title: IFNL4 ss469415590 polymorphism contributes to treatment decisions in patients with chronic hepatitis C virus genotype 1b, but not 2a, infection.
abstract: Recently, the dinucleotide variant ss469415590 (TT/ΔG) in a novel gene, interferon lambda 4 (IFNL4), was identified as a stronger predictor of hepatitis C virus (HCV) clearance in individuals of African ancestry compared with rs12979860. We aimed to determine whether this variant contributes to treatment decisions in a Chinese population. A total of 447 chronic hepatitis C (CHC) patients (including 328 treated with interferon alpha-2b and ribavirin), 129 individuals who had spontaneously cleared HCV (SHC), and 169 healthy controls were retrospectively investigated. ss469415590 genotyping was performed using a mass spectrometry method (SEQUENOM). A higher proportion of SHC individuals carried the TT/TT genotype compared with CHC patients (95.3% vs. 88.8%, P=0.027). In patients with HCV genotype 1b, the ss469415590 variant was independently associated with sustained virologic response (SVR) (odds ratio [OR]=3.247, 95% confidence interval [CI]=1.038-10.159, P=0.043) and on-treatment virological responses, including rapid (RVR), complete early (cEVR), early (EVR), and end-of-treatment (ETVR), with a minimal OR of 3.73. Especially for patients with high viral load (≥4×10(5) IU/ml), ΔG allele carriers had a lower chance of achieving SVR compared with those carrying the TT/TT genotype (7.1% vs. 36.0%, P=0.034, OR [95% CI]=7.24 [1.02-318.45], negative predictive value=92.9%). In patients with HCV genotype 2a, no significant association between the ss154949590 variant and the virological response was identified (P>0.05). Additionally, we found that ss154949590 was in complete linkage disequilibrium with rs12979860. In conclusion, the IFNL4 ss154949590 TT/TT genotype favors spontaneous clearance of HCV. This same variant is associated with treatment-induced clearance in patients with genotype 1b, but not 2a. ss469415590 (or rs12979860) genotyping should be considered for patients with HCV genotype 1b and high viral load when making a choice between standard dual therapy and an IFN-free direct-acting antiviral regimen.
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Ruihong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Chi
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Lv
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Xiuzhu
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Kong
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Hua
authors.affiliation: Department of Clinical Epidemiology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Street, Shanghai 200031, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
authors.affiliation: Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Street, Shanghai 200031, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China. Electronic address: panyu20000@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China. Electronic address: junqiniu@aliyun.com.
authors.forename: Junqi
authors.initials: J
authors.lastname: Niu
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D002681:China; D005260:Female; D016174:Hepacivirus / Q000145:classification / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012189:Retrospective Studies; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007378:Interleukins; D011994:Recombinant Proteins; D012254:Ribavirin; C579163:IFNL4 protein, human; D000095022:Interferon Lambda
keywords: Hepatitis C virus; IFNL4; Spontaneous clearance; Treatment outcome