The relationships between IFNL4 genotype, intrahepatic interferon‐stimulated gene expression and interferon treatment response differs in HCV‐1 compared with HCV‐3. Issue 3 (1st June 2015)

• Record Type: Journal Article
• Authors: Holmes, J. A.; Congiu, M.; Bonanzinga, S.; Sandhu, M. K.; Kia, Y. H.; Bell, S. J.; Nguyen, T.; Iser, D. M.; Visvanathan, K.; Sievert, W.; Bowden, D. S.; Desmond, P. V.; Thompson, A. J.
• Is Part Of: Alimentary pharmacology & therapeutics. Volume 42:Issue 3(2015)
• Page Start: 296
• Page End: 306
• Publication Date: 2015-06-01
• Subjects: Digestive organs -- Diseases -- Treatment -- Periodicals; Digestive organs -- Effect of drugs on -- Periodicals; Gastrointestinal system -- Diseases -- Treatment -- Periodicals; Gastrointestinal system -- Effect of drugs on -- Periodicals; 615.73
• DOI: 10.1111/apt.13263
• Languages: English
• ISSNs: 0269-2813

Abstract

<abstract abstract-type="main" id="apt13263-abs-0001"> <title>Summary</title> <sec id="apt13263-sec-0001" sec-type="section"> <title>Background</title> <p>The biological mechanism underlying the association between <italic>IFNL4/IFNL3</italic> 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 <italic>IFNL4</italic> polymorphism, PR treatment response and liver interferon‐stimulated gene expression in HCV‐3.</p> </sec> <sec id="apt13263-sec-0002" sec-type="section"> <title>Aim</title> <p>We evaluated the association between <italic>IFNL4/IFNL3</italic> genotypes, PR treatment outcomes and intrahepatic interferon‐stimulated gene expression, according to HCV genotype.</p> </sec> <sec id="apt13263-sec-0003" sec-type="section"> <title>Methods</title> <p>HCV‐1 and HCV‐3 patients who received PR therapy were identified. <italic>IFNL3</italic> (rs12979860) and <italic>IFNL4</italic> genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt‐PCR.</p> </sec> <sec id="apt13263-sec-0004" sec-type="section"> <title>Results</title> <p>Two hundred and fifty‐nine patients were identified: 55% HCV‐1, 45% HCV‐3. <italic>IFNL4</italic> genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with <italic>IFNL3</italic> genotype was high (<italic>r</italic><sup>2</sup><italic> </italic>=<italic> </italic>0.98). The association between <italic>IFNL4</italic> 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/ΔG vs. ΔG/ΔG, <italic>P</italic> = 0.09; HCV‐1: SVR: 82% vs. 29% vs. 24%, <italic>P</italic> < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV‐1. The association between <italic>IFNL4</italic> genotype and liver ISG expression was significantly different for HCV‐3 vs. HCV‐1 (<italic>P</italic>‐value for interaction = 0.046), with levels of interferon‐stimulated gene expression being highest in HCV‐1 patients who carried a poor‐response <italic>IFNL4</italic> genotype.</p> </sec> <sec id="apt13263-sec-0005" sec-type="section"> <title>Conclusions</title> <p>The relationship between <italic>IFNL4</italic> 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.</p> </sec> </abstract>