Screening toll-like receptor markers to predict latent tuberculosis infection and subsequent tuberculosis disease in a Chinese population

BMC Medical Genetics

Biao Xu¹  Weili Jiang¹  Dange Li¹  Yi Hu¹  Linlin Wu¹ 

[1] Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Shanghai, China

关键词: Susceptibility;    Latent tuberculosis infection;    Tuberculosis;    Polymorphism;    Toll-like receptors;   

Others  :  1177686
DOI  :  10.1186/s12881-015-0166-1

 received in 2014-07-16, accepted in 2015-03-20,  发布年份 2015

【 摘 要 】

Background

We investigated whether polymorphisms in the toll-like receptor genes or gene–gene interactions are associated with susceptibility to latent tuberculosis infection (LTBI) or subsequent pulmonary tuberculosis (PTB) in a Chinese population.

Methods

Two matched case–control studies were undertaken. Previously reported polymorphisms in the toll-like receptors (TLRs) were compared between 422 healthy controls (HC) and 205 LTBI patients and between 205 LTBI patients and 109 PTB patients, to assess whether these polymorphisms and their interactions are associated with LTBI or PTB. A PCR-based restriction fragment length polymorphism analysis was used to detect genetic polymorphisms in the TLR genes. Nonparametric multifactor dimensionality reduction (MDR) was used to analyze the effects of interactions between complex disease genes and other genes or environmental factors.

Results

Sixteen markers in TLR1, TLR2, TLR4, TLR6, TLR8, TLR9, and TIRAP were detected. In TLR2, the frequencies of the CC genotype (OR = 2.262; 95% CI: 1.433–3.570) and C allele (OR = 1.566; 95% CI: 1.223–1.900) in single-nucleotide polymorphism (SNP) rs3804100 were significantly higher in the LTBI group than in the HC group, whereas the GA genotype of SNP rs5743708 was associated with PTB (OR = 6.087; 95% CI: 1.687–21.968). The frequencies of the GG genotype of SNP rs7873784 in TLR4 (OR = 2.136; 95% CI: 1.312–3.478) and the CC genotype of rs3764879 in TLR8 (OR = 1.982; 95% CI: 1.292-3.042) were also significantly higher in the PTB group than in the HC group. The TC genotype frequency of SNP rs5743836 in TLR9 was significantly higher in the LTBI group than in the HC group (OR = 1.664; 95% CI: 1.201–2.306). An MDR analysis of gene–gene and gene–environment interactions identified three SNPs (rs10759932, rs7873784, and rs10759931) that predicted LTBI with 84% accuracy (p = 0.0004) and three SNPs (rs3804100, rs1898830, and rs10759931) that predicted PTB with 80% accuracy (p = 0.0001).

Conclusions

Our results suggest that genetic variation in TLR2, 4, 8 and 9, implicating TLR-related pathways affecting the innate immunity response, modulate LTBI and PTB susceptibility in Chinese.

【 授权许可】

   
2015 Wu et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Eurosurveillance Editorial T. ECDC and WHO/Europe joint report on tuberculosis surveillance and monitoring in Europe. Euro Surveill. 2014;19(11).
• [2]Skamene E: Genetic control of susceptibility to infections with intracellular pathogens. Pathol Biol 1998, 46(9):689-92.
• [3]Castrillon DM, Mejia SA, Hernandez JM, Robledo J: Pulmonary tuberculosis in a 4-month-old twin: hereditary versus environmental factors. Int J Tuberc Lung Dis 2013, 17(6):848-9.
• [4]Sabri A, Grant AV, Cosker K, El Azbaoui S, Abid A, Rhorfi IA, et al.: Association study of genes controlling IL-12-dependent IFN-gamma immunity: STAT4 alleles increase risk of pulmonary tuberculosis in Morocco. J Infect Dis 2014, 210(4):611-618.
• [5]Misch EA, Hawn TR: Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci 2008, 114(5):347-60.
• [6]Fujiwara N, Porcelli SA, Naka T, Yano I, Maeda S, Kuwata H, et al.: Bacterial sphingophospholipids containing non-hydroxy fatty acid activate murine macrophages via Toll-like receptor 4 and stimulate bacterial clearance. Biochim Biophys Acta 2013, 1831(6):1177-84.
• [7]He S, Liang Y, Shao F, Wang X: Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc Natl Acad Sci U S A 2011, 108(50):20054-9.
• [8]Qian C, Cao X: Regulation of Toll-like receptor signaling pathways in innate immune responses. Ann N Y Acad Sci 2013, 1283:67-74.
• [9]Ma X, Liu Y, Gowen BB, Graviss EA, Clark AG, Musser JM: Full-exon resequencing reveals toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS One 2007, 2(12):e1318.
• [10]Etokebe GE, Skjeldal F, Nilsen N, Rodionov D, Knezevic J, Bulat-Kardum L, et al.: Toll-like receptor 2 (P631H) mutant impairs membrane internalization and is a dominant negative allele. Scand J Immunol 2010, 71(5):369-81.
• [11]Dalgic N, Tekin D, Kayaalti Z, Soylemezoglu T, Cakir E, Kilic B, et al.: Arg753Gln polymorphism of the human Toll-like receptor 2 gene from infection to disease in pediatric tuberculosis. Hum Immunol 2011, 72(5):440-5.
• [12]Ferwerda B, McCall MB, Alonso S, Giamarellos-Bourboulis EJ, Mouktaroudi M, Izagirre N, et al.: TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans. Proc Natl Acad Sci U S A 2007, 104(42):16645-50.
• [13]Selvaraj P, Harishankar M, Singh B, Jawahar MS, Banurekha VV: Toll-like receptor and TIRAP gene polymorphisms in pulmonary tuberculosis patients of South India. Tuberculosis 2010, 90(5):306-10.
• [14]Arentz M, Hawn TR: Tuberculosis infection: insight from immunogenomics. Drug Discov Today Dis Mech 2007, 4(4):231-6.
• [15]Berrington WR, Hawn TR: Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter? Immunol Rev 2007, 219:167-86.
• [16]Yu W: Technical guidance group of the fifth national TB epidemiological survey. Chin J Antituber 2012, 34(8):485-508.
• [17]Hu Y, Zhao Q, Graviss EA, Jiang W, Yuan Z, Xu B: Use of the T-SPOT.TB assay to screen latent tuberculosis infection among the TB contacts in Shanghai, China. J Infect 2012, 65(1):39-48.
• [18]Thiel S, Holmskov U, Hviid L, Laursen SB, Jensenius JC: The concentration of the C-type lectin, mannan-binding protein, in human plasma increases during an acute phase response. Clin Exp Immunol 1992, 90(1):31-5.
• [19]Rajalingam R, Mehra NK, Jain RC, Myneedu VP, Pande JN: Polymerase chain reaction–based sequence-specific oligonucleotide hybridization analysis of HLA class II antigens in pulmonary tuberculosis: relevance to chemotherapy and disease severity. J Infect Dis 1996, 173(3):669-76.
• [20]Nilsson D, Andiappan AK, Hallden C, De Yun W, Sall T, Tim CF, et al.: Toll-like receptor gene polymorphisms are associated with allergic rhinitis: a case control study. BMC Med Genet 2012, 13:66. BioMed Central Full Text
• [21]Folwaczny M, Glas J, Torok HP, Limbersky O, Folwaczny C: Toll-like receptor (TLR) 2 and 4 mutations in periodontal disease. Clin Exp Immunol 2004, 135(2):330-5.
• [22]Sole X, Guino E, Valls J, Iniesta R, Moreno V: SNPStats: a web tool for the analysis of association studies. Bioinformatics 2006, 22(15):1928-9.
• [23]Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, et al.: Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001, 69(1):138-47.
• [24]Reiling N, Holscher C, Fehrenbach A, Kroger S, Kirschning CJ, Goyert S, et al.: Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 2002, 169(7):3480-4.
• [25]Drennan MB, Nicolle D, Quesniaux VJ, Jacobs M, Allie N, Mpagi J, et al.: Toll-like receptor 2-deficient mice succumb to Mycobacterium tuberculosis infection. Am J Pathol 2004, 164(1):49-57.
• [26]Thuong NT, Hawn TR, Thwaites GE, Chau TT, Lan NT, Quy HT, et al.: A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun 2007, 8(5):422-8.
• [27]Ogus AC, Yoldas B, Ozdemir T, Uguz A, Olcen S, Keser I, et al.: The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 2004, 23(2):219-23.
• [28]Xue Y, Zhao ZQ, Wang HJ, Jin L, Liu CP, Wang Y, et al.: Toll-like receptors 2 and 4 gene polymorphisms in a southeastern Chinese population with tuberculosis. Int J Immunogenet 2010, 37(2):135-8.
• [29]Kobayashi K, Yuliwulandari R, Yanai H, Naka I, Lien LT, Hang NT, et al.: Association of TLR polymorphisms with development of tuberculosis in Indonesian females. Tissue Antigens 2012, 79(3):190-7.
• [30]Caws M, Thwaites G, Dunstan S, Hawn TR, Lan NT, Thuong NT, et al.: The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS Pathog 2008, 4(3):e1000034.
• [31]DeFranco AL, Crowley MT, Finn A, Hambleton J, Weinstein SL: The role of tyrosine kinases and map kinases in LPS-induced signaling. Prog Clin Biol Res 1998, 397:119-36.
• [32]Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al.: TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000, 25(2):187-91.
• [33]Hawn TR, Verbon A, Janer M, Zhao LP, Beutler B, Aderem A: Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires’ disease. Proc Natl Acad Sci U S A 2005, 102(7):2487-9.
• [34]Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, et al.: Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. J Commun Dis 2006, 38(3):230-45.
• [35]Schroder NW, Schumann RR: Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 2005, 5(3):156-64.
• [36]Xu J, Lowey J, Wiklund F, Sun J, Lindmark F, Hsu FC, et al.: The interaction of four genes in the inflammation pathway significantly predicts prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2005, 14(11 Pt 1):2563-8.
• [37]Huang X, Barrett RP, McClellan SA, Hazlett LD: Silencing Toll-like receptor-9 in Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 2005, 46(11):4209-16.
• [38]Suzuki K, Suda T, Naito T, Ide K, Chida K, Nakamura H: Impaired toll-like receptor 9 expression in alveolar macrophages with no sensitivity to CpG DNA. Am J Respir Crit Care Med 2005, 171(7):707-13.
• [39]Ng MT, Van’t Hof R, Crockett JC, Hope ME, Berry S, Thomson J, et al.: Increase in NF-kappaB binding affinity of the variant C allele of the toll-like receptor 9–1237 T/C polymorphism is associated with Helicobacter pylori-induced gastric disease. Infect Immun 2010, 78(3):1345-52.
• [40]Lange NE, Zhou X, Lasky-Su J, Himes BE, Lazarus R, Soto-Quiros M, et al.: Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes. BMC Med Genet 2011, 12:26. BioMed Central Full Text
• [41]Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al.: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006, 311(5768):1770-3.