Genetic polymorphisms in TNF genes and tuberculosis in North Indians

BMC Infectious Diseases, Jun 2010

Background Pulmonary tuberculosis, the most common clinical form of mycobacterial diseases, is a granulomatous disease of the lungs caused by Mycobaterium tuberculosis. A number of genes have been identified in studies of diverse origins to be important in tuberculosis. Of these, both tumor necrosis factor α (TNF-α) and lymphotoxin α (LT-α) play important immunoregulatory roles. Methods To investigate the association of TNF polymorphisms with tuberculosis in the Asian Indians, we genotyped five potentially functional promoter polymorphisms in the TNFA gene and a LTA_NcoI polymorphism (+252 position) of the LTA gene in a clinically well-defined cohort of North-Indian patients with tuberculosis (N = 185) and their regional controls (N = 155). Serum TNF-α (sTNF-α) levels were measured and correlated with genotypes and haplotypes. Results The comparison of the allele frequencies for the various loci investigated revealed no significant differences between the tuberculosis patients and controls. Also, when the patients were sub-grouped into minimal, moderately advanced and far advanced disease on the basis of chest radiographs, TST and the presence/absence of cavitary lesions, none of the polymorphisms showed a significant association with any of the patient sub-groups. Although a significant difference was observed in the serum TNF-α levels in the patients and the controls, none of the investigated polymorphisms were found to affect the sTNF-α levels. Interestingly, it was observed that patients with minimal severity were associated with lower log sTNF-α levels when compared to the patients with moderately advanced and far advanced severity. However, none of these differences were found to be statistically significant. Furthermore, when haplotypes were analyzed, no significant difference was observed. Conclusions Thus, our findings exclude the TNF genes as major risk factor for tuberculosis in the North Indians.

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Genetic polymorphisms in TNF genes and tuberculosis in North Indians

Shilpy Sharma 1 Jaishriram Rathored 0 1 Balaram Ghosh 1 Surendra K Sharma 0 1 0 Department of Medicine, All India Institute of Medical Sciences , New Delhi- 110029 , India 1 561: 01, 0102sesaesi Dsuoitcef nI CMB.l atea mrahS 561/01/4332-1741/ moc.l artnecde moi b. www//: ptth Background: Pulmonary tuberculosis, the most common clinical form of mycobacterial diseases, is a granulomatous disease of the lungs caused by Mycobaterium tuberculosis. A number of genes have been identified in studies of diverse origins to be important in tuberculosis. Of these, both tumor necrosis factor (TNF-) and lymphotoxin (LT-) play important immunoregulatory roles. Methods: To investigate the association of TNF polymorphisms with tuberculosis in the Asian Indians, we genotyped five potentially functional promoter polymorphisms in the TNFA gene and a LTA_NcoI polymorphism (+252 position) of the LTA gene in a clinically well-defined cohort of North-Indian patients with tuberculosis (N = 185) and their regional controls (N = 155). Serum TNF- (sTNF-) levels were measured and correlated with genotypes and haplotypes. Results: The comparison of the allele frequencies for the various loci investigated revealed no significant differences between the tuberculosis patients and controls. Also, when the patients were sub-grouped into minimal, moderately advanced and far advanced disease on the basis of chest radiographs, TST and the presence/absence of cavitary lesions, none of the polymorphisms showed a significant association with any of the patient sub-groups. Although a significant difference was observed in the serum TNF- levels in the patients and the controls, none of the investigated polymorphisms were found to affect the sTNF- levels. Interestingly, it was observed that patients with minimal severity were associated with lower log sTNF- levels when compared to the patients with moderately advanced and far advanced severity. However, none of these differences were found to be statistically significant. Furthermore, when haplotypes were analyzed, no significant difference was observed. Conclusions: Thus, our findings exclude the TNF genes as major risk factor for tuberculosis in the North Indians. - Background Mycobacterial diseases are a major health concern, with an estimate of approximately one-third of the world's population being affected by them [1,2]. Pulmonary tuberculosis, the most common clinical form of the disease, is a granulomatous disease of the lungs caused by Mycobaterium tuberculosis. However, only 5-10% of the infected people ever develop the disease. The genetic contribution of the host plays a significant role in determining susceptibility to developing the active form of the disease, the severity of infection and the health outcome of the patient [3,4]. A number of genes have been identified in studies of diverse origins to be important in tuberculosis [5-7]. The genes for tumor necrosis factor- (TNF-; TNFA) and lymphotoxin- (LT-; LTA), located within the MHC III region of chromosome 6, shows close linkage to the HLA class I (HLA-B) and class II (HLA-DR) genes [8]. Both TNF-, produced mainly by monocytes and activated macrophages; and LT-, produced mainly by activated T-cells, play important immunoregulatory roles [9]. Of these, TNF- contributes to the pathogenesis of tuberculosis due to its role in the formation and maintenance of granulomas [10]. Additionally, it also plays a major role in host defense to M. tuberculosis by its synergistic action with interferon- (IFN-) to activate macrophages and thereby impacts on disease perpetuation [11,12]. Elevated serum TNF- (sTNF-) levels have been reported in advanced tuberculosis patients when compared to those with mild tuberculosis and healthy individuals [13]. Studies on monozygotic twins and their first-degree relatives, using ex vivo endotoxin stimulated whole blood samples, have provided evidence that 60% of variation in the production capacity of TNF- appears to be genetically determined [14]. Several polymorphisms within the promoter region of TNFA and the intron 1 polymorphism of LTA, in particular, have been associated with altered levels of circulating TNF- [15,16]. A few of these polymorphisms have been also studied for determining susceptibility or resistance towards tuberculosis in several ethnic groups, the results of which have been inconclusive [17-26]. The aim of this study was to determine associations, if any, of potentially functional TNFA and LTA polymorphism(s), both individually and at the haplotype level, with tuberculosis in patients from North-India. In addition, we have attempted to explore whether any of these polymorphisms may be related to the severity and the associated features of the disease. We also attempt to correlate these polymorphisms with sTNF- levels in the patients and the controls. Methods Study Subjects 185 unrelated tuberculosis patients (mean age 32.16 13.8 years; male:female 0.42:0.58), who presented to th (...truncated)


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Shilpy Sharma, Jaishriram Rathored, Balaram Ghosh, Surendra K Sharma. Genetic polymorphisms in TNF genes and tuberculosis in North Indians, BMC Infectious Diseases, 2010, pp. 165, 10, DOI: 10.1186/1471-2334-10-165