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Tuberculosis (TB) is still remains the major threat for human health worldwide. Several case-control, candidate-gene, family studies and genome-wide association studies (GWAS) suggested the association of host genetic factors to TB susceptibility or resistance in various ethnic populations. Moreover, these factors modulate the host immune responses to tuberculosis. Studies have reported genetic markers to predict TB development in human leukocyte antigen (HLA) and non-HLA genes like killer immunoglobulin-like receptor (KIR), toll-like receptors (TLRs), cytokine/chemokines and their receptors, vitamin D receptor (VDR) and SLC11A1 etc. Highly polymorphic HLA loci may influence antigen presentation specificities by modifying peptide binding motifs. The recent meta-analysis studies revealed the association of several HLA alleles in particular class II HLA-DRB1 with TB susceptibility and valuable marker for disease development especially in Asian populations. Case-control studies have found the association of HLA-DR2 in some populations, but not in other populations, this could be due to an ethnic specific association of gene variants. Recently, GWAS conducted in case-control and family based studies in Russia, Chinese Han, Morocco, Uganda and Tanzania revealed the association of genes such as ASAP1, Alkylglycerol monooxygenase (AGMO), Forkhead BoxP1 (FOXP1), C-terminal domain phosphatase 1 (UBLCP1) and intergenic SNP rs932347C/T with TB. Whereas, SNP rs10956514A/G were not associated with TB in western Chinese Han and Tibetan population. In this review, we summarize the recent findings of genetic variants with susceptibility/resistance to TB.

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BACKGROUND: Genetic factors play an important role in the development of disease susceptibility or protection. Cytokine gene polymorphisms are reported to be associated with altered levels of cytokine production that can impact disease progression in HIV and TB. OBJECTIVE: In this study, we studied IL-10 -592(C/A) and TGF-ß -509 (C/T) promoter polymorphisms to understand their role in susceptibility or resistance to HIV and TB in a South Indian population. METHOD: Genomic DNA was isolated from healthy controls, pulmonary tuberculosis patients (n=122) and HIV positive individuals (n=100) and used for genotyping by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Results revealed that under dominant model (CC vs CA+AA), IL-10 -592 'A' allele either 'CA' or 'AA' combinations significantly associated with susceptibility to HIV compared to healthy controls (OR: 1.88(1.05-3.35); p=0.030). However, we found no significant association with TB. TGF-ß -509 polymorphism did not associate with either HIV or TB under overdominant model. Neither of the promoter polymorphisms associated with sex in either HIV or TB. However, a trend towards higher risk to HIV was found in females compared with males in IL-10 -592 'AA' genotype. CONCLUSION: This study suggests the association of IL-10 -592 "AA" genotype with susceptibility to HIV under dominant model in the Southern Indian population. Future studies are needed with a larger sample size in order to confirm the observations made in this study.

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PURPOSE: We studied the effect of 1,25(OH)2D3 (vitamin D3) on intracellular chemokine-positive T-cell subsets in whole blood cultures of healthy controls and patients with pulmonary tuberculosis. METHODS: Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. The regulatory role of the Cdx2 and 3'UTR TaqI gene variants on chemokine-positive T-cell subsets was studied from culture filtrate antigen stimulated with or without vitamin D3 treated whole blood cultures of 60 healthy controls and 50 patients with pulmonary tuberculosis. FINDINGS: Vitamin D3 significantly suppressed monocyte chemoattractant protein 1, macrophage inhibitory protein (MIP)-1α, MIP-1ß, regulated on activation, normal T-cell expressed and secreted (RANTES), and interferon-γ inducible protein 10 (IP-10)-positive T-cell subsets compared with culture filtrate antigen stimulated cells without vitamin D3 treatment. In the Cdx2 AA genotype, vitamin D3 decreased MIP-1α, MIP-1ß, and RANTES-positive T cells compared with the GG genotype. Whereas in the TaqI tt genotype, decreased MIP-1ß and RANTES and increased IP-10-positive T cells were observed compared with the TT genotype in vitamin D3 treated cells (p < 0.05). IMPLICATIONS: This study suggests that vitamin D3 may regulate the chemokine-positive T cells through the Cdx2 AA and TaqI tt genotypes. This could be helpful to regulate chemokine-mediated inflammatory response during active disease condition. Hence, vitamin D3 supplementation along with tuberculosis drugs may be useful for faster recovery from the disease.

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Tuberculosis (TB) is a major global health problem and often coincides with vitamin D deficiency. High doses of vitamin D were widely used to treat TB during the pre-antibiotic era. Vitamin D exerts its action through vitamin D receptor (VDR), and VDR gene polymorphisms are associated with susceptibility or resistance to tuberculosis as well as sputum smear and culture conversion during anti-TB treatment. In-vitro studies have revealed that 1,25-dihydroxyvitamin D3 enhances innate immunity by increased expression of various antimicrobial peptides, including cathelicidin, and induction of autophagy of the infected cells thus restricts the intracellular growth of Mycobacterium tuberculosis in macrophages. On the other hand, vitamin D has been shown to suppress the pro-inflammatory cytokine response and enhance the anti-inflammatory response. Supplementation with vitamin D in concert with treatment for TB may be beneficial with respect to minimizing the excessive tissue damage that occurs during the active stage of tuberculosis disease. Several clinical trials have evaluated vitamin D supplementation as an adjunct therapy in the treatment for tuberculosis. However, results are conflicting, owing to variations in dose regimens and outcomes. Further investigations are needed to find the optimal concentration of vitamin D for supplementation with standard anti-TB drugs to optimize treatment, which could help to effectively manage both drug-sensitive and drug-resistant tuberculosis.

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that is essential for growth and development of progenitors of granulocytes and monocytes/macrophages. In this study, we report molecular cloning, sequencing and characterization of GM-CSF from Indian water buffalo, Bubalus bubalis. In addition, we performed sequence and structural analysis for buffalo GM-CSF. Buffalo GM-CSF has been compared with 17 mammalian GM-CSFs using multiple sequence alignment and phylogenetic tree. Three-dimensional model for buffalo GM-CSF and human receptor complex was built using homology modelling to study cross-reactivity between two species. Detailed analysis was performed to study GM-CSF interface and various interactions at the interface.

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