IFNL3/4 genotype is associated with altered immune cell populations in peripheral blood in chronic hepatitis C infection.
Single-nucleotide polymorphisms near the interferon lambda 3 (IFNL3) gene predict outcomes to infection and anti-viral treatment in hepatitis C virus (HCV) infection. To identify IFNL3 genotype effects on peripheral blood, we collected phenotype data on 400 patients with genotype 1 chronic hepatitis C (CHC). The IFNL3 responder genotype predicted significantly lower white blood cells (WBCs), as well as lower absolute numbers of monocytes, neutrophils and lymphocytes for both rs8099917 and rs12979860. We sought to define the WBC subsets driving this association using flow cytometry of 67 untreated CHC individuals. Genotype-associated differences were seen in the ratio of CD4CD45RO+ to CD4CD45RO-; CD8CD45RO+ to CD8CD45RO-, NK CD56 dim to bright and monocyte numbers and percentages. Whole blood expression levels of IFNL3, IFNLR1 (interferon lambda receptor 1), IFNLR1-mem (a membrane-associated receptor), IFNLR1-sol (a truncated soluble receptor), MxA and T- and NK (natural killer) cell transcription factors TBX21, GATA3, RORC, FOXP3 and EOMES in two subjects were also determined. CHC patients demonstrated endogenous IFN activation with higher levels of MxA, IFNLR1, IFNLR1-mem and IFNLR1-sol, and IFNL3 genotype-associated differences in transcription factors. Taken together, these data provide evidence of an IFNL3 genotype association with differences in monocyte, T- and NK cell levels in the peripheral blood of patients with CHC. This could underpin genotype associations with spontaneous and treatment-induced HCV clearance and hepatic necroinflammation.
Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
K S
KS
O'Connor
Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
S A
SA
Read
Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
M
M
Wang
Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
S
S
Schibeci
Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
M
M
Eslam
Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.|Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney and Westmead Hospital, Sydney, NSW, Australia.
A
A
Ong
Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia.
M D
MD
Weltman
Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.|Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney and Westmead Hospital, Sydney, NSW, Australia.
M W
MW
Douglas
Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Palermo, Italy.
A
A
Mazzola
Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Palermo, Italy.
A
A
Craxì
Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Palermo, Italy.
S
S
Petta
Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
G J
GJ
Stewart
Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
C
C
Liddle
Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
J
J
George
Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
G
G
Ahlenstiel
Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
D R
DR
Booth
D000943:Antigens, Differentiation / Q000378:metabolism; D015331:Cohort Studies; D005434:Flow Cytometry; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D007694:Killer Cells, Natural / Q000166:cytology; D009000:Monocytes / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism; D019562:Viral Load; D000095022:Interferon Lambda
D000943:Antigens, Differentiation; D007372:Interferons; D007378:Interleukins; D014157:Transcription Factors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human