Polymorphisms in vitamin D receptor, toll-like receptor 2 and Toll-Like receptor 4 genes links with Dengue susceptibility.

Arvind Kumar Singh

doi:10.6026/97320630017506

Abstract

Host genetic factors are known to determine disease susceptibility in dengue virus infection. Therefore, in this study association of gene polymorphisms of Vitamin D Receptor [rs731236 (Taq) and rs7975232 (Apa1)], Toll-like receptor 2 [rs5743708 (Arg735Gln) and rs5743704 (Pro631His)] and Toll-like receptor 4 [rs4986790A/G(Asp299Gly13843) and rs4986791 C/T(Thr399Ile)] were studied in cases with dengue as compared to controls. Total 98 cases of confirmed dengue virus infection and 98 age, sex and geographically matched healthy controls were enrolled and their genetic polymorphisms for the above mentioned regions were studied by Sanger sequencing. Mutant genotypes CC of VDR rs731236 (Taq1) [(OR 3.808, p value =0.02, CI 1.160-12.498)], GG of VDR rs7975232 (Apa1) [(OR 3.485, p value =0.02, CI 1.162-10.45)] and heterozygous genotypes of TLR4 rs4986790 A/G Asp299Gly [OR 2.40, p value= 0.02, CI 1.12-5.14], TLR4 rs4986791 C/T Thr399Ile [OR 2.09, p value=0.02, CI 1.12-5.14] were found to be significantly more in cases with dengue virus infection as compared to the controls. Also, at these positions mutant alleles were observed in significantly higher number of cases than controls. The values for C allele at VDR rs731236 (Taq1) were OR 1.86, p value 0.009, CI 1.162-3.001; for allele G at rs7975232( Apa1) were OR 2.71, p value 0.006, CI 1.196-2.98 for allele G at TLR4s rs4986790 A/G Asp299Gly were OR 2.35, p value 0.009, CI 1.23-4.50 and for allele T at rs4986791 C/T Thr399Ile were OR 2.36, p value=0.006, CI 1.28-4.38. VDR and TLR4 but not TLR2 gene polymorphisms were found to be associated with dengue susceptibility in Indian population.

Highlights

Dengue fever is one of the most important arthropod borne endemic diseases in some Asian and Latin American countries [1]
The host susceptibility to dengue may be influenced by host immune response and genetic factors, which includes single nucleotide polymorphisms (SNPs) of genes such as Toll like receptors 2 and 4 (TLR-2, TLR-4) present on the cytoplasmic membrane [2] and Vitamin D Receptor (VDR) present on nuclear membrane [3]
Few functional polymorphisms of TLR2 gene such as Arg735Gln, and Pro 631 His are known, which alter the activity of receptor [4] or impair receptor signalling, which in turn increases the susceptibility to dengue virus infection

Summary

Introduction

Dengue fever is one of the most important arthropod borne endemic diseases in some Asian and Latin American countries [1]. Multiple important roles of VDR are known such as modulation of immunoregulatory effects of 1,25 dihydroxy vitamin D3, monocyte activation, stimulation of cellular immune responses, antagonism production of immunoglobulin and regulating lymphocyte proliferation [3]. It may affect pathogenesis of Dengue virus infection. Several SNPs in TLR4, Asp299Gly and Thr399Ile, are known to be associated with severe forms of diseases such as falciparum malaria [2], neurocysticercosis [5] Role of these polymorphisms in pathogenesis of dengue fever is yet not known. Since several gaps exist in the present knowledge of factors affecting host susceptibility to dengue, the present study was done to study the association between genetic polymorphisms of TLR-2 [rs5743708 (Arg735Gln) and rs5743704 (Pro 631 His)], TLR-4 [A/G (Asp299Gly-13843) and rs4986791 C/T (Thr399Ile)], and VDR [rs731236 (Taq) and rs7975232(Apa1)] with susceptibility to dengue virus infection

Methods

Results

Conclusion