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.
/RELEVANCE Alcohol abuse is a leading cause of morbidity and mortality worldwide. In the US, 18 million Americans abuse alcohol, with alcoholic liver disease affecting over 10 million people. Alcohol abuse's deleterious effects on the liver leads to pathologically distinct entities: steatosis, steatohepatitis (ASH), fibrosis and cirrhosis. Disease progression only occurs in a sub-set of heavy drinkers, suggesting a role for genetic and environmental risk factors. There is a pressing clinical need to develop improved therapies for patients with ASH, as the current strategy of glucocorticoid (GC) treatment is only effective in a sub-set of patients. Here we propose to combine our experimental and analytical resources with the ongoing ASH UO1 Clinical and Translational studies to identify novel genetic contributions to ASH. We will leverage the technical expertise of the Laboratory for Neuro Genetics at NIAAA to carry out whole exome sequencing of DNA collected from patients with ASH and heavy drinking controls without liver disease. We propose to conduct novel, state of the art analysis of the DNA data, integrating the unique compendium of phenotypic data on this large cohort of patients with AH and heavy drinkers without disease. We will make use of state of the art bioinformatics, including rare variant analysis, analysis of tracts of homozygosity and gene/environment interactions, to identify the genetic underpinnings for the risk for:1) Susceptibility to severe alcoholic hepatitis, 2) Risk for early mortality from AH, 3) Response to therapy and 4) 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.
