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

Eldafashi, Nardeen, Darlay, Rebecca, Shukla, Ruchi, McCain, Misti Vanette, Watson, Robyn, Liu, Yang Lin, McStraw, Nikki, Fathy, Moustafa, Fawzy, Michael Atef, Zaki, Marco Y. W., Daly, Ann K., Maurício, João P., Burt, Alastair D., Haugk, Beate, Cordell, Heather J., Bianco, Cristiana, Dufour, Jean-François, Valenti, Luca, Anstee, Quentin M. and Reeves, Helen L. (2021) A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC? Cancers, 13 (6). p. 1412. ISSN 2072-6694

cancers-13-01412.pdf - Published Version
Available under License Creative Commons Attribution 4.0.

Download (1MB) | Preview
Official URL: https://doi.org/10.3390/cancers13061412


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.

Item Type: Article
Additional Information: Funding Information: Patient recruitment in Newcastle was supported by the European Community’s Seventh Framework Programme (FP7/2010-2013) under grant agreement HEALTH-F2-2009-241762 for the project FLIP, the CR UK Newcastle Experimental Cancer Medicine Center award (C9380/A18084) and CR UK programme grant C18342/A23390, as well as the European Community’s Horizon 2020 Programme (EPoS Grant Agreement 634413), IMI2 (LITMUS Grant Agreement 777377) and the European NAFLD Registry. HLR, MMC, RW and QMA were supported by the CR UK HUNTER Accelerator (C9380/A26813). RS is supported by Newcastle University Research Fellowship. LV was also supported by Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, the European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS, and Programme “Photonics” under grant agreement “101016726” for the project REVEAL; Fondazione IRCCS Ca’ Granda “Ricerca corrente”, Fondazione Sviluppo Ca’ Granda (PR-0391, RC100017A).
Uncontrolled Keywords: Genetic predisposition, Hepatocellular carcinoma, Metabolic syndrome, PD-1, PDCD1, PNPLA3, Primary liver cancer, Single-nucleotide polymorphism, TM6SF2
Subjects: C400 Genetics
C500 Microbiology
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Rachel Branson
Date Deposited: 16 Feb 2023 14:33
Last Modified: 16 Feb 2023 14:45
URI: https://nrl.northumbria.ac.uk/id/eprint/51418

Actions (login required)

View Item View Item


Downloads per month over past year

View more statistics