Estimating the Contribution of Alcohol and Metabolic Risk to Liver Disease Progression to Inform Personalized Interventions

项目摘要/摘要 酒精性(ALD)和非酒精性脂肪性(NAFLD)肝病是肝病的两大病因， 占肝脏相关死亡的50%以上，两者的发病率都在迅速上升。ALD和NAFLD 在组织学上难以区分，但在临床上按不同的酒精阈值分层-然而，酒精使用和 新陈代谢风险通常在个体中共存。尽管这些风险经常交叉，但纵向 酒精使用和代谢风险随着时间的推移对肝病进展的影响还没有得到充分研究。一种改进的 了解这些相互作用，特别是不同个人特征(即年龄、性别、种族)之间的相互作用，可以 告知用于纤维化评估和监测的个性化算法，以及针对 酒精使用干预。新型生物标志物(如原蛋白转换酶枯草杆菌可信9型)的研究 [PCSK9])可能导致精确的干预措施来预防和治疗肝病。要解决这些知识 为了弥补差距，我们将利用CARDIA(一个拥有35年预期酒精和新陈代谢经验的大型混血儿队列 数据)通过对先前储存的血清样本进行系列增强肝纤维化(ELF)检测而扩增。这个 科学目标是：(1)确定饮酒和肥胖的轨迹和阈值， 肝纤维化的存在和进展(目标1)；(2)开发针对性别和种族的模型，以确定 肝病风险最高的个人，按人口、代谢和酒精情况分列(目标1a)；(3)评估 通过人口统计学、代谢和酒精特征研究PCSK9无效等位基因在肝纤维化中的作用(目标2)。这个 培训目标，将通过正式课程、讲习班、教学、实践经验和 有组织的指导：(1)培养新陈代谢风险和酒精相互关系方面的专门知识；(2) 在多层次的相互作用和纵向分析中学习先进的生物统计方法(例如轨迹和 JoinPoint)；(3)获取翻译生物标记物和遗传流行病学方面的知识，重点是临床 干预措施。这些科学目标和培训目标是由丰富的科学环境使之成为可能的 南加州大学，获得一个独特的基于社区的队列(CARDIA)，以及一个 强大的多学科指导团队，由Terrault博士(慢性肝病、临床和 翻译研究、临床试验专家)、Mack博士(高级生物统计学、遗传流行病学、临床试验 莱文塔尔博士(酒精与成瘾，纵向研究专家)。所有导师都有重要的 从K到R-导师的经验，并将确保Lee博士在里程碑中的成就，这将导致他的 作为一名富有成效的独立调查员。这项研究将为未来NIH R资助奠定基础 研究集中在ALD/NAFLD中筛查和预测的个性化方法 交叉，利用观察性(复杂的纵向生物统计学)和转换方面的专业知识 (生物标记物，遗传流行病学)研究，以及抗PCSK9在ALD的试点临床试验。

PROJECT SUMMARY/ABSTRACT Alcohol- (ALD) and non-alcoholic fatty (NAFLD) liver disease are the two leading etiologies of liver disease, accounting for more than 50% of liver-related mortality, and both rapidly rising in incidence. ALD and NAFLD are histologically indistinguishable, but clinically stratified by distinct alcohol thresholds—yet, alcohol use and metabolic risk often co-exist in individuals. Despite the frequent intersection of these risks, the longitudinal effects of alcohol use and metabolic risk over time on liver disease progression are understudied. An improved understanding of these interactions, particularly among different individual profiles (i.e. age, sex, race), can inform personalized algorithms for fibrosis assessment and surveillance, and individualized thresholds for alcohol use interventions. Investigation of novel biomarkers (e.g. proprotein convertase subtilisin kexin type 9 [PCSK9]) may lead to precision-interventions to prevent and treat liver disease. To address these knowledge gaps, we will leverage CARDIA (a large biracial cohort with 35 years of prospective alcohol and metabolic data) amplified by serial Enhanced Liver Fibrosis (ELF) testing of previously banked serum samples. The scientific aims are to: (i) identify trajectories and thresholds of alcohol use and obesity, associated with presence and progression of liver fibrosis (Aim 1); (ii) develop sex- and race-specific models to identify individuals at highest risk of liver disease, by demographic, metabolic, and alcohol profiles (Aim 1a); (iii) assess the role of null PCSK9 alleles on liver fibrosis by demographic, metabolic, and alcohol profiles (Aim 2). The training goals, which will be achieved through formal courses, workshops, didactics, hands-on experience and structured mentorship, are to: (i) develop expertise in metabolic risks and inter-relatedness with alcohol; (ii) learn advanced biostatistical methods in multi-level interactions and longitudinal analyses (e.g. trajectory and JoinPoint); (iii) acquire knowledge in translational biomarkers and genetic epidemiology, focused on clinical interventions. These scientific aims and training goals are made possible by a rich scientific environment at University of Southern California, access to a unique prospective community-based cohort (CARDIA), and a strong multidisciplinary mentorship team consisting of Dr. Terrault (chronic liver diseases, clinical and translational studies, clinical trials expert), Dr. Mack (advanced biostatistics, genetic epidemiology, clinical trials expert), and Dr. Leventhal (alcohol and addiction, longitudinal studies expert). All mentors have significant experience with K to R-mentorship, and will ensure Dr. Lee’s achievement in milestones that will lead to his position as a productive independent investigator. This research will set the stage for future NIH R-funded studies focused on personalized approaches to the screening and prognostication within the ALD/NAFLD intersection, leveraging expertise in observational (complex longitudinal biostatistics) and translational (biomarkers, genetic epidemiology) research, in addition to a pilot clinical trial of anti-PCSK9 in ALD.