Association of IFN-gamma and IL-10 gene variants with the risk of extrapulmonary tuberculosis.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is a chronic infectious disease. Interferon-gamma (IFN-γ) is an important cytokine imparting resistance to mycobacterial diseases. It is believed that IFN-γ and Interleukin-10 (IL-10) play divergent roles in the host immune system against MTB infection. IL-10 is an important inhibitory cytokine and helps balancing the inflammatory and immune responses. IL-10 is involved in down regulation of Th1 cytokines, MHC class II antigen and co-stimulatory molecular expression on macrophages, while IFN-γ results in macrophage activation allowing them to exert the microbicidal role. The objectives were to find out the association of IL-10 (-1082 A/G) and IFN-γ (+874 A/T) single nucleotide polymorphisms (SNPs) with extrapulmonary tuberculosis in ethnic Kashmiri population. A total of 100 extrapulmonary tuberculosis cases and 102 healthy controls were analyzed for IL-10 (-1082 A/G) and IFN- γ (+874 A/T) SNPs using Allele-Specific PCR. We found a significant association of IFN-γ + 874 'TT' genotype with extrapulmonary tuberculosis (p = 0.006) and in case of IL-10 (-1082 A/G) we found a significant association with extrapulmonary tuberculosis under recessive model (GG vs GA + AA) (p = 0.03) in Kashmiri population. IL-10 (-1082 A/G) and IFN-γ (+874 A/T) have a significant association with extrapulmonary tuberculosis in ethnic Kashmiri population.

Role of genetic variants of Vitamin D receptor, Toll-like receptor 2 and Toll-like receptor 4 in extrapulmonary tuberculosis.

BACKGROUND: Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB). Vitamin D deficiency and vitamin D receptor (VDR) gene abnormalities confer susceptibility to tuberculosis. Toll-like receptors (TLRs), such as TLR-2, are also important mediators of inflammatory response against Mycobacterium tuberculosis. We evaluated VDR, TLR-2 and TLR-4 gene polymorphisms in patients with extrapulmonary tuberculosis (EPTB). OBJECTIVES: To find out a possible association of Vitamin D receptor (VDR) (rs731236), TLR-2 (196-174 Ins > Del) and TLR-4 (Thr399Ile) gene polymorphisms with extrapulmonary tuberculosis in ethnic Kashmiri population. METHODS: A total of 100 extrapulmunary tuberculosis cases and 102 healthy controls were analyzed for Vitamin D receptor (VDR) (rs731236), TLR-2 (196-174 ins > del) and TLR-4 (Thr399Ile) gene polymorphisms using PCR-RFLP and Allele-Specific PCR methods. RESULTS: We found increased frequency of TLR-4 Thr/Ile heterozygous genotype in cases as compared with healthy controls (22% vs 5.8%). Thus acting as a risk factor for extrapulmonary tuberculosis, as was elucidated from statistical analysis [OR, 4.5; 95% CI (1.74-11.68); P < 0.001]. In case of TLR-2 (196-174 ins > del) we observed significant differences in the homozygous variant (Del/Del) genotype of cases and controls (28% in cases & 2.94% in controls). Thus, TLR-2 (Del/Del) genotype acts as a strong risk factor for extrapulmonary tuberculosis predisposition [OR, 12.2; 95% CI (3.5-42.69); P < 0.001]. We did not find any significant differences in the genotypic distribution of (VDR) (rs731236) T > C SNP between cases and controls (P > 0.05). CONCLUSION: TLR-4 (Thr/Ile) and TLR-2 (Del/Del) act as significant risk factors for extrapulmonary tuberculosis predisposition in ethnic Kashmiri population.

Significant Pattern of Promoter Hypermethylation of UNC5C Gene in Colorectal Cancer and Its Implication in Late Stage Disease

Background:The development of Colorectal Cancer (CRC) is a complex multistep process involving an accumulation of multiple genetic and epigenetic alterations. Epigenetic modifications, particularly DNA methylation in selected gene are recognized as common molecular alterations in human tumors. Netrin-1 receptors are aberrantly methylated in primary colorectal cancer. Epigenetic alterations in the netrin-1 receptors have been found to be related with the malignant potential of CRC. Purpose: In the present study, we evaluated the role of promoter hypermethylation of UNC5C gene (one of the netrin-1 receptors) in colorectal cancer patients of Kashmiri population (North India). Hypermethylation in tumour tissue was detected by Methylation- Specific Polymerase Chain Reaction (MS-PCR). Results: UNC5C promoter hypermethylation was significantly found to be associated with colorectal cancer cases where frequency was 62% (31 of 50) and 38% (19 of 50) patients were unmethylated (p<0.0001).UNC5C methylation was significantly higher in CRCs with a frequency of 62% than 10% in corresponding normal mucosa of (p<0.0001). Further, UNC5C hypermethylation was found to be significantly associated with stage-III/IV as compared to stage I/II with a frequency of 75.8% and 42.8% respectively(p>0.05). Conclusion: We conclude that UNC5C hypermethylation is implicated in CRC which plays a role in its tumorigenesis and may predict the late stage disease.