Associations of Toll-like receptor 7 and 8 Polymorphisms with Asthma and Asthma-related Phenotypes in a Chinese Han Population
-
Qian Zhang
,
Fen-Hong Qian
,
Xiao-Wei Yin
,
Qi Cao
,
Jian-Ling Bai
,
Qiang Du
,
Yi Shi
Abstract
Toll-like receptor (TLR) 7 and 8 mediate anti-virus immunity and are of particular relevance to asthma. However, very little information about genetic association on TLR7/8 and asthma are available. This study aimed to evaluate the effects of polymorphisms in TLR7 and 8 on asthma risk and asthma-related phenotypes in a Chinese Han population. We enrolled 462 unrelated adult asthmatic patients and 398 healthy volunteers. The genotypes of tagging single nucleotide polymorphisms (SNPs) in TLR7 and 8 genes were determined using multiplex SNaPshot SNP genotyping assay. We used case-control and case-only studies to assess any links with asthma and asthma-related phenotypes. There was no association between the variants in TLR7 and 8 and asthma susceptibility. However, our results revealed that the genetic variants in TLR7 and 8 were associated with asthma-related phenotypes, including eosinophil counts, serum immunoglobulin E levels, lung function, and asthma severity as well. Our study suggests that TLR7 and 8 polymorphisms may play a considerable role in the pathogenesis of asthma. It will help in better understanding the pathogenesis of asthma and development of more effective strategies for asthma prevention, prediction, and therapy.
1. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001; 344(5):350-62.
2. Akhabir L, Sandford AJ. Genome-wide association studies for discovery of genes involved in asthma. Respirology 2011; 16(3):396-406.
3. Romagnani S. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? Immunology 2004; 112(3):352-63.
4. Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science 2010;327(5963):291-5.
5. Barton GM, Medzhitov R. Toll-like receptor signaling pathways. Science 2003; 300(5625):1524-5.
6. Sun J, Walsh M, Villarino AV, Cervi L, Hunter CA, Choi Y, et al. TLR ligands can activate dendritic cells to provide a MyD88-dependent negative signal for Th2 cell development. J Immunol 2005; 174(2):742-51.
7. Conroy H, Marshall NA, Mills KH. TLR ligand suppression or enhancement of Treg cells? A double- edged sword in immunity to tumours. Oncogene 2008;27(2):168-80.
8. Cherfils-Vicini J, Platonova S, Gillard M, Laurans L, Validire P, Caliandro R, et al. Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest 2010;120(4):1285-97.
9. Ekman AK, Adner M, Cardell LO. Toll-like receptor 7 activation reduces the contractile response of airway smooth muscle. Eur J Pharmacol 2011; 652(1-3):145-51.
10. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8.Science 2004; 303(5663):1526-9.
11. Xirakia C, Koltsida O, Stavropoulos A, Thanassopoulou A, Aidinis V, Sideras P, at al. Toll-like receptor 7- triggered immune response in the lung mediates acute and long-lasting suppression of experimental asthma. Am J Respir Crit Care Med 2010; 181(11):1207-16.
12. Van LP, Bardel E, Gregoire S, Vanoirbeek J, Schneider E, Dy M, et al. Treatment with the TLR7 agonist R848 induces regulatory T-cell-mediated suppression of established asthma symptoms. Eur J Immunol 2011;41(7):1992-9.
13. Grela F, Aumeunier A, Bardel E, Van LP, Bourgeois E, Vanoirbeek J, et al. The TLR7 agonist R848 alleviates allergic inflammation by targeting invariant NKT cells to produce IFN-gamma. J Immunol 2011; 186(1):284-90.
14. Edwards S, Jones C, Leishman AJ, Young BW, Matsui H, Tomizawa H, et al. TLR7 stimulation of APCs results in inhibition of IL-5 through type I IFN and Notch signaling pathways in human peripheral blood mononuclear cells. J Immunol 2013; 190(6):2585-92.
15. Greiff L, Cervin A, Ahlstrom-Emanuelsson C, Almqvist G, Andersson M, Dolata J, et al. Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis. Respir Res 2012; 13:53.
16. Drake MG, Scott GD, Proskocil BJ, Fryer AD, Jacoby DB, Kaufman EH. Toll-like receptor 7 rapidly relaxes human airways. Am J Respir Crit Care Med 2013;188(6):664-72.
17. Chuang TH, Ulevitch RJ. Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur Cytokine Netw 2000; 11(3):372-8.
18. Enevold C, Nielsen CH, Jacobsen RS, Hermansen ML, Molbo D, Avlund K, et al. Single nucleotide polymorphisms in genes encoding toll-like receptors 7, 8 and 9 in Danish patients with systemic lupus erythematosus. Mol Biol Rep 2014; 41(9):5755-63.
19. Wang CH, Eng HL, Lin KH, Liu HC, Chang CH, Lin TM. Functional polymorphisms of TLR8 are associated with hepatitis C virus infection. Immunology 2014;141(4):540-8.
20. Sada T, Ota M, Katsuyama Y, Meguro A, Nomura E, Uemoto R, et al. Association analysis of Toll-like receptor 7 gene polymorphisms and Behçet's disease in Japanese patients. Hum Immunol 2011; 72(3):269-72.
21. Oh DY, Baumann K, Hamouda O, Eckert JK, Neumann K, Kücherer C, et al. A frequent functional toll-like receptor 7 polymorphism is associated with accelerated HIV-1 disease progression. AIDS 2009; 23(3):297-307.
22. Nilsson D, Andiappan AK, Halldén C, De Yun W, Säll 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.
23. Møller-Larsen S, Nyegaard M, Haagerup A, Vestbo J, Kruse TA, Børglum AD. Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders. Thorax 2008;63(12):1064-9.
24. Zhang Q, Qian FH, Zhou LF, Wei GZ, Wang Y, Hu ZB, et al. Polymorphisms of TLR7 and TLR8 associated with risk of asthma and asthma-related phenotypes in a southeastern Chinese Han population. Journal of Nanjing Medical University 2009; 23(1):25-32.
25. The Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) 2010. Available from: http://www.ginasthma.org/.
26. Wu X, Gu J, Grossman HB, Amos CI, Etzel C, Huang M, et al. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am J Hum Genet 2006; 78(3):464-79.
27. Qian FH, Zhang Q, Zhou LF, Liu H, Huang M, Zhang XL, et al. High sensitivity C-reactive protein: a predicative marker in severe asthma. Respirology 2008;13(5):664-9.
28. Hu XP, Wu JQ, Zhu LP, Wang X, Xu B, Wang RY, et al.Association of Fcγ receptor IIB polymorphism with cryptococcal meningitis in HIV-uninfected Chinese patients. PLoS One 2012; 7(8):e42439.
29. Esteves LM, Bulhões SM, Brilhante MJ, Mota-Vieira L.
Three multiplex snapshot assays for SNP genotyping in candidate innate immune genes. BMC Res Notes 2013;6:54.
30. Yang K, Puel A, Zhang S, Eidenschenk C, Ku CL, Casrouge A, et al. Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 2005; 23(5):465-78.
31. Du Q, Zhou LF, Chen Z, Gu XY, Huang M, Yin KS.Imiquimod, a toll-like receptor 7 ligand, inhibits airway remodelling in a murine model of chronic asthma. Clin Exp Pharmacol Physiol 2009; 36(1):43-8.
32. Vultaggio A, Nencini F, Pratesi S, Maggi L, Guarna A, Annunziato F, et al. The TLR7 ligand 9-benzyl-2-butoxy-8-hydroxy adenine inhibits IL-17 response by eliciting IL-10 and IL-10-inducing cytokines. J Immunol 2011;186(8):4707-15.
33. Frotscher B, Anton K, Worm M. Inhibition of IgE production by the imidazoquinoline resiquimod in nonallergic and allergic donors. J Invest Dermatol 2002;119(5):1059-64.
34. Filì L, Ferri S, Guarna F, Sampognaro S, Manuelli C, Liotta F, et al. Redirection of allergen-specific TH2 responses by a modified adenine through Toll-like receptor 7 interaction and IL-12/IFN release. J Allergy Clin Immunol 2006; 118(2):511-7.
35. Roponen M, Yerkovich ST, Hollams E, Sly PD, Holt PG, Upham JW. Toll-like receptor 7 function is reduced in adolescents with asthma. Eur Respir J 2010; 35(1):64-71.
36. Sykes A, Edwards MR, Macintyre J, del Rosario A, Bakhsoliani E, Trujillo-Torralbo MB, et al. Rhinovirus 16-induced IFN-α and IFN-β are deficient in bronchoalveolar lavage cells in asthmatic patients. J Allergy Clin Immunol 2012; 129(6):1506-1514.e6.
37. Sykes A, Macintyre J, Edwards MR, Del Rosario A, Haas J, Gielen V, et al. Rhinovirus-induced interferon production is not deficient in well controlled asthma. Thorax 2014; 69(3):240-6.
38. Zhang Q, Qian FH, Zhou LF, Wei GZ, Jin GF, Bai JL, et al. Polymorphisms in toll-like receptor 4 gene are associated with asthma severity but not susceptibility in a Chinese Han population. J Investig Allergol Clin Immunol 2011; 21(5):370-7.
39. Qian FH, Zhang Q, Zhou LF, Jin GF, Bai JL, Yin KS.Polymorphisms in the toll-like receptor 2 subfamily and risk of asthma: a case-control analysis in a Chinese population. J Investig Allergol Clin Immunol 2010;20(4):340-6.
40. Kvarnhammar AM, Cardell LO. Pattern-recognition receptors in human eosinophils. Immunology 2012;136(1):11-20.
41. Månsson A, Cardell LO. Role of atopic status in Toll-like receptor (TLR)7- and TLR9-mediated activation of human eosinophils. J Leukoc Biol 2009; 85(4):719-27.
42. Nagase H, Okugawa S, Ota Y, Yamaguchi M, Tomizawa H, Matsushima K, et al. Expression and function of Toll- like receptors in eosinophils: activation by Toll-like receptor 7 ligand. J Immunol 2003; 171(8):3977-82.
43. Shen E, Lu L, Wu C. TLR7/8 ligand, R-848, inhibits IgE synthesis by acting directly on B lymphocytes. Scand J Immunol 2008; 67(6):560-8.
44. Sackesen C, van de Veen W, Akdis M, Soyer O, Zumkehr J, Ruckert B, et al. Suppression of B-cell activation and IgE, IgA, IgG1 and IgG4 production by mammalian telomeric oligonucleotides. Allergy 2013;68(5):593-603.
45. Kaufman EH, Fryer AD, Jacoby DB. Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs. J Allergy Clin Immunol 2011; 127(2):462-9.
46. Shen N, Fu Q, Deng Y, Qian X, Zhao J, Kaufman KM, et al. Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci U S A 2010; 107(36):15838-43.
47. Yue M, Feng L, Tang SD, Wang JJ, Xue XX, Ding WL, et al. Sex-specific association between X-linked Toll-like receptor 7 with the outcomes of hepatitis C virus infection. Gene 2014; 548(2):244-50.
48. Schott E, Witt H, Neumann K, Taube S, Oh DY, Schreier E, et al. A Toll-like receptor 7 single nucleotide polymorphism protects from advanced inflammation and fibrosis in male patients with chronic HCV-infection. J Hepatol 2007; 47(2):203-11.
49. Osman M, Hansell AL, Simpson CR, Hollowell J, Helms PJ. Gender-specific presentations for asthma, allergic rhinitis and eczema in primary care. Prim Care Respir J 2007; 16(1):28-35.
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| Issue | Vol 14, No 6 (2015) | |
| Section | Original Article(s) | |
| Keywords | ||
| Asthma Allergy Genotype Polymorphism Toll-like receptor 7 and 8 | ||
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