A protein-truncating HSD17B13 variant and protection from chronic liver disease.

Authors: Abul-Husn, Noura S and Cheng, Xiping and Li, Alexander H and Xin, Yurong and Schurmann, Claudia and Stevis, Panayiotis and Liu, Yashu and Kozlitina, Julia and Stender, Stefan and Wood, G Craig and Stepanchick, Ann N and Still, Matthew D and McCarthy, Shane and O'Dushlaine, Colm and Packer, Jonathan S and Balasubramanian, Suganthi and Gosalia, Nehal and Esopi, David and Kim, Sun Y and Mukherjee, Semanti and Lopez, Alexander E and Fuller, Erin D and Penn, John and Chu, Xin and Luo, Jonathan Z and Mirshahi, Uyenlinh L and Carey, David J and Still, Christopher D and Feldman, Michael D and Small, Aeron and Damrauer, Scott M and Rader, Daniel J and Zambrowicz, Brian and Olson, William and Murphy, Andrew J and Borecki, Ingrid B and Shuldiner, Alan R and Reid, Jeffrey G and Overton, John D and Yancopoulos, George D and Hobbs, Helen H and Cohen, Jonathan C and Gottesman, Omri and Teslovich, Tanya M and Baras, Aris and Mirshahi, Tooraj and Gromada, Jesper and Dewey, Frederick E

Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets.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.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.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.).

Journal: The New England journal of medicine
DOI: 10.1056/NEJMoa1712191
Year: 2018

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