Abstract
The toll-like receptor 2 (TLR2)-mediated immune response is critical for host defense against Mycobacterium tuberculosis. There is evidence that TLR10, a TLR2 signaling modulator, may be involved in progression of tuberculosis (TB). Using a self-validating case-control design, we tested for an association between seven TLR10 polymorphisms and susceptibility to TB in three independent series with two distinct populations. Single-nucleotide polymorphism (SNP) genotypes were determined by the SNPscanTM method. Three genetic models (additive, dominant, and recessive) as well as multiple-SNP score analyses were used to evaluate the risk of TB associated with the TLR10 SNPs. By comparing TB patients with healthy controls, we observed two SNPs (rs11466617 and rs4129009) that were associated with decreased risk of TB in the Tibetan population, but did not in the Chinese Han population. Further analysis demonstrated that the rs11466617 Chengdu cohort genotype served as a protective factor against the progression of latent TB infection (LTBI) to active TB under the recessive model. None of the SNPs were significantly different in comparisons of TB-uninfected people with LTBI individuals. Additionally, when the underlying four TB-associated loci were considered together in a multiple-SNP score analysis, we observed an allele dose-dependent decrease in TB risk in Tibetans. Variants of TLR10 may show an ethnic specificity on susceptibility to TB in Tibetan individuals. rs11466617 affected the susceptibility to progress from LTBI to active TB disease, but was not associated with the establishment of LTBI after M. tuberculosis exposure. More studies are needed to verify this genetic epidemiological result and unravel the role of TLR10 SNPs in the pathogenesis of TB.
Highlights
Tuberculosis (TB), a chronic pulmonary disease caused by Mycobacterium tuberculosis (Mtb) infection, remains a leading global health threat with an estimated 10.4 million incident cases and 1.8 million deaths worldwide in 2015 [1]
Numerous candidate genes have been associated with risk of TB, including members of the toll-like receptor (TLR) family (TLR1, toll-like receptor 2 (TLR2), TLR4, TLR6, TLR9, TLR10, TIRAP) [7,8,9], which are widely expressed on various immune cells including monocytes, macrophages, dendritic cells, and lymphocytes and may modulate activation via TLR ligands [10, 11]
Association Analysis in Chengdu latent TB infection (LTBI) Cohort Due to a poor verification in the Chengdu cohort (CC), we further investigated the association between TLR10 single-nucleotide polymorphisms (SNPs) and TB risk by comparing the genotype distributions in the TB-uninfected group, the LTBI group, and the active TB group
Summary
Tuberculosis (TB), a chronic pulmonary disease caused by Mycobacterium tuberculosis (Mtb) infection, remains a leading global health threat with an estimated 10.4 million incident cases and 1.8 million deaths worldwide in 2015 [1]. It is estimated that one third of the world’s population is infected with Mtb, yet only approximately 5–15% of infected individuals develop active TB and the Association of TLR10 Polymorphisms and TB Susceptibility rest remain asymptomatic, which is termed latent TB infection (LTBI) [2]. In addition to environmental risk factors, genetic polymorphisms can influence the expression and/or activity of proteins involved in host immunity, which may result in susceptibility to TB and, to some extent, explain the TB patients without identifiable risk factors [5, 6]. The toll-like receptor 2 (TLR2)-mediated immune response is critical for host defense against Mycobacterium tuberculosis. There is evidence that TLR10, a TLR2 signaling modulator, may be involved in progression of tuberculosis (TB)
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