A genetic basis of mitochondrial DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide but only a subset of NAFLD individuals may progress to nonalcoholic steatohepatitis (NASH). While NASH is an important etiology of hepatocellular carcinoma (HCC), the underlying mechanisms responsible for conversion of NAFLD to NASH, and then to HCC are poorly understood. We aimed to identify genetic risk genes that drive NASH and NASH-related HCC. Approach and Results: We searched genetic alleles among the 24 most significant alleles associated with body fat distribution from a genome-wide association study of 344,369 individuals and validated the top allele in three independent cohorts of American and European patients (N=1,380) with NAFLD/NASH/HCC. We identified a rs3747579-TT variant significantly associated with NASH-related HCC and demonstrated that rs3747579 is eQTL of a mitochondrial DNAJA3. We also found that rs3747579-TT and a previously identified PNPLA3 as a functional variant of NAFLD to have a significant additional interactions with NASH/HCC risk. HCC patients with rs3747579-TT had a reduced expression of DNAJA3 and had an unfavorable prognosis. Furthermore, mice with hepatocyte-specific Dnaja3 depletion developed NASH-dependent HCC either spontaneously under a normal diet or enhanced by diethylnitrosamine. Dnaja3-deficient mice developed NASH/HCC characterized by significant mitochondrial dysfunction, which was accompanied by excessive lipid accumulation and inflammatory responses. The molecular features of NASH/HCC in the Dnaja3 deficient mice were closely associated with human NASH/HCC. Conclusion: We uncovered a genetic basis of DNAJA3 as a key player of NASH-related HCC.