Toll-like receptor gene polymorphisms are associated with susceptibility to graves' ophthalmopathy in Taiwan males
Wen-Ling Liao
0
1
Rong-Hsing Chen
2
Hui-Ju Lin
5
Yu-Huei Liu
0
1
Wen-Chi Chen
4
Yuhsin Tsai
1
Lei Wan
0
1
3
Fuu-J
n Ts
i
0
1
3
0
Genetic Center, China Medical University Hospital
,
Taichung
,
Taiwan
1
School of Chinese Medicine, China Medical University
,
Taichung
,
Taiwan
2
School of Post Baccalaureate Chinese Medicine; China Medical University
,
Taichung
,
Taiwan
3
Department of Biotechnology, Asia University
,
Taichung
,
Taiwan
4
Graduate Institute of Integrated Medicine; China Medical University
,
Taichung
,
Taiwan
5
Department of Ophthalmology, China Medical University Hospital
,
Taichung
,
Taiwan
Background: Toll-like receptors (TLRs) are a family of pattern-recognition receptors, which plays a role in eliciting innate/adaptive immune responses and developing chronic inflammation. The polymorphisms of TLRs have been associated with the risk of various autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis and rheumatorid arthritis. The aim of this study was to evaluate whether TLR genes could be used as genetic markers for the development of Graves' ophthalmopathy (GO). Methods: 6 TLR-4 and 2 TLR-9 gene polymorphisms in 471 GD patients (200 patients with GO and 271 patients without GO) from a Taiwan Chinese population were evaluated. Results: No statistically significant difference was observed in the genotypic and allelic frequencies of TLR-4 and TLR-9 gene polymorphisms between the GD patients with and without GO. However, sex-stratified analyses showed that the association between TLR-9 gene polymorphism and GO phenotype was more pronounced in the male patients. The odds ratios (ORs) was 2.11 (95% confidence interval [CI] = 1.14-3.91) for rs187084 AG polymorphism and 1.97 (95% CI = 1.07-3.62) for rs352140 AG polymorphism among the male patients. Increasing one G allele of rs287084 and one A allele of rs352140 increased the risk of GO (p values for trend tests were 0.0195 and 0.0345, respectively). Further, in haplotype analyses, the male patients carrying the GA haplotype had a higher risk of GO (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.09-3.73) than those not carrying the GA haplotype. Conclusion: The present data suggest that TLR-9 gene polymorphisms were significantly associated with increased susceptibility of ophthalmopathy in male GD patients.
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Background
Graves disease (GD) is an organ-specific autoimmune
thyroid disease, one of the manifestations of which is
ophthalmopathy [1]. Graves ophthalmopathy (GO) is
characterized by inflammation and fat deposition in the
eye muscles and the connective tissue surrounding the
eye. It is known that multiple factors contribute to the
etiology and severity of GD, including the hosts genetic
factors as well as environmental factors [2,3]. Female
sex, old age, and smoking history are common risk
factors for GD [4-8]. With regard to genetic factors, the
classical major histocompatibility complex class II genes
and cytotoxic T cell antigen-4 genes (CTLA-4) [9-11]
have been consistently reported to be associated with
GD. Also, there were published studies on association of
GO and genes such as CD103 [12], CTLA-4 and IL-13
[13]. However, the findings of most genes effect in GD
or GO were inconsistent. Recently, toll-like receptors
(TLRs) which play important roles in eliciting human
innate/adaptive immune responses and developing
chronic inflammation [14] are a new area of basic
immunological investigation and could be associated
with autoimmune thyroiditis [15].
TLRs are a family of pattern-recognition receptors and
can be expressed in several types of cells and tissues
such as macrophages, dendritic cells (DCs), B cells,
T cells and monocytes. A total of 10 human TLRs have
been identified and the functions of human TLR-1 to
TLR-9 have been characterized [16,17,14,15]. TLRs are
well known to recognize a variety of microbial
molecules such as TLR-4 can recognize lipopolysaccharides
(LPSs) in gram-negative bacteria and TLR-9 activation
can be triggered by unmethylated CpG DNA of bacteria.
Once TLRs are activated by microbial molecules,
downstream signalling pathway via myeloid differentiation
factor 88 (MyD88) and interleukin-1R (IL-1R)-associated
kinase (IRAK) activates nuclear factor B (NF- B),
leading to cytokine production, and even to apoptosis. TLRs
could response to not only exogenous, microbe derived
pathogen associated molecular patterns (PAMPs) but
also endogenous or self ligands. Recently, the ability of
TLRs to recognize host-derived danger signals, which
are produced on cell damage and necrosis, was also
recognized [18,19]. Moreover, studies have found that
the immune complexes containing self-RNA and/or
selfDNA can act as endogenous triggers for the activation
of TLRs [20-22].
Recently, release of endogenous TLR ligands during
inflammation and the consequent activation of TLR
signaling pathways have been indicated and polymorphism
of the TLR4 and TLR9 gene have been reported to be
associated wi (...truncated)