Genetic variation in toll‐like receptors and retinoic acid‐inducible gene I and outcome of hepatitis C virus infection: a candidate gene association study

Abstract

We evaluated the effects of genetic variation in toll-like receptors (TLR), retinoic acid-inducible gene I (RIG-I) and their signalling pathways on spontaneous hepatitis C virus (HCV) resolution. We screened 95 single-nucleotide polymorphisms (SNPs) in 22 genes. SNPs significantly associated with resolution in the discovery cohort were genotyped in a validation cohort. Multivariate logistic regression adjusted for sex, hepatitis B surface antigen, HIV infection and the interleukin-28B rs12979860 SNP was performed in the combined cohort. Haplotype reconstruction and linkage disequilibrium analysis were performed. srs2233437, rs730775 and rs28362857 in Inhibitor of NF-kB ε (IkBε) and rs352140 in TLR9 were associated with spontaneous HCV resolution (P ≤ 0.05) in the discovery cohort (n = 308). In the validation cohort (n = 216), we replicated a significant association with HCV resolution for two SNPs in the IkBε, rs2233437 and rs730775. Presence of one or two of the variant allele in rs2233437 had more than twofold higher odds of resolution in adjusted logistic regression (adjusted odds ratio (aOR), 2.6; (95% CI, 1.4, 4.8) P = 0.002). We identified polymorphisms in the IkBε gene associated with spontaneous HCV resolution in two independent cohorts.

Assessment of Genetic Associations between Common Single Nucleotide Polymorphisms in RIG-I-Like Receptor and IL-4 Signaling Genes and Severe Respiratory Syncytial Virus Infection in Children: A Candidate Gene Case-Control Study

“…The SNPs in the gene coding for MAVS appeared to be associated with systemic lupus erythematosus in the Chinese population, albeit only in patients with renal nephritis and arthritis, respectively [47]. Another study did not find an association between either of the SNPs in the genes coding for RIG-I and MAVS and outcome of hepatitis C virus infections [48]. Other variants with more deleterious effects on RIG-I [45] and MAVS [49] expression or function are rare, and therefore are unlikely to play a significant role in the outcome of RSV infection at the population level.…”

Alteration of Antiviral Signalling by Single Nucleotide Polymorphisms (SNPs) of Mitochondrial Antiviral Signalling Protein (MAVS)

“…So far, polymorphisms in RIG-I have been shown to be associated with resistance to type I diabetes [ 28 ], a decreased antibody level in response to rubella vaccination [ 29 ] and modification of the innate immune response of human dendritic cells [ 30 ]. Polymorphisms in Ibo, a molecule downstream of MAVS, were also identified to be involved in spontaneous hepatitis C virus (HCV) infection resolution in two independent cohorts [ 31 ]. Therefore, we initially thought that variants in the MAVS gene should result in dysfunction of the innate immune system, especially in the infectious diseases due to the gene’s crucial role in antiviral signalling.…”

“…Here, we first reported that the R65W and R218C SNPs exerted inhibitory effects on antiviral signalling in response to dsRNA. The R65W variant is located in the CARD domain of MAVS; therefore this variant may affect the interaction of MAVS and RIG-I through alterations in surface structure and hydrophobicity [ 31 ]. Mutation in the CARD domain also affects the significantly reduced interaction of MAVS with TRAF3, as shown by co-IP assays [ 21 ].…”

Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children

“…Activation of nuclear factor (NF)-κB through Toll-like receptor binding is considered to be the central initiating event of host responses to invasion of microbial pathogens, including encapsulated bacteria ( Rahman and McFadden, 2011 , Clausen et al, 2013 ). Innate and adaptive immune responses are dependent on activation of the NF-κB pathway ( Janssen et al, 2004 ).…”