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.
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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)