The toll-like receptor (TLR) genes were shown to be involved in the pathogenesis of rheumatoid arthritis (RA). We aimed to investigate the genetic associations between the TLR-1, -2, -4, and -6 genes polymorphisms with RA susceptibility in a Chinese Han population.
Methods:
Six polymorphisms [TLR-1 (rs5743610, rs5743618), -2 (rs5743708), -4 (rs4986790, rs4986791), and -6 (rs5743810)] in TLRs genes were genotyped in 360 patients with RA and 560 matched healthy controls by direct sequencing. The odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated using a standard logistic regression analysis.
Results:
No significant associations were observed under the allelic, dominant, or recessive models for TLR-1 rs5743610, TLR-2 rs5743708, TLR-4 rs4986790 and rs4986791, and TLR-6 rs5743810 polymorphisms and RA risk (all p > 0.05). However, significant associations were detected under the allelic, dominant, and recessive models for TLR-1 rs5743618 and RA risk (allelic: OR [95% CI] = 2.21 [1.73-2.81], p < 0.0001; dominant: OR [95% CI] = 2.33 [1.75-3.09], p < 0.0001; recessive models: OR [95% CI] = 3.70 [1.85-7.41], p = 0.0002). In addition, TLR6 rs5743810 was found to be associated with the rheumatoid factor (RF)− and anticyclic citrullinated peptide (anti-CCP)− antibody in RA group (RF: OR [95% CI] = 2.29 [1.42-3.69], p = 0.0007; anti-CCP: OR [95% CI] = 2.33 [1.39-3.89], p = 0.001).
Conclusions:
The allelic, dominant, and recessive models of TLR1 rs5743618 might be associated with RA susceptibility. Also, the TLR6 rs5743810 marker may be associated with RF and the anti-CCP antibody of RA in the Chinese Han population.
Get full access to this article
View all access options for this article.
References
1.
Alarcón-SegoviaD, Alarcón-RiquelmeME, CardielMH, et al. (2005) Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheumatol, 52:1138-1147.
2.
BulutY, FaureE, ThomasL, et al. (2001) Cooperation of toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein a lipoprotein: role of toll-interacting protein and IL-1 receptor signaling molecules in toll-like receptor 2 signaling. J Immunol, 167:987-994.
3.
ChenYC, GiovannucciE, KraftP, et al. (2007) Association between Toll-like receptor gene cluster (TLR6, TLR1, and TLR10) and prostate cancer. Cancer Epidemiol Biomark Prev, 16:1982.
4.
ChoK, WenchengL, TakeshitaS, et al. (2017) Evidence for the presence of cell-surface-bound and intracellular bactericidal toxins in the dinoflagellate, Heterocapsa circularisquama. Aquat Toxicol, 189:209-215.
5.
ElassE, LaëtitiaAubry, MassonM, et al. (2005) Mycobacterial lipomannan induces matrix metalloproteinase-9 expression in human macrophagic cells through a toll-like receptor 1 (TLR1)/TLR2- and CD14-dependent mechanism. Infect Immunity, 73:7064-7068.
6.
GallacherR (2015) Rheumatoid arthritis. Nursing standard: official newspaper of the Royal Coll Nurs, 30:61-62.
7.
HoffjanS, StemmlerS, ParwezQ, et al. (2005) Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease. BMC Med Genet, 6:34.
8.
HuangQQ, MaY, AdebayoA, et al. (2007) Increased macrophage activation mediated through Toll-like receptors in rheumatoid arthritis. Arthrit Rheumatol, 56:2192-2201.
9.
IwahashiM, YamamuraM, AitaT, et al. (2004) Expression of toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthrit Rheumatol, 50:1457-1467.
10.
JaenO, Petit-TeixeiraE, KirstenH, et al. (2009) No evidence of major effects in several Toll-like receptor gene polymorphisms in rheumatoid arthritis. Arthrit Res Ther, 11:R5.
11.
KangES, LeeJ (2007) Genotypic analysis of Asp299Gly and Thr399Ile polymorphism of Toll-like receptor. Rheumatol Int, 27:887-889.
12.
KarlsonEW, DingB, KeenanBT, et al. (2013) Association of environmental and genetic factors and gene-environment interactions with risk of developing rheumatoid arthritis. Arthrit Care Res, 65:1147-1156.
13.
KeshS, MensahNY, PeterlongoP, et al. (2005) TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation. Ann N Y Acad Sci, 1062:95-103.
14.
KildingR, AkilM, TillS, et al. (2003) A biologically important single nucleotide polymorphism within the toll-like receptor-4 gene is not associated with rheumatoid arthritis. Clin Exp Rheumatol, 21:340-342.
15.
KuoCF, GraingeMJ, ValdesAM, et al. (2017) Familial aggregation of rheumatoid arthritis and co-aggregation of autoimmune diseases in affected families: a nationwide population-based study. Rheumatology, 56:928-933.
16.
KuulialaK, OrpanaA, Leirisalo-RepoM, et al. (2006) Polymorphism at position +896 of the toll-like receptor 4 gene interferes with rapid response to treatment in rheumatoid arthritis. Ann Rheum Dis, 65:1241-1243.
17.
LeeYH, SongGG (2013) Meta-analysis demonstrates association between TLR polymorphisms and rheumatoid arthritis. Genet Mol Res, 12:328-334.
18.
LeorattiFM, FariasL, AlvesFP, et al. (2008) Variants in the Toll-like receptor signaling pathway and clinical outcomes of malaria. J Infect Dis, 198:772-780.
19.
MajewskaM, SzczepanikM (2006) The role of Toll-like receptors (TLR) in innate and adaptive immune responses and their function in immune response regulation. Postep Hig Med Dosw, 60:52-63.
MassariP, VisintinA, GunawardanaJ, et al. (2006) Meningococcal porin PorB binds to TLR2 and requires TLR1 for signaling. J Immunol, 176:2373-2380.
22.
MassonnetB, DelwailA, AyraultJM, et al. (2009) Increased immunoglobulin A in alcoholic liver cirrhosis: exploring the response of B cells to Toll-like receptor 9 activation. Clin Exp Immunol, 158:115-124.
23.
MikacenicC, ReinerAP, HoldenTD, et al. (2013) Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of inter-individual difference in TLR1/2-mediated responses. Genes Immun, 14:52-57.
24.
MischEA. VerbonA, PrinsJM, et al. (2013) A TLR6 polymorphism is associated with increased risk of Legionnaires' disease. Genes Immun, 14:420-426.
25.
MorganAR, LamWJ, HanDY, et al. (2012) Genetic variation within TLR10 is associated with Crohn's disease in a New Zealand population. Hum Immunol, 73:416-420.
26.
NeteaMG, MeerJWMVD, KullbergBJ (2006) Recognition of pathogenic microorganisms by Toll-like receptors. Drugs Today (Barcelona, Spain: 1998) 42 Suppl, A:99-105.
27.
OspeltC, BrentanoF, RengelY, et al. (2008) Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum, 58:3684-3692.
28.
OspeltC, GayS (2010) TLRs and chronic inflammation. Int J Biochem Cell Biol, 42:500-505.
29.
RadstakeTR, FrankeB, HanssenS, et al. (2004) The Toll-like receptor 4 Asp299Gly functional variant is associated with decreased rheumatoid arthritis disease susceptibility but does not influence disease severity and/or outcome. Arthritis Rheum, 50:999-1001.
30.
RequenaT, GazquezI, MorenoA, et al. (2013) Allelic variants in TLR10 gene may influence bilateral affectation and clinical course of Meniere’ s disease. Immunogenetic, 65:345-355.
31.
RuckdeschelK, PfaffingerG, HaaseR, et al. (2004) Signaling of apoptosis through TLRs critically involves Toll/IL-1 receptor domain-containing adapter inducing IFN-a, but not MyD88, in bacteria-infected murine macrophages. J Immunol, 173:3320-3328.
32.
SacreS, LoA, GregoryB, et al. (2016) Oligodeoxynucleotide inhibition of Toll-like receptors 3, 7, 8, and 9 suppresses cytokine production in a human rheumatoid arthritis model. Eur J Immunol, 46:772-781.
33.
SanchezE, OrozcoG, Lopez-NevotMA, et al. (2004) Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lupus erythematosus. Tissue Antigens, 63:54-57.
34.
SheyMS, RandhawaAK, BowmakerM, et al. (2010) Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion. Genes Immun, 11:561-572.
StappersMHT, ThysY, OostingM, et al. (2014) TLR1, TLR2, and TLR6 gene polymorphisms are associated with increased susceptibility to complicated skin and skin structure infections. J Infect Dis, 210:311.
37.
StevensVL, HsingAW, TalbotJT, et al. (2010) Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer risk. Int J Cancer, 123:2644-2650.
38.
SunL, DaiC, WuJ, et al. (2018) TSLP-activated dendritic cells induce T helper type 2 inflammation in Aspergillus fumigatus keratitis. Exp Eye Res, 171:120-130.
39.
ThwaitesR, ChamberlainG, SacreS (2014) Emerging role of endosomal toll-like receptors in rheumatoid arthritis. Front Immunol, 5:1.
40.
TizaouiK, NaoualiA, KaabachiW, et al. (2015) Association of Toll like receptor Asp299Gly with rheumatoid arthritis risk: a systematic review of case-control studies and meta-analysis. Pathol Res Pract, 211:219-225.
41.
VeltkampM, MoorselC, RijkersGT, et al. (2011) Genetic variation in the Toll-like receptor gene cluster (TLR10-TLR1-TLR6) influences disease course in sarcoidosis. Tissue Antigens, 79:25-32.
42.
XiaoWJ, LiuZL, LinJH, et al. (2014) Polymorphisms in TLR1, TLR6 and TLR10 genes and the risk of Graves' disease. Autoimmunity, 48:1-6.
43.
YangLL, MiYY, WangYF, et al. (2011) Expression and significance of TLR2 in rheumatoid arthritis. China Modern Doctor, 49:19-20.
44.
YuC, LiM, DuanX, et al. (2018) Chinese registry of rheumatoid arthritis (CREDIT): introduction and prevalence of remission in Chinese patients with rheumatoid arthritis. Clin Exp Rheumatol, 36:836-840.
45.
YuanM, XiaJ, MaL, et al. (2010) Lack of the toll-like receptor 4 gene polymorphisms Asp299Gly and Thr399ile in a Chinese population. Int J Neurosci, 120:415-420.
46.
ZhangY, JiangT, YangX, et al. (2013) Toll-like receptor -1, -2, and -6 polymorphisms and pulmonary tuberculosis susceptibility: a systematic review and meta-analysis. PLoS One, 8:e63357.
47.
ZhengB, LiQ, WeiC, et al. (2010) Lack of association of TLR4 gene Asp299Gly and Thr399Ile polymorphisms with rheumatoid arthritis in Chinese Han population of Yunnan Province. Rheumatol Int, 30:1249-1252.
