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

doi:10.3390/cancers13061412

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 language	English
Article number	1412
Number of pages	17
Journal	Cancers
Volume	13
Issue number	6
DOIs	https://doi.org/10.3390/cancers13061412
Publication status	Published - 19 Mar 2021
Externally published	Yes

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers13061412Licence: CC BY

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Cite this

Eldafashi, N., Darlay, R., Shukla, R., McCain, M. V., Watson, R., Liu, Y. L., McStraw, N., Fathy, M., Fawzy, M. A., Zaki, M. Y. W., Daly, A. K., Maurício, J. P., Burt, A. D., Haugk, B., Cordell, H. J., Bianco, C., Dufour, J. F., Valenti, L., Anstee, Q. M., & Reeves, H. L. (2021). A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC? Cancers, 13(6), Article 1412. https://doi.org/10.3390/cancers13061412

@article{338ceb493aa5432d8e03099be841f5f5,

title = "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 (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.",

keywords = "Genetic predisposition, Hepatocellular carcinoma, Metabolic syndrome, PD-1, PDCD1, PNPLA3, Primary liver cancer, Single-nucleotide polymorphism, TM6SF2",

author = "Nardeen Eldafashi and Rebecca Darlay and Ruchi Shukla and McCain, {Misti Vanette} and Robyn Watson and Liu, {Yang Lin} and Nikki McStraw and Moustafa Fathy and Fawzy, {Michael Atef} and Zaki, {Marco Y.W.} and Daly, {Ann K.} and Maur{\'i}cio, {Jo{\~a}o P.} and Burt, {Alastair D.} and Beate Haugk and Cordell, {Heather J.} and Cristiana Bianco and Dufour, {Jean Fran{\c c}ois} and Luca Valenti and Anstee, {Quentin M.} and Reeves, {Helen L.}",

note = "Funding Information: Patient recruitment in Newcastle was supported by the European Community{\textquoteright}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{\textquoteright}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{\textquoteright} 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{\textquoteright} Granda “Ricerca corrente”, Fondazione Sviluppo Ca{\textquoteright} Granda (PR-0391, RC100017A).",

year = "2021",

month = mar,

day = "19",

doi = "10.3390/cancers13061412",

language = "English",

volume = "13",

journal = "Cancers",

issn = "2072-6694",