A Protein-TruncatingHSD17B13Variant and Protection from Chronic Liver Disease

Abstract

A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).

Diagnosis and Treatment of Alcohol‐Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases

“…PNPLA3 and TM6SF2 polymorphisms are also associated with increased risk of HCC in ALD . Most recently, Abul‐Husn et al described a polymorphism related to a hepatic lipid droplet protein hydroxysteroid 17‐beta dehydrogenase 13 ( HSD17B13 ), the presence of which confers protection against the progression from steatosis to steatohepatitis in alcohol‐associated and non‐alcohol‐associated chronic liver disease …”

Genetics Meets Therapy? Exome‐wide Association Study Reveals a Loss‐of‐Function Variant in 17‐Beta‐Hydroxysteroid Dehydrogenase 13 That Protects Patients From Liver Damage and Nonalcoholic Fatty Liver Disease Progression

“…Among the 502,219 variants initially tested for association with aminotransferase levels, there were 35 variants in 19 target genes that reached exome‐wide significance ( p < 1 × 10 –7 ) in the discovery cohort. Further replication in ~12,527 persons led to refinement of 13 variants in nine genes, which not surprisingly included not only PNPLA3 , TM6SF2 , SERPINA1 , SAMM50 , and ERLIN1 but GPT , GOT1 (the genes encoding ALT and AST), and SLC39A12 . The rs72613567:TA variant of HSD17B13 was found to be reproducibly associated with decreased levels of ALT and AST and with lower odds of both NAFLD and ALD disease severity.…”

“…Armed with exome‐sequence data coupled to electronic health records of 46,455 participants from a large collaborative study, Abul‐Husn and colleagues explored variants associated with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, which were primarily regarded as surrogate indicators of liver damage . The study design consisted of subsequent stages of validation and replication, including functional exploration of the variant at the gene and protein levels that involved RNA sequencing and assessment of HSD17B13 enzymatic activity, respectively . Among the 502,219 variants initially tested for association with aminotransferase levels, there were 35 variants in 19 target genes that reached exome‐wide significance ( p < 1 × 10 –7 ) in the discovery cohort.…”

“…A new study by Abul‐Husn et al reveals that a loss‐of‐function variation in the 17‐beta‐hydroxysteroid dehydrogenase 13 ( HSD17B13 ) gene confers protection against chronic liver injury and mitigates the progression of NAFLD and ALD in European Americans . These new findings open the possibility that therapeutic inhibition of HSD17B13 could represent a new strategy to treat NAFLD and ALD.…”

Future directions for high‐throughput splicing assays in precision medicine

“…MyCode participants are also consented for recontact for additional research which allows for additional clinical evaluation with more targeted phenotyping to supplement the rich data set that already exists in the EHR. DiscovEHR has already been proven to be a tremendous resource for genomic discovery (Abul‐Husn et al, ; Gusarova et al, ; Verma et al, ).…”