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

By N. Abul-Husn, Xi-ping Cheng, Alexander Hanbo Li, Yurong Xin, C. Schurmann, P. Stevis, Yashu Liu, J. Kozlitina, S. Stender, C. Wood and 38 more. New England Journal of Medicine, 2018

665 citations recorded by the source corpus.

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 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 associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk‐increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS 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.)

Subfields: Epidemiology, Genetics, Hepatology

View Paper: https://www.semanticscholar.org/paper/0948e47234d66b8f909580a55b0d521ce103a7d3

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In Epidemiology

1. S. Friedman
2. Gerald I. Shulman
3. G. Szabo
4. R. Loomba
5. Y. Saiman
6. J. Puche
7. J. Bonner
8. D. Clegg

In Genetics

1. S. Friedman

In Hepatology

1. S. Friedman
2. Gerald I. Shulman
3. R. Loomba
4. Y. Saiman
5. J. Puche
6. J. Bonner

Citations in the corpus

• Mechanisms and disease consequences of nonalcoholic fatty liver disease (2021, background): “Similar to PNPLA3, a new disease mechanism has been suggested by discovery of a variant of 17-beta hydroxysteroid dehydrogenase 13, encoded by the HSD17B13 gene, a poorly characterized enzyme present in hepatocytes (Abul-Husn et al., 2018).”
• Diagnosis and Treatment of Alcohol‐Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases (2020, positive): “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.(110) Co-e”