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Constitutional, environmental, and genetic risk factors influence the development of alcohol-related cirrhosis. The amount of alcohol consumed and whether excessive drinking continues after the identification of pre-cirrhotic liver damage are key risk factors. Female sex, ethnicity, obesity, coffee consumption, cigarette smoking, and exposure to other causes of liver injury also influence the risk of disease development. More recently several genetic loci have been robustly associated with the risk for developing significant alcohol-related liver disease. It remains unclear whether additional risk factors are involved in the development of the clinical syndrome of alcoholic hepatitis, but the genetic evidence is suggestive.

Introduction Alcoholic liver disease (ALD) is a complex disorder, resulting from the interplay of environmental and genetic factors. Severe alcoholic hepatitis (AH) is an acute clinical manifestation of ALD, which has a high associated mortality but develops in only a minority of patients, estimated to be Methods Cases with severe AH were recruited from the UK Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial (n = 812). Controls with a history of alcohol dependence but without evidence of significant liver injury were recruited from the Centre of Hepatology, Royal Free Hospital, London (n = 936). All participants were of white British/Irish descent. DNA was genotyped using two platforms Illumina HumanCoreExome BeadChip (Illumina, San Diego, USA) and Illumina PsychArray Beadchip (Illumina, San Diego, USA). Separate GWAS analyses were undertaken on each array using Plink v1.9 followed by meta-analysis in METAL. MAGMA gene and gene-set analyses were carried out using FUMA. Results The variant rs738409 in PNPLA3 was associated with severe AH at genome-wide significance (PTHRESHOLD Conclusions The pivotal role of PNPLA3:rs738409 in determining the risk for developing severe AH was confirmed in this study. In addition, potential risk loci were identified in ATP2C2, which encodes a Mn+/Ca2+ transporter and is highly expressed in the gastrointestinal tract; PHYH which is implicated in phytanic acid metabolism; phytanic acid binds to and/or activates the transcription factors PPAR-alpha and retinoid X receptor; and ANGPT1 which encodes the angiogenic promoter angiopoietin 1. Additionally, a number of potential pathways were identified, through gene set analysis, which appear to be involved in severe AH, influencing lipid metabolism and inflammation. These novel findings open new avenues for investigation and therapeutic endeavour.