title: Resistin reinforces interferon λ-3 to eliminate hepatitis C virus with fine-tuning from RETN single-nucleotide polymorphisms.
abstract: The effect of resistin (RETN) on the response to anti-HCV therapy remains unclear. A prospective cohort study was performed using 655 consecutive HCV patients, of whom 513 had completed a course of interferon-based therapy. Multivariate and GEE analyses revealed four RETN single-nucleotide polymorphisms (SNPs), rs34861192, rs3219175, rs3745367 and rs1423096, to be synergistically associated with resistin levels. After adjusting for co-factors such as interferon λ-3 (IFNL3)-rs12979860, the resistin level and the hyper-resistinemic genotype at the 4 RETN SNPs were positively and negatively associated with a sustained virological response (SVR), respectively. RETN-rs3745367 was in linkage disequilibrium with IFNL3-rs12979860. Compared to non-SVR patients, SVR patients had higher levels of pre-therapy resistin, primarily originating from intrahepatic lymphocytes, stellate cells, Kupffer cells, hepatic progenitor cells and hepatocytes. This difference diminished over the course of therapy, as only SVR patients exhibited a 24-week post-therapy decrease in resistin. Both resistin and IFNL3 mRNAs were upregulated, but only resistin mRNA was upregulated by recombinant resistin in peripheral blood mononuclear cells with and without hyper-resistinemic genotypes of the 4 RETN SNPs, respectively. Fine-tuned by RETN SNPs, intrahepatic, multi-cellular resistin reinforced IFNL3 in eliminating HCV via immunomodulation to counteract pro-inflammation. These results encourage the development of novel resistin-targeted anti-viral agents.
authors.affiliation: Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ming-Ling
authors.initials: ML
authors.lastname: Chang
authors.affiliation: Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Kung-Hao
authors.initials: KH
authors.lastname: Liang
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Ku
authors.affiliation: Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lo
authors.affiliation: Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Cheng
authors.affiliation: Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Hsu
authors.affiliation: Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Cheng-Tang
authors.initials: CT
authors.lastname: Chiu
mesh_terms: D000328:Adult; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D052243:Resistin / Q000235:genetics / Q000276:immunology; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; D052243:Resistin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C499624:RETN protein, human