Polymorphisms of the BCL2 gene associated with susceptibility to tuberculosis

Abstract

Although tuberculosis (TB) is a serious public health concern, we still don't understand why only 10% of people infected will develop the disease. Apoptosis plays a role in the interaction of Mycobacterium tuberculosis (Mtb) with the human host and it may be modified by subtle alterations in the B-cell lymphoma 2 (BCL2) gene, an anti-apoptotic regulatory element. Therefore, we investigated whether there is an association between BCL2 polymorphisms and susceptibility to TB by analyzing 130 TB cases, 108 subjects with latent TB infection (LTBI), and 163 healthy controls (HC). Logistic regression was used to calculate odds ratios (ORs) and 95% confidential intervals (95% CIs) for possible associations between single nucleotide polymorphisms (SNPs) in BCL2 and the risk of tuberculosis. We found that the G allele of rs80030866 (OR=0.62, 95%CI:0.42-0.91, P=0.015), and also the G allele of rs9955190 (OR=0.58, 95%CI:0.38-0.88, P=0.011) were less frequent in the TB group compared with the LTBI group. In addition, individuals with rs2551402 CC genotype were more likely to have LTBI than those with AA genotype (OR=2.166, 95%CI:1.046-4.484, P=0.037). Our study suggests that BCL2 gene polymorphisms may be correlated with susceptibility to both TB and LTBI.

Combination of MCL-1 and BCL-2 inhibitors is a promising approach for a host-directed therapy for tuberculosis

“…Although inducing apoptosis has been a focus for boosting cancer treatment and polymorphisms in MCL-1 [ 13 ] and BCL-2 [ 14 ] are associated with susceptibility to TB disease, we were the first to interrogate inducing apoptosis through targeted inhibition of the anti-apoptotic BCL-2 proteins (specifically, MCL-1) for TB treatment [ 15 ]. Our previous work showed that targeted MCL-1 inhibition reduced M.tb growth in human macrophages, but that inhibition of multiple anti-apoptotic BCL-2 proteins (with pan inhibitors that inhibited anti-apoptotic MCL-1, BCL-2, and BCL-X L ) was required to reduce M.tb growth in a more complex model of human granuloma-like structures [ 15 ].…”