Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers

Abstract

Network funded by the German Federal Ministry for Education and Research (BmBF) to JH. HDN and US were supported by a grant from the Deutsche Krebshilfe (70112169).

Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

“…6 Twin studies suggest that there is a heritable component to alcohol-related liver disease, 7,8 yet genomewide association studies (GWAS) undertaken to date have identified only a handful of specific risk variants, including PNPLA3:rs738409, TM6SF2:rs58542926, MBOAT7:rs641738, and HSD17B13:rs72613567. [9][10][11][12] Two factors are likely to have limited the yield of GWAS studies for alcohol-related cirrhosis (and chronic liver disease in general) [9][10][11] : firstly, the lack of statistical power, and secondly, the limited range of endophenotypes used in discovery analyses. The development of alcohol-related cirrhosis is strongly underpinned by fibrogenesis, a process that causes substitution of the liver parenchyma with nonfunctional mesenchymal scar tissue.…”

HSD17B13 as a promising therapeutic target against chronic liver disease

“…8 The hepatoprotective effect of the variant has since been replicated in cohorts from Argentina, 9 the United States, 10 and several European countries. [11][12][13][14][15] In this issue of Liver International, Kallwitz and colleagues 16 What makes HSD17B13 an attractive drug target? A key question when evaluating any genetically identified drug target is to determine if the beneficial effect associated with the variant is due to loss or gain of function of the implicated gene.…”

Characterization of essential domains in HSD17B13 for cellular localization and enzymatic activity

“…Human genetic studies identified an association between the HSD17B13 gene and NASH (17,19,20), alcoholic liver disease (17,19), and hepatocellular carcinoma (HCC) (21,22). Enzymatically inactive protein mutants of HSD17B13, generated by genetic variants, confer protection from progression of fatty liver disease (17,19) confirming the importance of enzymatic activity of HSD17B13, although this protection was not seen in Hsd17b13-knock out mice (40).…”

“…HSD17B13 is a hepatic lipid-droplet associated enzyme with steroid substrates, bioactive lipids (19), and retinol (17) suggested as potential enzymatic substrates. Three independent genetic variants in HSD17B13 were found to confer protection from injury in NASH (17,19,20), alcoholic liver disease (17,19), and hepatocellular carcinoma (HCC) (21,22). We and others identified a splice-site single nucleotide polymorphism (SNP) rs72613567 that leads to the formation of two novel splicing variants (HSD17B13-G insertion and HSD17B13-Exon 6 deletion) (17,19,23); the non-synonymous SNP rs62305723 encodes a proline to serine mutation at amino acid position 260 (17); and the rs143404524 SNP leading to premature truncation (24).…”