Genetics of Alcoholic Liver Disease

Alcoholic liver disease (ALD) accounts for over fifty percent of all chronic liver diseases in industri-alized countries and is responsible for &>; 25,000 deaths in 2005 in the United States alone. ALD comprises a spectrum of liver injury ranging from simple steatosis to alcohol-induced fibrosis and cirrhosis, either with or without inflammation. While many heavy drinkers have steatosis, only 10-35 % develop hepatic inflammation and 10-20% progress to cirrhosis. Progression of ALD is modu-lated by environmental factors such as gender, obesity and coinfection with chronic viral hepatitis. Twin studies suggested that up to 50% of the risk of cirrhosis in alcoholics is determined by genetic factors. The search for genetic factors that modulate the progression of ALD has resulted in abun-dant data from candidate gene case control studies which, however, have not been confirmed in independent replication cohorts. A highly topical finding con-stitutes the recent identification of genetic variants in PNPLA3 as risk factors for advanced ALD in ethnically admixed Mestizo subjects. We have recently confirmed this for Caucasian alcoholics in a large candidate gene study and estimated the population attributable fraction at ~25% indicating that the remaining risk is governed by yet unidentified genetic factors. Herewith, a systematic genetic search for yet unknown susceptibility variants of ALD shall be combined with a focused translational program of human disease genes into suitable animal models. Specifically, a genome-wide association analysis in 500 cases of alcoholic liver cirrhosis and 700 alcoholics without rele-vant liver injury using the Illumina OmniExpress array (700K) (AIM1) is projected. Replication of the top 100 leads will be performed in independent 800 cases of alcoholic cirrhosis and compared to 1300 alcoholics without relevant liver injury (AIM2). The relevance of the identified variants shall be evaluated further in ~13,000 Danish individuals from the MONICA cohorts with standardized alco-hol history, information on the presence of cirrhosis in the 10 year follow-up and longitudinal ALT levels. In addition, ~10,000 individuals from North East Germany with detailed sonographic and MRI liver phenotypes will be analyzed (AIM3). Targeted deep sequencing will be used to identify causal variants at two loci, followed by genotyp-ing in the large patient cohorts as appropriate (AIM4). To provide guidance for in-vivo experiments, genotyped frozen human liver tissues shall be used to assess the tissue distribution and expression of the genes at the risk loci (AIM5). Starting with PNPLA3, the impact of risk genes shall be evaluated using appropriate animal models of ALD in knock-out mice (AIM6), which will further direct deep sequencing (AIM4). Finally, identified genetic variants shall be tested as predictors of fibrosis progression in populationbased cohorts of alcoholics, and other chronic fibrosing liver disorders (AIM7). The research is structured as a Swiss/German/Austrian consortium since this generates access to unique patient collections, expertise and infrastructure required for systematic genetic mapping, in vivo functional and clinical translation.