开发合理的酒精性肝炎(AH)治疗方法和 在2012/2013年成立了酒精性肝炎财团(ASH U01)，资助了四个独立财团 对中、重度酒精性肝炎患者进行临床和翻译研究。虽然每一位 这四个联盟开发了独立的临床方法、遗传物质的收集以及 对所有患者进行广泛的表型分析，是四组患者的共同主题。在这个U01中， 这是与大卫·戈德曼博士在神经遗传学实验室的一次墙外/墙内合作 (液化天然气)在NIAAA，我们正在结合所有四个财团的努力，以及布鲁斯博士的持续支持 Barton与马萨诸塞州大学AlcHepNet数据协调中心合作，以便利用这些重要的 将生物标本和临床数据整合到一个大到足以研究基因的单个队列中 对AH的贡献。此外，由NIH/NIAAA临床中心收集的整个外显子组序列数据将 从大约800名无肝病的酗酒者中获得，作为重要的对照队列。特定的 目的1：对急性肝炎患者的DNA进行完整的外显子组测序。 没有肝病的大量饮酒控制组：这一目标已经完成。WES是在 1-3年，然后将数据传输到印第安纳大学并通过他们的数据进行处理 清洁管道的具体目标2：延迟启动：确定遗传基因的新分析方法 AH的关键决定因素的风险：我们最初的计划是在第4年开始分析。然而，我们浪费了时间 由于新冠肺炎大流行。我们在决定在哪里以及如何转移和存储数据时遇到了延迟 数据，最终决定将其存储在马萨诸塞州大学/MGHPCC。访问密歇根大学马萨诸塞州/MGHPCC 服务器延迟了很多，这与大多数管理员在家中工作有关 大流行。第四年也出现了类似的行政延误，因为我们最后敲定了 机构；所有必要的许可和访问程序只是在 限制流行的工作环境。行政补充申请：由于这些延误相关 对于这一大流行病，我们希望请求一份行政补编，以处理数据费用增加的问题。 在我们拨款的第五年进行分析。通过为PI及其工作人员增加努力，我们将能够加快基因组 对数据进行分析，弥补大流行期间损失的时间。第五年的计划是确定 遗传学对急性肝炎的易感性和严重性，并发表了一篇关于结果的手稿。世界银行的目标是 拟议的补充材料完全在理事会批准的原始研究范围内，不会移动 在新的方向；补充将仅用于弥补在数据分析期间损失的时间 拨款的第四年。

PROJECT SUMMARY/ABSTRACT - SUPPLEMENT NIAAA recognized the critical need to develop rationally-based therapies for alcoholic hepatitis (AH) and established the Alcoholic Hepatitis Consortia (ASH U01) in 2012/2013, funding four independent consortia to conduct clinical and translational studies in patients with moderate to severe alcoholic hepatitis. While each of the four consortia developed independent clinical approaches, the collection of genetic material, as well as an extensive phenotypic analysis of all patients, was a common theme amongst the four groups. In this U01, which is an extramural/intramural collaboration with Dr. David Goldman in the Laboratory of Neurogenetics (LNG) at NIAAA, we are combining the efforts of all four consortia, and the ongoing support from Dr. Bruce Barton with the AlcHepNet Data Coordinating Center at UMASS, in order to leverage these important biospecimens and clinical data into a single cohort large enough for investigations into the genetic contributions to AH. In addition, whole exome sequence data, collected by the NIH/NIAAA Clinical Center, will be available from ~800 heavy drinkers without liver disease to serve as an important control cohort. Specific Aim 1: COMPLETED Whole exome sequencing (WES) of the DNA from patients with AH, as well as a cohort of heavy drinking controls without liver disease: This aim is completed. WES was carried out in years 1-3 by LNG and then data were transferred to Indiana University and processed through their data cleaning pipeline Specific Aim 2: DELAYED START: Novel analytical approaches to determine genetic risk for key determinants of AH: Our original plan was to begin analysis in Year 4. However, we lost time due to the COVID-19 pandemic. We incurred delays determining where and how to transfer and store the data, with the eventual decision to store it at UMASS/MGHPCC. Getting access to the UMASS/MGHPCC server was considerably delayed, related to most of the administrators working from home during the pandemic. Similar administrative delays in year 4 occurred as we finalized all the MTAs/DUAs between institutions; all the necessary permissions and access procedures just took much longer than usual during the pandemic-limited work environment. Administrative Supplement Request: Because of these delays related to the pandemic, we would like to request an Administrative Supplement to handle the increased cost for data analysis in year 5 of our grant. By adding effort for PIs and their staff, we will be able to speed up the genomic analysis of the data and make up for lost time during the pandemic. The plan for year 5 is to determine genetics for susceptibility and severity of AH and publish a manuscript on the results. The goals of the proposed supplement are well within the original Council-approved scope of the research and does not move in new directions; the supplement will be used solely to make up for lost time in the analysis of the data during year 4 of the grant.