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

项目摘要/摘要 1800万美国人酗酒，酒精性肝病(ALD)影响着1000多万人。酒精 滥用对肝脏的有害影响会导致不同的病理实体，包括脂肪变性， 脂肪性肝炎、纤维化和肝硬化；患者在任何时候都可能发展为酒精性肝炎(AH)。 疾病的发展。AH是ALD最严重的形式，只发生在酗酒者的一小部分人中， 暗示了遗传和环境风险因素的作用。AH是ALD的一种特别昂贵的呈现方式； 据估计，每个患者的治疗费用约为4万美元，平均住院时间为6-9天。 虽然严重急性肝炎的标准治疗方法是糖皮质激素，但许多患者对类固醇耐药；类固醇- 耐药患者的6个月死亡率超过45%。同样至关重要的是，没有 目前批准用于中度急性呼吸窘迫综合征的治疗；中度急性呼吸窘迫综合征患者28天的死亡率约为10-15%。 NIAAA认识到开发基于理性的治疗方法的重要性，并建立了酒精性 肝炎财团(ASH UO1)在2012/2013年，资助四个独立财团进行临床和 中重度酒精性肝炎患者的翻译研究。与此同时，每个财团都在发展 独立的临床方法、遗传物质的收集以及广泛的表型分析 在所有患者中，这是四组患者的共同主题。我们现在正在结合所有四个人的努力 联盟，以便利用这些关键的生物谱系和临床数据到一个大到足以 探讨遗传性早幼粒细胞白血病的遗传贡献。为了进行彻底的基因分析，我们在这里 建议校外/校内协作(PAR-16-104校外/校内酒精计划 与David Goldman博士在NIAAA神经遗传学实验室(LNG)的研究合作(U01)。 古德曼博士和他的团队在整个外显子组测序和等位基因分析方面拥有广泛的专业知识 与酗酒有关的频率。广泛的生物信息库和表型数据的结合 来自ASH UO1财团，拥有内部LNG的专业知识，使我们的团队有资格确定 导致急性早幼粒细胞白血病的关键遗传成分以及对治疗干预的敏感性。鉴定 可能会提供关于为什么只有一部分酗酒患者的洞察 开发AH并确定潜在的可用药分子驱动因素。在此，我们建议进行以下工作 具体目标：1)对约1000名急性肝炎患者的DNA进行完整的外显子组测序，以及一组 无肝病的大量饮酒控制和2)确定遗传风险的新分析方法 急性酒精中毒的关键决定因素包括a)酗酒者患急性酒精中毒的易感性，b)早期发生急性酒精中毒的风险 急性脑出血死亡率，c)治疗反应和d)酗酒复发。总之，我们的组合 通过我们的生物信息学专业知识，具有良好的特征的独特的重度饮酒者群体，有无急性酒精中毒 将使我们的财团能够确定关键的基因决定因素，以确定急性肾功能衰竭的风险和存活。

PROJECT SUMMARY/ABSTRACT 18 million Americans abuse alcohol, with alcoholic liver disease (ALD) affecting over 10 million people. Alcohol abuse's deleterious effects on the liver leads to pathologically distinct entities including steatosis, steatohepatitis, fibrosis and cirrhosis; patients can develop alcoholic hepatitis (AH) at any time in the progression of disease. AH is the most severe form of ALD and only occurs in a sub-set of heavy drinkers, suggesting a role for genetic and environmental risk factors. AH is a particularly costly presentation of ALD; treatment costs are estimated to be ~$40K per patient with average length of stay in hospital lasting 6-9 days. While the standard therapy for severe AH is glucocorticoids, many patients are steroid-resistant; steroid- resistant patients have a 6 month mortality rate greater than 45%. Also of critical importance, there is no currently approved treatment for patients with moderate AH; 28 day mortality in moderate AH is ~10-15%. NIAAA recognized the great need to develop rationally-based therapies of AH and established the Alcoholic Hepatitis Consortia (ASH UO1) in 2012/2013, funding four independent consortia to conduct clinical and translational studies in patients with moderate to severe alcoholic hepatitis. While each 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. We are now combining the efforts of all 4 consortia in order to leverage these critical biospecimens and clinical data into a single cohort large enough for investigations into the genetic contributions to AH. In order to carry out a thorough genetic analysis, here we propose an extramural/intramural collaboration (PAR-16-104 Program for Extramural/ Intramural Alcohol Research Collaborations (U01)) with Dr. David Goldman in the Laboratory of Neuro Genetics (LNG) at NIAAA. Dr. Goldman and his team have extensive expertise in whole exome sequencing and analysis of allele frequencies related to alcohol abuse. The combination of the extensive biorepository and phenotypic data from the ASH UO1 consortia with the expertise of the intramural LNG uniquely qualifies our team to identify critical genetic components leading to AH, as well as the sensitivity to therapeutic intervention. Identification of specific genetic components will likely provide insights into why only a subset of patients who abuse alcohol develop AH and identify potential druggable molecular drivers. Here we propose to carry out the following Specific Aims: 1) Whole exome sequencing of the DNA from ~1000 patients with AH, as well as a cohort of heavy drinking controls without liver disease and 2) Novel analytical approaches to determine genetic risk for key determinants of AH including a) Susceptibility for developing AH among heavy drinkers, b) Risk for early mortality from AH, c) Response to therapy and d) Alcohol Recidivism. In summary, the combination of our well-characterized unique population of heavy drinkers with and without AH with our bioinformatics expertise will enable our consortium to identify key genetic determinants for determining risk for and survival after AH.