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

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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.