Investigation of Toll-Like Receptor-2 (2258G/A) and Interferon Gamma (+874T/A) Gene Polymorphisms among Infertile Women with Female Genital Tuberculosis.

Venkanna Bhanothu,Prabhakar Badhini,Vemu Lakshmi,Roya Rozati,Boda Vijayalaxmi,Jane P Theophilus

doi:10.1371/journal.pone.0130273

Venkanna Bhanothu, Prabhakar Badhini + Show 4 more

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https://doi.org/10.1371/journal.pone.0130273

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Abstract

BackgroundToll-like receptor 2 (TLR2) and interferon-gamma (IFN-γ) coordinate with a diverse array of cellular programs through the transcriptional regulation of immunologically relevant genes and play an important role in immune system, reproductive physiology and basic pathology. Alterations in the functions of TLR2 2258G (guanine)/ A, IFN-γ (+874T/A) and signalling molecules that result from polymorphisms are often associated with susceptibility or resistance, which may, in turn, establish the innate host response to various infectious diseases. Presently, we proposed to investigate the risk of common single nucleotide polymorphism (SNP) of TLR2 and IFN-γ genes, for their effect on infertility in women with female genital tuberculosis (FGTB) and healthy women as controls.Methodology/Principal FindingsGenotyping of TLR2 and IFN-γ gene polymorphisms was performed by amplification refractory mutation system multi-gene/multi-primer polymerase chain reaction followed by restriction fragment length polymorphism in 175 FGTB patients and 100 healthy control women (HCW). The TLR2 polymorphism [adenine (A) allele] was observed in 57.7 and 58.0% of FGTB patients and HCW, respectively. The IFN-γ (+874T/A) polymorphism (A allele) was significant in 74.3 and 71.0% of FGTB patients and HCW, respectively, while the odds ratios for the AA and TA genotypes for predisposition of FGTB were found to be 0.304 and 1.650 in HCW, respectively. The SNP of TLR2 was not associated with FGTB but the SNP of IFN-γ was found to be associated with mycobacteria infections and to induce infertility.Conclusions/SignificanceAt present, we hypothesize that infertile women with FGTB and HCW without tuberculosis (TB) have identical frequency of TLR variants, which may be adequate in the production of IFN-γ in response to Mycobacterium tuberculosis infections. Thus, the study appears to be the first of its kind reporting a mutation in the IFN-γ gene [+874 T (thymine) to A] responsible for susceptibility to TB infections and further inducing infertility.

Highlights

Female genital tuberculosis (FGTB) is usually an asymptomatic disease diagnosed during investigations for infertility [1,2,3]
It usually spread to genital site from three routes, including hematogenous, sexual transmission [106], lymphatic or adjacent viscera [14], while it most commonly affects the fallopian tubes (95–100%), followed by the endometrium (50–60%), ovaries (20–30%), cervix (5–15%), and vulva/vagina (1%) and the myometrium (2.5%). [107, 108] The infections utmost depends on the site of inflammation
The heterogeneity in the clinical expression of female genital tuberculosis (FGTB) strongly suggests the involvement of genetic factors on its immune pathogenesis, through the impact on gene expression of cytokines, chemokines and lymphokines, which are implicated in the host immune response and reproductive system

Summary

Introduction

Female genital tuberculosis (FGTB) is usually an asymptomatic disease diagnosed during investigations for infertility [1,2,3]. Evidence suggests that the occurrence of tuberculosis (TB) at different rates among particular races, ethnicities, families, age group, gender and geographic area are majorly explained due to potential strains of microbial agents, defective host genetic factors and environmental factors [15,16,17,18] These factors play a critical role in the susceptibility of M. tuberculosis infection, and, subsequently, in the development of infertility. Toll-like receptor 2 (TLR2) and interferon-gamma (IFN-γ) coordinate with a diverse array of cellular programs through the transcriptional regulation of immunologically relevant genes and play an important role in immune system, reproductive physiology and basic pathology. We proposed to investigate the risk of common single nucleotide polymorphism (SNP) of TLR2 and IFN-γ genes, for their effect on infertility in women with female genital tuberculosis (FGTB) and healthy women as controls

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