Abstract
Toll-like receptors (TLRs) 2, 4, and the vitamin D receptor (VDR) are central components of the innate and adaptive immunity against Mycobacterium tuberculosis (Mtb). TLR2, TLR4, and VDR polymorphisms were previously associated with tuberculosis (TB) and were here investigated as candidates for pulmonary TB (PTB) susceptibility in a Moroccan population group. Genomic DNA from 343 PTB patients and 203 healthy controls were analyzed for 12 single nucleotide polymorphisms (SNPs) located in TLR2, TLR4, and VDR genes using polymerase chain reaction-based restriction fragment length polymorphism and TaqMan SNP genotyping assays. The TLR2 +597 CT genotype was associated with protection against PTB (corrected p [pc] = 0.04; odds ratio (OR) = 0.65; 95% confidence interval (CI) = 0.45 - 0.94), and the TLR4 +7263 C allele was significantly associated with PTB susceptibility (pc = 0.04; OR = 1.63; CI = 1.06 - 2.57). The VDR [f,b,a,T] haplotype was found to confer protection (pc < 0.00001; OR = 0.18; CI = 0.09 - 0.35), while the TLR2 [-16934T,+597C,+1349T] haplotype seemed to be at risk (p = 0.03; OR = 1.52; CI = 1.01 - 2.30), but statistical significance was not reached. Finally, cross-analysis between polymorphisms of the three studied genes revealed significant interaction between TLR2 +597 and TLR4 +4434 SNPs towards protection against PTB (pc = 0.036), suggesting that the functionally relevant TLR4 +4434 SNP may act synergistically with TLR2 SNPs. TLR2 and TLR4 interaction and a specific VDR haplotype influence protection against PTB in Moroccans patients.
Highlights
Toll-like receptors (TLRs) 2, 4, and the vitamin D receptor (VDR) are central components of the innate and adaptive immunity against Mycobacterium tuberculosis (Mtb)
Among TLR2 single nucleotide polymorphisms (SNPs), the TLR2 +597 TC heterozygous genotype was found to be more prevalent in controls than in patients (60% vs. 49%, respectively; pc = 0.04, p = 0.01, odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.45-0.94 (Table 2)
The observed association between the TC genotype and protection against pulmonary TB (PTB) was further confirmed by a logistic regression analysis (p = 0.012, adjusted OR = 0.64, 95% confidence interval (95% CI) = 0.44-0.90) (Table 4)
Summary
Toll-like receptors (TLRs) 2, 4, and the vitamin D receptor (VDR) are central components of the innate and adaptive immunity against Mycobacterium tuberculosis (Mtb). TLR2, TLR4, and VDR polymorphisms were previously associated with tuberculosis (TB) and were here investigated as candidates for pulmonary TB (PTB) susceptibility in a Moroccan population group. While the total number of subjects infected with Mycobacterium tuberculosis (Mtb) is far larger (approximately two billion), the vast majority keeps the pathogen under control and never develops the disease. Innate immunity genes are important in modulating host susceptibility to TB because the first line of defense against Mtb involves the identification and uptake of the pathogen by macrophages and dendritic cells. Relevant genes for susceptibility to pulmonary TB (PTB) that contribute to this immune response include toll-like receptors (TLRs) 2 and 4 and the vitamin D receptor (VDR)
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