Clinical Trials Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2018; 24(20): 2191-2202
Published online May 28, 2018. doi: 10.3748/wjg.v24.i20.2191
Regulatory polymorphism of CXCL10 rs1439490 in seronegative occult hepatitis C virus infection
Xu Wang, Song Wang, Zhen-Hua Liu, Wen-Qian Qi, Qian Zhang, Yong-Gui Zhang, De-Rong Sun, Yan Xu, Hong-Guang Wang, Zhong-Xie Li, Xian-Ling Cong, Ping Zhao, Chang-Yu Zhou, Jiang-Bin Wang
Xu Wang, Zhen-Hua Liu, Wen-Qian Qi, Qian Zhang, Yong-Gui Zhang, Yan Xu, Ping Zhao, Chang-Yu Zhou, Jiang-Bin Wang, Department of Digestive, China-Japan Union Hospital Affiliated to Jilin University, Changchun 130033, Jilin Province, China
Song Wang, Department of Urology, First Hospital Affiliated to Jilin University, Changchun 130000, Jilin Province, China
De-Rong Sun, Department of Infectious Disease, the Fourth Affiliated University of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
De-Rong Sun, Department of Digestive, the Second People’s Hospital of Daqing City, Daqing 163461, Heilongjiang Province, China
Hong-Guang Wang, Department of Digestive, People’s Hospital of Jilin City, Changchun 132000, Jilin Province, China
Zhong-Xie Li, Department of Digestive, People’s Hospital of Hunchun City, Hunchun 133300, Jilin Province, China
Xian-Ling Cong, Department of Pathology, China-Japan Union Hospital Affiliated to Jilin University, Changchun 130033, Jilin Province, China
Author contributions: Wang X, Wang S, Liu ZH, Qi WQ and Wang JB designed the study; Wang X, Zhang Q and Wang JB collected and analyzed the data; Cong XL advised on histological staining and analysis; Wang S, Sun DR, Wang HG, Li ZX, Zhao P and Zhou CY contributed to sample collection and intellectual input; Wang X and Wang JB drafted and wrote the manuscript; Wang X, Liu ZH, Qi WQ, Xu Y and Zhang YG revised the manuscript critically for intellectual content; all authors provided intellectual input to the study and approved the final version of the manuscript.
Supported by the National Natural Science Foundation of China, No. 81670533; the Jilin Provincial Science & Technology Department, No. 2013 0102088JC; and the Jilin Provincial Development and Reform Commission, No. 2013C028-3.
Institutional review board statement: This study was approved by the Institutional Review Boards of individual centers. All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Clinical trial registration statement: Chinese Clinical Trial Registry (Registration number: ChiCTR-ONRC-12002207). The registration information can be found on the following website:
Informed consent statement: Written informed consent was obtained from all individual participants included in the study.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Jiang-Bin Wang, MD, PhD, Professor, Department of Digestive, China-Japan Union Hospital Affiliated to Jilin University, No.126 Xiantai Street, Changchun 130033, Jilin Province, China.
Telephone: +86-431-84995303 Fax: +86-431-84641026
Received: February 10, 2018
Peer-review started: February 11, 2018
First decision: March 9, 2018
Revised: March 30, 2018
Accepted: May 11, 2018
Article in press: May 11, 2018
Published online: May 28, 2018
Research background

In the past two decades, some patients with chronic hepatitis C virus (HCV) infection (CHC) have been shown to be seronegative for anti-HCV antibodies and RNA, but have intrahepatic HCV RNA in liver biopsy. However, the etiology of this occult HCV infection (OCI) remains unclear.

Research motivation

Seronegative OCI patients were reported to have significantly lower serum CXCL10 levels than patients with CHC. Polymorphisms in the CXCL10 promoter have been implicated in the genetic variation underlying the susceptibility to chronic HBV infection (CHB) progression in Chinese populations. Moreover, CHC and CHB induce similar liver lesions and fibrosis through continuous infiltration of inflammatory cells, but do not damage hepatocytes directly. These phenomena promoted our interest to examine whether CXCL10 G-201A underlies the disease manifestation of OCI.

Research objectives

To investigate the allele frequency of CXCL10 single nucleotide polymorphisms (SNPs) in patients with OCI and whether they are associated with the low levels of CXCL10 in OCI patients.

Research methods

We characterized the expression frequency of CXCL10 G-201A (rs1439490), C-1513T (rs1440802), and IL-28B rs12979860 in seronegative OCI and seropositive CHC patients in Northeastern China. Serum CXCL10 levels were measured by ELISA. Intrahepatic CXCL10 levels were determined by quantitative PCR and immunohistochemical semi-quantitative scoring. Liver necroinflammation and fibrosis were scored according to the METAVIR system. The associations of CXCL10 rs1439490 with CXCL10 levels and antiviral efficacy in OCI were analyzed.

Research results

CXCL10 G-201A G/G was more prevalent in seronegative OCI patients than in seropositive CHC patients. Serum CXCL10 levels were lower in OCI patients than in CHC patients, but did not differ significantly between IL-28B rs12979860 C/C and non-C/C patients. Of IL-28B rs12979860 C/C patients, OCI patients with CXCL10 G-201A G/G had lower serum and liver levels of CXCL10, and lower levels of liver necroinflammation and fibrosis than non-G/G patients. OCI patients had high ALT normalization rates and serum CXCL10 decreased significantly after Peg-IFNα plus ribavirin treatment, most potently in G-201A G/G patients. Liver necroinflammation and fibrosis were alleviated in 8 OCI patients after treatment. Multivariate analysis indicated that CXCL10 G-201A G/G significantly influenced the occurrence of OCI in HCV infection.

Research conclusions

Our study revealed a higher prevalence of CXCL10 rs1439490 G/G genotype in OCI patients than in CHC patients. OCI patients with rs1439490 G/G genotype achieved better antiviral efficacy with Peg-IFN plus RBV. CXCL10 G-201A genotype is associated with the occurrence of seronegative OCI in patients with CHC, and may be an independent prognostic factor for IFN-based antiviral treatment.

Research perspectives

More paired liver biopsies before and after antiviral treatment are anticipated to examine the correlation of CXCL10 change with clinical outcomes of OCI. In addition, given the current availability of direct acting antiviral agents, the relationship between CXCL10 G-201A G/G and IFN-free anti-HCV regimens requires further study.