Toll-like receptor gene polymorphisms are associated with susceptibility to graves' ophthalmopathy in Taiwan males

BMC Medical Genetics, Nov 2010

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 AàG polymorphism and 1.97 (95% CI = 1.07-3.62) for rs352140 AàG 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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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. - 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)


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Wen-Ling Liao, Rong-Hsing Chen, Hui-Ju Lin, Yu-Huei Liu, Wen-Chi Chen, Yuhsin Tsai, Lei Wan, Fuu-Jen Tsai. Toll-like receptor gene polymorphisms are associated with susceptibility to graves' ophthalmopathy in Taiwan males, BMC Medical Genetics, 2010, pp. 154, 11, DOI: 10.1186/1471-2350-11-154