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.

中文翻译：

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非酒精性脂肪性肝炎相关肝细胞癌中线粒体 DNAJA3 的遗传基础。

背景目的非酒精性脂肪肝病（NAFLD）是全世界最常见的肝病形式，但只有一部分 NAFLD 个体可能进展为非酒精性脂肪性肝炎（NASH）。虽然 NASH 是肝细胞癌 (HCC) 的重要病因，但 NAFLD 转化为 NASH，然后转化为 HCC 的潜在机制尚不清楚。我们的目的是识别驱动 NASH 和 NASH 相关 HCC 的遗传风险基因。方法和结果 我们在一项涉及 344,369 名个体的全基因组关联研究中搜索了与身体脂肪分布相关的 24 个最重要等位基因中的遗传等位基因，并在美国和欧洲 NAFLD/NAFLD 患者 (N=1,380) 的三个独立队列中验证了最重要的等位基因。非酒精性脂肪性肝炎/肝癌。我们鉴定了与 NASH 相关 HCC 显着相关的 rs3747579-TT 变体，并证明 rs3747579 是线粒体 DNAJA3 的 eQTL。我们还发现 rs3747579-TT 和先前鉴定为 NAFLD 功能变异的 PNPLA3 与 NASH/HCC 风险具有显着的额外相互作用。rs3747579-TT的HCC患者DNAJA3表达降低，预后不良。此外，肝细胞特异性 Dnaja3 耗竭的小鼠在正常饮食下自发发生 NASH 依赖性 HCC，或在二乙基亚硝胺的作用下增强。Dnaja3缺陷小鼠出现NASH/HCC，其特征是显着的线粒体功能障碍，并伴有过度的脂质积累和炎症反应。Dnaja3缺陷小鼠的NASH/HCC分子特征与人类NASH/HCC密切相关。结论 我们发现了 DNAJA3 作为 NASH 相关 HCC 关键参与者的遗传基础。