Common Polymorphisms in the CD43 Gene Region Are Associated with Tuberculosis Disease and Mortality

Abstract

CD43, a surface glycoprotein, regulates Mycobacterium tuberculosis macrophage binding, replication, and proinflammatory cytokine induction in a murine model. We hypothesized that single-nucleotide polymorphisms (SNPs) in the CD43 gene region are associated with human tuberculosis (TB) susceptibility. We performed a casepopulation study in discovery (352 TB cases and 382 control subjects) and validation cohorts (339 TB cases and 376 control subjects). We examined whether 11 haplotype-tagging SNPs in the CD43 gene region were associated with tuberculous meningitis (TBM) and pulmonary TB (PTB) in Vietnam. Three SNPs from the CD43 gene region were associated with TB susceptibility with a genotypic model. The association fit a recessive genetic model and was greater for TBM than for PTB (for TBM: rs4788172, odds ratio [OR], 1.64; 95% confidence interval [CI], 1.04-2.59, rs17842268 [OR, 2.20; 95% CI, 1.29-3.76, and rs12596308 [OR, 2.38; 95% CI, 1.47-3.89]). Among TBM cases, rs17842268 was associated with decreased survival (hazard ratio, 2.7; 95% CI, 1.1-6.5; P = 0.011). In addition, rs12596308 and rs17842268 were associated with focal neurologic deficit at TBM presentation. Our data suggest that CD43 polymorphisms are associated with TB susceptibility, disease manifestations, and worse outcomes. To our knowledge, this is the first report that links CD43 genetic variants with susceptibility and outcome from a disease.

TLR9 gene region polymorphisms and susceptibility to tuberculosis in Vietnam

“…With regards to the risk attributable to the TLR9 polymorphisms, the odds ratios for rs352142 and rs352413 are 1.92 and 4.96, respectively (Table 3). These odds ratios are similar or higher than those found for the SNPs in SIGRR[7], TOLLIP[25], CD43[26] and LTA4H[28] which have also been associated with PTB and/or TBM. However, the frequencies of the TLR9 SNPs are both low which diminishes the population level attributable risk.…”

Interaction of the CD43 Sialomucin with the Mycobacterium tuberculosis Cpn60.2 Chaperonin Leads to Tumor Necrosis Factor Alpha Production

“…Interestingly, mice deficient in the CD43 molecule, a receptor for the M. tuberculosis chaperone Cpn60.2, develop unstructured granulomas and have a large increase in bacterial burden (20). Consistent with data describing CD43 as a molecule that significantly contributes to TNF-␣ production and growth inhibition of M. tuberculosis in macrophages (19,20,47), a recent report indicates that CD43 polymorphisms are associated with susceptibility to tuberculosis disease manifestations and worst outcomes (57). The fact that survival and replication of M. tuberculosis were significantly enhanced in CD43-deficient mice suggests that in addition to serving as an adhesion molecule that facilitates the uptake of the mycobacteria, CD43 participates in subsequent events within the macrophages (20), contributing to and shaping the outcome of the infection.…”

The pathogenesis of tuberculous meningitis

“…There are a number of other polymorphisms documented in the literature to relate to the pathogenesis of TBM. Polymorphisms in CD43 encoding a surface glycoprotein involved in M.tb adhesion and proinflammatory cytokine induction has been associated with decreased survival from TBM . The mannose binding protein (MBP) binds mycobacteria and acts as an opsonin in vitro.…”