Toll-like receptor 2 gene polymorphisms, pulmonary tuberculosis, and natural killer cell counts

Abstract

Background: To investigate whether the toll-like receptor 2 polymorphisms could influence susceptibility to pulmonary TB, its phenotypes, and blood lymphocyte subsets.

Methods: A total of 368 subjects, including 184 patients with pulmonary TB and 184 healthy controls, were examined for TLR2 polymorphisms over locus -100 (microsatellite guanine-thymine repeats), -16934 (T>A), -15607 (A>G), -196 to -174 (insertion>deletion), and 1350 (T>C). Eighty-six TB patients were examined to determine the peripheral blood lymphocyte subpopulations.

Results: We newly identified an association between the haplotype [A-G-(insertion)-T] and susceptibility to pulmonary TB (p = 0.006, false discovery rate q = 0.072). TB patients with systemic symptoms had a lower -196 to -174 deletion/deletion genotype frequency than those without systemic symptoms (5.7% vs. 17.7%; p = 0.01). TB patients with the deletion/deletion genotype had higher blood NK cell counts than those carrying the insertion allele (526 vs. 243.5 cells/microl, p = 0.009). TB patients with pleuritis had a higher 1350 CC genotype frequency than those without pleuritis (12.5% vs. 2.1%; p = 0.004). TB patients with the 1350 CC genotype had higher blood NK cell counts than those carrying the T allele (641 vs. 250 cells/microl, p = 0.004). TB patients carrying homozygous short alleles for GT repeats had higher blood NK cell counts than those carrying one or no short allele (641 vs. 250 cells/microl, p = 0.004).

Conclusions: TLR2 genetic polymorphisms influence susceptibility to pulmonary TB. TLR2 variants play a role in the development of TB phenotypes, probably by controlling the expansion of NK cells.

Figure 1

Linkage disequilibrium plots. TLR2 gene loci of the four investigated polymorphisms on chromosome 4q32, and description of intra-genetic linkage disequilibrium patterns: (A) and (B) r² and D' plots, respectively.

Figure 2

Homozygous TLR2 -100 GT repeat polymorphism and absolute natural killer (NK) cell counts measured at diagnosis. TB patients carrying homozygous S alleles for TLR2 -100 microsatellite GT repeat polymorphism (SS genotype) had higher blood absolute NK cell counts compared with those carrying one S allele or without carrying S allele (p = 0.004). The box plots show 25^th, 50^th, and 75^th percentiles, maximal, minimal, outliers (○).

Figure 3

Homozygous TLR2 -196 to -174 Ins>Del polymorphism and absolute natural killer (NK) cell counts measured at diagnosis. TB patients carrying homozygous rare alleles for TLR2 -196 to -174 deletion/deletion genotype had higher blood absolute NK cell counts compared with those carrying common insertion allele (p = 0.009). The box plots show 25^th, 50^th, and 75^th percentiles, maximal, minimal, outliers (○).

Figure 4

Homozygous TLR2 1350 T>C polymorphism and absolute natural killer (NK) cell counts measured at diagnosis. TB patients carrying homozygous rare alleles for TLR2 1350 CC genotype had higher blood absolute NK cell counts compared with those carrying common allele (p = 0.004). The box plots show 25^th, 50^th, and 75^th percentiles, maximal, minimal, outliers (○).