Association of genetic polymorphisms in interferon gamma and its receptor genes with tuberculosis

Abstract

Tuberculosis (TB) causes high morbidity and mortality in the world. With approximately 1/4th of total TB burden of the world, India is the highest TB burden country. Understanding genetic determinants behind pathogenesis of TB can give vital insights into underlying molecular mechanisms and combating this dreaded disease. Interferon-and#947; (IFN-and#947;) encoded by IFNG gene is an essential pro-inflammatory cytokine involved in immunity against TB. It mediates its functions through IFN-and#947; receptor complex, which consists of two subunits, IFN-and#947;R1 (encoded by IFNGR1) and IFN-and#947;R2 (encoded by IFNGR2). Single nucleotide polymorphisms (SNPs) in IFNG or its receptor genes can alter IFN-and#947; signalling, thus influencing host susceptibility to TB. The present study analysed the association of IFNG, IFNGR1 and IFNGR2 with TB at genetic, transcriptional and translational level in the population of Himachal Pradesh, India. A total of 415 subjects were genotyped for important SNPs of these genes using ARMS-PCR or HRM-analysis. The mRNA and protein expression was evaluated by RT-PCR, ELISA and flow-cytometry. SNPs rs1861494, rs2069718 and rs2234711 were found to be associated with TB. Interestingly, TB patients were found with low mRNA but high plasma protein expression of IFNG in comparison to HCs. The mRNA and surface expression of IFNGR1 and IFNGR2 was found to be down-regulated in male TB patients. Some SNPs were found to be significantly associated with altered gene expression. More such studies on other populations can be pursued to understand TB pathogenesis at molecular level, which could help in devising effective strategies to eradicate this menace from earth. newline