A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease

Abstract Background Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. Methods We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. Results A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was found to be associated with reduced levels of ALT (P=4.2×10−12) and AST (P=6.2×10−10). Among DiscovEHR study participants, this variant was found to be associated with a re...