DNA sequence variation and regulation of genes involved in pathogenesis of pulmonary tuberculosis.

DNA sequence variations [copy number variations, single nucleotide polymorphisms (SNPs) and microsatellite repeats] play an important role in susceptibility/resistance to tuberculosis and other infectious diseases like malaria and HIV. Different population exhibit variable associations with tuberculosis susceptibility and severity because of DNA sequence variations in both host and parasite. A number of genes and their polymorphisms have been identified that appear to be important in tuberculosis. In this article, several case-control studies of tuberculosis including a number of genes in different population have been explored. Furthermore, this review summarizes the current studies of host polymorphisms and their association with tuberculosis in different population. We have computationally predicted 275 SNPs which occur in transcription factor binding sites for transcription factors in 19 genes involved in pathogenesis of tuberculosis. Some common SNPs are rs1327474, rs755622, rs1801274, rs396991, rs5030737, rs1800451, rs1800450, rs3763313 rs3763313, rs9268494 and rs9268492 that have been found to play a role in disease. Presence of non-synonimous polymorphisms in coding region might affect the structure of protein, whereas polymorphisms in promoter region affect the level of gene products, consequently altering the susceptibility/resistance to disease. Based on this prediction, we hypothesize that these genes play an important role in susceptibility to tuberculosis through an altered expression of gene product via the modification of transcriptional regulation of gene.

Tumour necrosis factor gene polymorphism and disease prevalence.

Tumour necrosis factor (TNF), an important proinflammatory cytokine, plays a role in the regulation of cell differentiation, proliferation and death, as well as in inflammation, innate and adaptive immune responses, and also implicated in a wide variety of human diseases. The presence of DNA sequence variations in regulatory region might interfere with transcription of TNF gene, influencing the circulating level of TNF and thus increases the susceptibility to human diseases (infectious, cancer, autoimmune, neurodegenerative and other diseases). In this review, we have comprehensively analysed various published case-control studies of different types of human diseases, in which TNF gene polymorphism played a role, and computationally predicted several single nucleotide polymorphisms (SNPs) lie in transcription factor-binding sites (TFBS) of transcription factors (TFs). It has been observed that TNF enhancer polymorphism is implicated in several diseases, and TNF rs1800629 and rs361525 SNPs are the most important in human disease susceptibility as these might influence the transcription of TNF gene. Thirty-two SNPs lies in TFBS of 20 TFs have been detected in the TNF upstream region. It has been found that TNF enhancer polymorphism influences the serum level of TNF in different human diseases and thus affects the susceptibility to diseases. The presence of DNA sequence variation in TNF gene causes the modification of transcriptional regulation and thus responsible for association of susceptibility/resistance with human diseases.

Inducible nitric oxide synthase (iNOS) gene polymorphism and disease prevalence.

Nitric oxide synthase gene is present on chromosome 17 and has been implicated in a wide variety of diseases. The nitric oxide synthase enzyme forms nitric oxide that besides being a signalling molecule plays an important role in host immune response. Inducible nitric oxide synthase expression is regulated at the level of transcription. Single-nucleotide polymorphisms, copy number variation and simple sequence repeat are important variations that have been reported in human genome. The presence of such variations in the regulatory region affects the level of gene product in the cell, while variation in the coding region influences the structure of proteins and its activity. This alteration in the level of gene product and the structure of the protein molecule might be responsible for the final outcome of genetic as well as infectious diseases. In the present manuscript, we review the role of inducible nitric oxide synthase (iNOS) gene polymorphisms in different diseases and populations. The iNOS gene with one pentanucleotide repeat, two single-nucleotide polymorphisms in promoter region and one polymorphism in exon 16 has been implicated in several diseases. We have also predicted several polymorphisms in the promoter region of iNOS computationally, which might affect the transcription factor binding site (TFBS) and hypothesize that these polymorphisms have some putative role in the outcome of disease(s).