A pdcd1 role in the genetic predisposition to nafld-hcc?

Nardeen Eldafashi, Rebecca Darlay, Ruchi Shukla, Misti Vanette McCain, Robyn Watson, Yang Lin Liu, Nikki McStraw, Moustafa Fathy, Michael Atef Fawzy, Marco Y.W. Zaki, Ann K. Daly, João P. Maurício, Alastair D. Burt, Beate Haugk, Heather J. Cordell, Cristiana Bianco, Jean François Dufour, Luca Valenti, Quentin M. Anstee, Helen L. Reeves

Research output: Contribution to journalArticlepeer-review

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 (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 three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. 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, while PDCD1 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.

Original languageEnglish
Article number1412
Pages (from-to)1-17
Number of pages17
JournalCancers
Volume13
Issue number6
DOIs
Publication statusPublished - Mar 2 2021

Keywords

  • Genetic predisposition
  • Hepatocellular carcinoma
  • Metabolic syndrome
  • PD-1
  • PDCD1
  • PNPLA3
  • Primary liver cancer
  • Single-nucleotide polymorphism
  • TM6SF2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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