Severe alcoholic hepatitis is a florid presentation of alcohol-related liver disease and is associated with very high short-term mortality, in excess of 20% within 28 days. Severe alcoholic hepatitis occurs in a minority of patients who develop alcohol-related liver disease. A combination of genetic and environmental factors is likely to predispose to severe alcoholic hepatitis. To date the clinical phenotype has not been extensively examined in candidate gene studies and has been the subject of a single, small genome-wide association study. A genome-wide association study of severe alcoholic hepatitis identified two loci potentially associated with the risk of developing severe alcoholic hepatitis: i) A strong association with PNPLA3, a well-recognised risk locus for alcohol-related liver disease, and ii) a novel but weaker association with SLC38A4, an amino acid transporter. The primary genetic variant at each locus was evaluated to determine whether there was an influence on disease phenotype or outcome. The primary variant in PNPLA3, rs738409, is a missense variant. Analyses indicated a deleterious effect of homozygosity on medium-term survival in addition to more severe disease on baseline histology and a slower recovery in liver function over the short-term period; consistent with established literature in alcohol-related cirrhosis. In contrast the primary variant in SLC38A4, rs11183620, is intronic with no clear evidence for an effect on gene expression or function. Analyses did not indicate an influence on histology, clinical phenotypes or outcomes. In light of the locus’ novelty further work was undertaken to determine any potential contribution to disease pathogenesis. SLC38A4 was down-regulated in whole liver tissue in severe alcoholic hepatitis. Experiments with cell lines in culture suggested the pro-inflammatory cytokine IL-1 as a potential driver. SLC38A4 knockdown resulted in upregulation of some cellular responses associated with nutrient deprivation. There was no influence of the variant on serum amino acid profiles. The functional significance of SLC38A4 down-regulation remains the subject of ongoing work.