A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?

Abstract

Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in 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 (<i>PNPLA3</i> rs738409; <i>TM6SF2</i> rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes (<i>MICA</i> rs2596542; <i>CD44</i> rs187115; <i>PDCD1</i> rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. <i>PNPLA3</i> and <i>TM6SF2</i> SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while <i>PDCD1</i> SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. <i>PDCD1</i> rs7421861 was independently associated with NAFLD-HCC development, while <i>PDCD1</i> rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The 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.