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Genetic variation in TLR pathway and the risk of pulmonary tuberculosis in a Moldavian population

Varzari, Alexander, Deyneko, Igor V., Vladei, Iuri, Grallert, Harald, Schieck, Maximilian, Tudor, Elena, Illig, Thomas
Infection, genetics, and evolution 2019 v.68 pp. 84-90
Toll-like receptor 2, Toll-like receptor 4, Toll-like receptor 8, Toll-like receptor 9, alleles, females, genetic variation, genotyping, immune response, males, models, patients, quality control, risk, single nucleotide polymorphism, tuberculosis
Toll-like receptors (TLRs) play a critical role in initiating an immune response to infections. In this study, we examined whether single nucleotide polymorphisms (SNPs) in TLR pathway genes are associated with pulmonary tuberculosis (PTB) in a Moldavian population. Thirty-four SNPs in genes associated with the TLR pathway and two SNPs in ASAP1 gene identified by GWAS were selected for genotyping in 272 patients and 251 community-matched healthy controls. Twenty-nine SNPs passed quality control and were statistically evaluated. SNPs TLR9 rs352139, TLR2 rs3804099 and MYD88 rs4988453 were associated with PTB in females (OR = 0.49, p = 0.0009; OR = 0.51, p = 0.0008; OR = 0.33, p = 0.027; here and below log-additive model with minor alleles assumed as effect associated alleles), while SNP TLR8 rs3764880 showed a significant association in males (OR = 0.44, p = 0.0087). Furthermore, SNPs TLR9 rs352139 and TLR8 rs3764880 were associated with PTB in the late-onset (≥39-year-old) patient group (OR = 0.60, p = 0.0029 and OR = 0.70, p = 0.021, respectively) and SNPs TLR2 rs3804099, TLR4 rs4986790 and TLR4 rs1927906 in the early-onset (≤ 38-year-old) group (OR = 0.53, p = 0.0012; OR = 3.45, p = 0.013; OR = 2.31, p = 0.044, respectively). After correction for multiple testing, only SNPs TLR9 rs352139 and TLR2 rs3804099 in the female group and SNP TLR2 rs3804099 in the early-onset group remained significant. In summary, we show an association of SNP TLR8 rs3764880 with PTB in the Moldavian male population, providing support to previous studies conducted on other populations. Polymorphisms rs3804099 (TLR2) and rs352139 (TLR9) may also be associated with PTB risk in the Moldavian population but their effect is less consistent across different studies. Additional large-scale association studies along with functional tests are required to dissect the relevance of these associations.