Abstract
BackgroundPakistan ranks 7th globally in terms of tuberculosis (TB) disease burden (incidence 181/100000 pop./yr; prevalence of 329/pop./yr). Reports from different populations show variable associations of TB susceptibility and severity with cytokine gene polymorphisms. Tuberculosis clinical severity is multi-factorial and cytokines play a pivotal role in the modulation of disease severity. We have recently reported that the ratio of two key cytokines (IFNγ and IL10) show significant correlation with the severity spectrum of tuberculosis. The objective of the current study was to analyze the frequency of cytokine gene polymorphisms linked to high and low responder phenotypes (IFNγ +874 T hi→A lo and IL10 −1082 G lo→A hi) in tuberculosis patients.Methods and FindingsStudy groups were stratified according to disease site as well as disease severity: Pulmonary N = 111 (Minimal, PMN = 19; Moderate, PMD = 63; Advance, PAD = 29); Extra-pulmonary N = 67 (Disseminated DTB = 20, Localized LTB = 47) and compared with healthy controls (TBNA = 188). Genotype analyses were carried out using amplification refractory mutation system-PCR (ARMS-PCR) and stimulated whole blood (WB) culture assay was used for assessing cytokine profiles. Our results suggest that the IFNγ +874 TT genotype and T allele was overrepresented in PMN (p = 0.01) and PMD (p = 0.02). IFNγ +874 TT in combination with IL10 GG lo genotypes showed the highest association (χ2 = 6.66, OR = 6.06, 95% CI = 1.31–28.07, p = 0.01). IFNγ AA lo on the other hand in combination with IL10 GG lo increased the risk of PAD (OR = 5.26; p = 0.005) and DTB (OR = 3.59; p = 0.045).ConclusionThese findings are consistent with the role of IL10 in reducing collateral tissue damage and the protective role of IFNγ in limiting disease in the lung.
Highlights
Pakistan ranks 7th globally in terms of tuberculosis disease burden with an incidence of 181/100000 pop./yr and a prevalence of 329/ pop. /yr
Polymorphisms in IL10 [11] linked to high and low producer phenotypes have shown conflicting associations with tuberculosis disease susceptibility and disease severity in different patient populations [12,13]. This is not surprising as, IFNc may be a key cytokine in activation of macrophages for mycobacterial stasis and killing [14], disease severity outcomes in tuberculosis depend on the balance among several different cytokines in situ, depending on the disease site
We have recently reported that the ratio of these two key cytokines (IFNc/IL10) shows significant correlation with clinical severity in extra-pulmonary tuberculosis [16],with higher IFNc/IL10 ratio relating to less severe disease
Summary
Pakistan ranks 7th globally in terms of tuberculosis disease burden with an incidence of 181/100000 pop./yr and a prevalence of 329/ pop. /yr. Polymorphisms in IL10 [11] linked to high and low producer phenotypes have shown conflicting associations with tuberculosis disease susceptibility and disease severity in different patient populations [12,13]. This is not surprising as, IFNc may be a key cytokine in activation of macrophages for mycobacterial stasis and killing [14], disease severity outcomes in tuberculosis depend on the balance among several different cytokines in situ, depending on the disease site. The objective of the current study was to analyze the frequency of cytokine gene polymorphisms linked to high and low responder phenotypes (IFNc +874 ThiRAlo and IL10 21082 GloRAhi) in tuberculosis patients
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