title: Sex-specific association between X-linked Toll-like receptor 7 with the outcomes of hepatitis C virus infection.
abstract: Toll-like receptor 7 (TLR7) senses hepatitis C virus (HCV) infection and drives the host specific innate and adaptive immune response. The aim of this study was to estimate the distributions of TLR7 single nucleotide polymorphisms (SNPs), including rs179019 and rs3853839, as well as the effect of TLR7 gene variants on TLR7 mRNA expression and cytokine production in response to TLR7 agonist in vitro. TLR7 SNP genotyping was performed among a Chinese sample population of 418 patients with persistent HCV infection, 317 patients with HCV spontaneous clearance, and 989 healthy controls. TLR7 mRNA expression and TLR7-specific IFN-α and IL-6 secretion in peripheral blood mononuclear cells, derived from 60 healthy individuals in vitro, were then quantified. We identified the association of TLR7 rs3853839C allele, haplotype CC and haplotype AC (rs179019/rs3853839) with protection against HCV persistence in Chinese females (OR=0.49, 95% CI=0.29-0.81, P=0.01 for rs3853839 GC; OR=0.29, 95% CI=0.11-0.75, P=0.01 for rs3853839 CC; OR=0.51, 95% CI=0.38-0.77, P<0.01 for haplotype CC; OR=0.29, 95% CI=0.10-0.88, P=0.03 for haplotype AC). In addition, the rs3853839 CC genotype among female carriers had significantly low TLR7 mRNA expression (P=0.006 for GG vs. CC, P=0.021 for GC vs. CC), along with decreased IFN-α (P=0.002 for GG vs. CC, P=0.021 for GC vs. CC) and increased antiviral IL-6 production (P=0.002 for GG vs. CC, P=0.030 for GC vs. CC), after treatment with Imiquimod in vitro. The cytokine profile among rs3853839 CC genotype female carriers may indicate a pronounced protective effect against persistent HCV infection. The functional polymorphism of TLR7 rs3853839C allele was found to be sex-specific and associated with protection against HCV persistence among Chinese females, which may be due to specific IFN-α and IL-6 secretion profiles.
authors.affiliation: Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China; School of Life Science and Technology, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yue
authors.affiliation: Department of Infection and Immunity, Yixing People's Hospital, No. 75 Tongzhenguan Road, Yixing 214200, Jiangsu, China.
authors.forename: Le
authors.initials: L
authors.lastname: Feng
authors.affiliation: Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China.
authors.forename: Shai-di
authors.initials: SD
authors.lastname: Tang
authors.affiliation: Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China.
authors.forename: Jia-jia
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China.
authors.forename: Xing-xin
authors.initials: XX
authors.lastname: Xue
authors.affiliation: Department of Clinical Laboratory, Yixing People's Hospital, No. 75 Tongzhenguan Road, Yixing 214200, Jiangsu, China.
authors.forename: Wei-liang
authors.initials: WL
authors.lastname: Ding
authors.affiliation: Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China. Electronic address: zhangyunvip@126.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China. Electronic address: dengxiaozhao1002@vip.sina.com.
authors.forename: Xiao-zhao
authors.initials: XZ
authors.lastname: Deng
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D044466:Asian People / Q000235:genetics; D002478:Cells, Cultured; D041321:Chromosomes, Human, X; D005260:Female; D020869:Gene Expression Profiling; D050172:Genes, X-Linked; D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000235:genetics* / Q000517:prevention & control / Q000821:virology*; D006801:Humans; D000077271:Imiquimod; D007369:Interferon Inducers / Q000494:pharmacology; D016898:Interferon-alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; C508600:IL6 protein, human; D007369:Interferon Inducers; D016898:Interferon-alpha; D015850:Interleukin-6; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D000077271:Imiquimod
keywords: Cytokine; Estrogen receptor; Hepatitis C virus; Persistence; Polymorphism; Toll-like receptor 7