A newly identified gene variant reduces risk of chronic liver disease (CLD) and cirrhosis, according to a new study.
CLD and cirrhosis are important global causes of morbidity and mortality. Whereas the environmental factors contributing to the development and progression of CLD, such as alcohol and viral hepatitis, are well-understood, a large proportion of the genetic risk component is either unexplained or poorly characterized. For instance, the mechanisms underlying the association between PNPLA3 sequence variance and increased risk of NAFLD and cirrhosis remain unclear a decade after this relationship was first reported.
To identify additional genetic associations with CLD, Abul-Husn and colleagues tested exome sequence data from 46,544 individuals (median BMI 30 kg/m2) for associations between single-nucleotide polymorphisms and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This analysis uncovered a novel association between a variant in HSD17B13, which encodes hydroxysteroid 17-β dehydrogenase 13, and decreased ALT and AST levels. The variant allele (allele frequency 26%) was also negatively associated with CLD: in heterozygotes, risk of alcoholic cirrhosis and nonalcoholic cirrhosis was decreased 42% and 26% respectively; for homozygotes, the respective risk reductions were 73% and 49%. Notably, the variant was not associated with simple steatosis, suggesting that it mitigates CLD progression.
Functional analyses revealed that HSD17B13 was enriched on membranes surrounding lipid droplets in human hepatocyte cell lines. The HSD17B13 variant was found to alter mRNA splicing, yielding a truncated protein with reduced enzymatic activity against the experimentally determined enzymatic substrates of HSD17B13, steroids (such as estradiol) and bio-active lipids (such as leukotriene B4). These findings suggest that modulating HSD17B13 activity could be a therapeutic target for treating CLD.
Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J Med. 378, 1096–1106 (2018)
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Thomas, H. An HSD17B13 variant reduces cirrhosis risk. Nat Rev Gastroenterol Hepatol 15, 328 (2018). https://doi.org/10.1038/s41575-018-0016-7