Ethnicity based comprehensive evaluation of polymorphism in interferon-gamma gene and its association with pulmonary and extra-pulmonary tuberculosis risk: An updated trial sequential meta-analysis.

Abstract

Host genetic background plays an important role in susceptibility to intracellular infectious pathogens like Mycobacterium tuberculosis (Mtb). Cellular immune response activation is vital for protection to these pathogens. Interferon-gamma (IFN-γ) plays a crucial role in this activation and preventing the intracellular growth of Mtb. A mutation in the IFN-γ gene, therefore, may lead to increased susceptibility to tuberculosis (TB) that may vary in different ethnic groups and its consequence also varies in pulmonary and extra-pulmonary TB (EPTB). Several IFN-γ gene polymorphisms are investigated for susceptibility to TB, but their associations are not always consistent as its impact may vary from one ethnicity to the other as well as with the type of TB. Hence, we performed a meta-analysis to overcome this problem. The present study involves comprehensive meta-analysis of + 874T/A polymorphism in the IFN-γ gene based on type of TB within five different ethnic groups to show its association with increased susceptibility to TB. Using PubMed and Google Scholar databases, a total of 50 case-control studies were retrieved having 8152 cases and 9755 controls in this meta-analysis. Thirty-eight studies of + 874T/A polymorphism of IFN-γ gene were correlated for Pooled odds ratios with 95% confidence intervals. The polymorphism was analyzed for six genetic models for five major ethnic groups accounting for heterogeneity among studies. Moreover, the sub-group analysis was based on the type of TB within each ethnic group. Trial sequential analysis was also performed for all the sub-groups to estimate the statistical consistency. IFN-γ +874 T/A polymorphism analysis clearly confirmed the increased association of + 874AA genotype with increased TB risk. This polymorphism also showed significant association in East Asian, European, American, and African ethnic groups whereas no such association was found in Asians. Patients with pulmonary TB (PTB) confirmed the association in East Asians, Africans, and Americans, whereas patients with EPTB showed association in Asian and East Asian populations only. This study reaffirms the association of IFN-γ+874 T/A polymorphism with TB risk. It specifically confirms that IFN-γ+874 T/A polymorphism increases the susceptibility of pulmonary infection in Africans and Americans, while the East Asian population is more susceptible to both, pulmonary and EPTB.