Synergetic Effect of TLR4 Gene (D299G and T399I) Polymorphisms in Susceptibility to Pulmonary Tuberculosis

Abstract

Background: Toll-like receptor 4 (TLR4) is an essential component of the innate immune response to various microorganisms. Genetic polymorphisms in TLR4 are often associated with susceptibility to mycobacterial infection. Objective: The present study examines the influence of TLR4 896 A/G (Asp299Gly) and 1196 C/T (Thr399Ile) polymorphism in the susceptibility to develop pulmonary tuberculosis (PTB) in Indians. Materials & Methods: Single nucleotide polymorphisms (SNPs) of the TLR4 gene were genotyped using PCR-RFLP and sequenced in 198 patients with PTB and 60 healthy controls. Results: The frequency of mutant allele 299Gly and 399Ile of the TLR4 gene (14.4%; p < 0.048; RR=1.919; OR=2.074 & 14.6%; p < 0.020, RR=2.197; OR=2.402) was predominant in PTB patient as compared to healthy controls (7.5% & 6.7%), respectively. Data was further analysed under the dominant model (CT+TT (Thr/Ile + Ile/Ile)) at 399 position revealed preponderance of mutant allele in PTB patients (25.8%; p < 0.045; OR=2.555). On the other hand, combined evaluation of polymorphisms showed heterozygous/heterozygous (AG299+CT399) genotype was higher (16.2% vs 6.7%; p=0.063) in PTB patients than in control subjects. However homozygous/homozygous (GG299+TT399) genotype was observed only in PTB patients (3%).Conclusion: The current observation suggests the contribution of mutant allele 'Gly' & 'Ile' towards the increased risk of development of tuberculosis in North Indian population. As per our knowledge, this is first Indian study indicating the synergetic effect of two mutant (Asp299Gly and Thr399Ile) / alleles influencing the PTB infection. Further investigation on association of TLR-4 as an innate immunity biomarker with tuberculosis diseases need to be evaluated.