الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise of deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver (PNPLA3 rs738409; TM6SF2 rs58542926).
Here we have considered single nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes (MICA rs2596542; CD44 rs187115; PDCD1 rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from 3 European centres to highlight the significance of SNP variation in immunoregulatory genes in the development of HCC on the background of NAFLD. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored.
This study reproduced the predictive role of PNPLA3 and TM6SF2 on HCC development. In addition, the study statistically proved that both PNPLA3 minor allele G and TM6SF2 minor allele T SNPs predisposed to liver cirrhosis that is the main risk factor for the development of HCC. PNPLA3 and TM6SF2 SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while PDCD1 SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. PDCD1 rs7421861 was independently associated with NAFLD-HCC development in prescence of other confounding factors like age,sex,T2DM,BMI and cirrhosis; the major allele A increases the risk of NAFLD/HCC development and the minor allele shows protective effect even in NC cohort.
However, PDCD1 rs10204525 minor allele T acquired significance after adjusting for other risks even in condition with other risk SNPs, PNPLA3 and TM6SF2, being most notable in the smaller numbers of women with NAFLD-HCC. Our study highlights the potential impact of inter-individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis.
Thus, the core and novel finding of this study was, however, the pivotal role of PDCD1 SNPs in the development and progression of HCC. Regardless to the presence of well-established cirrhosis, the presence of PDCD1 SNPs predicted the development of HCC. Moreover, both PDCD1 SNPs were associated with the expression of the immune exhaustion marker PD1 and with different splicing variants that may have different functions in the process of T-cell exhaustion and anti-tumour immunity.
Figure 16: Graphical abstract summarizing the key findings of the present study.