The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3

Jacinta A Holmes, Mario Congiu, Sara Bonanzinga, Manjeet K Sandhu, Y H Kia, Sally J Bell, Tin Nguyen, David M Iser, Kumar Visvanathan, William Sievert, David Scott Bowden, Paul V Desmond, Alexander James V Thompson

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Abstract

BACKGROUND: The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM: We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. METHODS: HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS: Two hundred and fifty-nine patients were identified: 55 HCV-1, 45 HCV-3. IFNL4 genotype frequency was TT/TT 44 , TT/DeltaG 42 andDeltaG/DeltaG 14 . Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89 vs. 76 vs. 72 for TT/TT vs. TT/DeltaG vs. DeltaG/DeltaG, P = 0.09; HCV-1: SVR: 82 vs. 29 vs. 24 , P <0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61 HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS: The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.
Original languageEnglish
Pages (from-to)296 - 306
Number of pages11
JournalAlimentary Pharmacology and Therapeutics
Volume42
Issue number3
DOIs
Publication statusPublished - 2015

Cite this

Holmes, Jacinta A ; Congiu, Mario ; Bonanzinga, Sara ; Sandhu, Manjeet K ; Kia, Y H ; Bell, Sally J ; Nguyen, Tin ; Iser, David M ; Visvanathan, Kumar ; Sievert, William ; Bowden, David Scott ; Desmond, Paul V ; Thompson, Alexander James V. / The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3. In: Alimentary Pharmacology and Therapeutics. 2015 ; Vol. 42, No. 3. pp. 296 - 306.
@article{fc6eb5d5a40d4d848d619cb46f9854b0,
title = "The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3",
abstract = "BACKGROUND: The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM: We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. METHODS: HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS: Two hundred and fifty-nine patients were identified: 55 HCV-1, 45 HCV-3. IFNL4 genotype frequency was TT/TT 44 , TT/DeltaG 42 andDeltaG/DeltaG 14 . Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89 vs. 76 vs. 72 for TT/TT vs. TT/DeltaG vs. DeltaG/DeltaG, P = 0.09; HCV-1: SVR: 82 vs. 29 vs. 24 , P <0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61 HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS: The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.",
author = "Holmes, {Jacinta A} and Mario Congiu and Sara Bonanzinga and Sandhu, {Manjeet K} and Kia, {Y H} and Bell, {Sally J} and Tin Nguyen and Iser, {David M} and Kumar Visvanathan and William Sievert and Bowden, {David Scott} and Desmond, {Paul V} and Thompson, {Alexander James V}",
year = "2015",
doi = "10.1111/apt.13263",
language = "English",
volume = "42",
pages = "296 -- 306",
journal = "Alimentary Pharmacology and Therapeutics",
issn = "0269-2813",
publisher = "Wiley-Blackwell",
number = "3",

}

Holmes, JA, Congiu, M, Bonanzinga, S, Sandhu, MK, Kia, YH, Bell, SJ, Nguyen, T, Iser, DM, Visvanathan, K, Sievert, W, Bowden, DS, Desmond, PV & Thompson, AJV 2015, 'The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3', Alimentary Pharmacology and Therapeutics, vol. 42, no. 3, pp. 296 - 306. https://doi.org/10.1111/apt.13263

The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3. / Holmes, Jacinta A; Congiu, Mario; Bonanzinga, Sara; Sandhu, Manjeet K; Kia, Y H; Bell, Sally J; Nguyen, Tin; Iser, David M; Visvanathan, Kumar; Sievert, William; Bowden, David Scott; Desmond, Paul V; Thompson, Alexander James V.

In: Alimentary Pharmacology and Therapeutics, Vol. 42, No. 3, 2015, p. 296 - 306.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3

AU - Holmes, Jacinta A

AU - Congiu, Mario

AU - Bonanzinga, Sara

AU - Sandhu, Manjeet K

AU - Kia, Y H

AU - Bell, Sally J

AU - Nguyen, Tin

AU - Iser, David M

AU - Visvanathan, Kumar

AU - Sievert, William

AU - Bowden, David Scott

AU - Desmond, Paul V

AU - Thompson, Alexander James V

PY - 2015

Y1 - 2015

N2 - BACKGROUND: The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM: We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. METHODS: HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS: Two hundred and fifty-nine patients were identified: 55 HCV-1, 45 HCV-3. IFNL4 genotype frequency was TT/TT 44 , TT/DeltaG 42 andDeltaG/DeltaG 14 . Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89 vs. 76 vs. 72 for TT/TT vs. TT/DeltaG vs. DeltaG/DeltaG, P = 0.09; HCV-1: SVR: 82 vs. 29 vs. 24 , P <0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61 HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS: The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.

AB - BACKGROUND: The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM: We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. METHODS: HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS: Two hundred and fifty-nine patients were identified: 55 HCV-1, 45 HCV-3. IFNL4 genotype frequency was TT/TT 44 , TT/DeltaG 42 andDeltaG/DeltaG 14 . Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89 vs. 76 vs. 72 for TT/TT vs. TT/DeltaG vs. DeltaG/DeltaG, P = 0.09; HCV-1: SVR: 82 vs. 29 vs. 24 , P <0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61 HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS: The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.

UR - http://onlinelibrary.wiley.com/doi/10.1111/apt.13263/pdf

U2 - 10.1111/apt.13263

DO - 10.1111/apt.13263

M3 - Article

VL - 42

SP - 296

EP - 306

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

SN - 0269-2813

IS - 3

ER -