Non-HLA gene polymorphisms and their implications on dengue virus infection

Exposure to the dengue virus (DENV) evokes a variety of genetically-controlled immunological responses. Genetic variants involved in viral entry, replication and innate immunity pathways play an important role in the causal pathway of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Here we have reviewed implications of some genetic polymorphisms of the pathways related to DENV infection susceptibility, protection and severity. Large case-control studies examining a variety of single-nucleotide polymorphisms (SNPs) in a variety of genes have been performed in DENV patients in some countries. SNP gene candidates that have shown associations with DENV infection are mannose-binding lectin (MBL), interleukin (IL)-4, IL-6, IL-10, interleukin-1 receptor antagonist (IL-1RA), toll-like receptor 4 (TLR4), cytotoxic T-lymphocyte antigen 4 (CTLA-4), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, Fcγ receptor II (FcγRII), vitamin D receptor (VDR), interferon (IFN)-γ, human platelet antigens (HPA), transporters associated with antigen processing (TAP), dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) and Janus kinase 1 (JAK1), although some of these genes failed to show statistical significance. Briefly, polymorphism in TNF-α, FcγRII, CTLA-4, TGF-β1, HPA, DC-SIGN, TAP and JAK1 genes has been associated with DHF/DSS development. Polymorphism in MBL2 gene was shown to be associated with thrombocytopenia and increased risk of DHF development. In contrary, polymorphism in VDR gene shows moderate associations with resistance to the most severe form of DHF. However, neutral associations have been reported for IL-4 promoters, IL-1RA, IFN-γ, IL-6, TLR4 and IL-10 gene polymorphism. In conclusion, there are strong evidences from several epidemiological studies indicating host genetic factors as important components in DENV infection susceptibility, protection and severity.