Association of genetic variations in FoxP3 gene with Graves' disease in a Southwest Chinese Han population.

BACKGROUND: Graves' disease (GD) is a T cell-mediated organ-specific autoimmune disease. Forkhead box P3 (FoxP3) is an excellent marker for the induction and development of regulatory T cells (Tregs). Recent studies showed that single-nucleotide polymorphisms (SNPs) in the FoxP3 gene were associated with the increased susceptibility to several autoimmune diseases. In the present study, we investigated the association of FoxP3 gene polymorphisms with GD in a Southwest Chinese Han population. METHODS: A two-stage case-control study was performed in 890 healthy controls (male, 282; female, 608) and 503 patients with GD (male, 138; female, 365). Four SNPs (rs3761548, rs3761549, rs3761547, and rs2280883) were genotyped by the polymerase chain reaction-restriction fragment length polymorphism assay. The χ2 test was used to compare the genotype distributions and allele frequencies between GD patients and healthy controls. RESULTS: In the first stage, the significantly increased frequencies of the A allele (p = .031, odds ratio [OR] = 1.635) and AA genotype (p = .023, OR = 3.257), together with a significantly decreased frequency of the C allele (p = .031, OR = 0.611) of FoxP3/rs3761548 were found in female patients with GD. None of the other FoxP3 SNPs was associated with GD susceptibility. Subsequent validation and combination of data confirmed the association between FoxP3/rs3761548 and the female patients with GD (A allele: p < .001, OR = 1.672; AA genotype: p = .005, OR = 2.488; CC genotype: p = .001, OR = 0.622; C allele: p < .001, OR = 0.615, respectively). CONCLUSION: Our findings suggest that FoxP3/rs3761548 is significantly associated with female GD patients in a Southwest Chinese Han population.

The emerging role of epigenetics and gut microbiota in Vogt-Koyanagi-Harada syndrome.

Vogt-Koyanagi-Harada (VKH) syndrome is an autoimmune disorder characterized often by acute diffuse uveitis, also known as idiopathic uveoencephalitis. The associated complications can potentially affect multiple systems throughout the body, including eyes, ears, skin and nervous system. Although the pathogenesis of VKH syndrome remains unclear, it has been established that the various genetic factors, epigenetic factors and the imbalance in immune regulation can significantly contribute to the development of this disease. In addition, the experimental autoimmune uveitis (EAU) has been commonly used to further explore the pathogenesis of the disease. Herein, in this review article, we discuss about the major research advances made in understanding of the different epigenetic factors and gut microbes involved in the pathogenesis of VKH syndrome as well as EAU. The information discussed can help to better understand the pathogenesis of VKH syndrome, and thereby might provide a basis for finding novel molecular targets and innovative treatment strategies in the future.

Predisposition to Graves' disease and Graves' ophthalmopathy by genetic variants of IL2RA.

Previous studies have identified that Th17/Treg cells were involved in the occurrence and development of Graves' disease (GD). This study aimed at clarifying the association between GD susceptibility and nine single nucleotide polymorphisms (SNPs) of Th17/Treg cell-related genes, including IL2RA, miR27a, miR182, and FoxO1. A two-stage association study was performed in 650 GD patients and 1300 healthy controls. PCR-RFLP assays, real-time PCR, and ELISA were performed. In the first stage, association analysis has identified that IL2RA/rs3118470 TT genotype (Pc = 0.027, OR = 1.688) and IL2RA/rs2104286 AA genotype (Pc = 0.027, OR = 1.658) has significantly increased frequencies in patients with GD than control subjects. In the second stage, the result of rs2104286 was consistent with the first-stage results (AA genotype: Pc = 0.006, OR = 1.618). The combined data showed that IL2RA/rs2104286 AA genotype had increased frequencies in patients with GD (Pc = 8.772 × 10-6, OR = 1.636). Stratification analysis also revealed that rs2104286 AA genotype was significantly associated with Graves' ophthalmopathy (GO) susceptibility (Pc = 9.150 × 10-4, OR = 1.851). Functional studies showed that carriers of the rs2104286 AA genotype had lower IL2RA mRNA expression than AG genotype carriers (P = 0.021). Cytokine analyses revealed that the rs2104286 AA genotype individuals had lower IL-10 levels (P = 0.015) and increased IL-17 levels than AG genotype carriers (P = 1.467 × 10-4). In conclusion, our findings suggested that IL2RA/rs2104286 was associated with GD and GO susceptibility in Southwest Chinese Han population, which may be involved in the occurrence of GD and GO by affecting the mRNA expression of IL2RA gene and the cytokine production. KEY MESSAGES: We identified that IL2RA/rs2104286 locus contributed to the predisposition of Graves' disease (GD) and Graves' ophthalmopathy (GO). Functional analyses suggested that IL2RA/rs2104286 may participate in the occurrence of GD and GO by affecting the mRNA expression of IL2RA and cytokine (IL-10 and IL-17) secretion. We found that IL2RA (rs3118470, rs7093069), miR27a/rs895819, miR182/rs76481776, and FoxO1 (rs2297626, rs17592236, rs9549241, rs12585277) loci polymorphisms were not associated with GD susceptibility.

The VDR gene confers a genetic predisposition to Graves' disease and Graves' ophthalmopathy in the Southwest Chinese Han population.

OBJECTIVE: Graves' disease (GD) is a common autoimmune disease manifesting with diffuse symmetric thyroid gland enlargement, pretibial myxedema, and Graves' ophthalmopathy (GO). Recently, the vitamin D receptor (VDR) gene has been linked to various autoimmune diseases. This study aimed to investigate the association of VDR gene polymorphisms with susceptibility to GD and GO in the Southwest Chinese Han population. METHODS: A two-stage association study was performed in 1,209 controls and 650 GD patients by PCR-RFLP assay. Real-time PCR and ELISA were carried out to quantify gene expression and cytokine production. RESULTS: The first-stage study showed that the frequency of VDR/Apa I AA genotype was significantly increased in GD (Pc = 1.67 × 10-2, OR = 1.98). The second-stage and combined studies confirmed the association of VDR/Apa I with GD (AA genotype: Pc = 3.45 × 10-4, OR = 1.87; A allele: Pc = 2.62 × 10-2, OR = 1.20). The stratification analysis showed that GO patients had a higher frequency of the VDR/Apa I AA genotype (Pc = 8.69 × 10-5, OR = 2.84). Functional experiments showed a decreased VDR expression and TGF-ß1 production as well as an increased IL-17 production in VDR/Apa I AA genotype carriers. CONCLUSION: The VDR/Apa I polymorphism is significantly associated with GD and GO, and it may be involved in the development of GD and GO by influencing VDR mRNA expression levels and the secretion levels of cytokines.

Meta-analysis reveals significant association between FOXP3 polymorphisms and susceptibility to Graves' disease.

OBJECTIVE: This meta-analysis aimed to determine the associations between the rs3761547, rs3761548, and rs3761549 single-nucleotide polymorphisms (SNPs) of the forkhead box P3 (FOXP3) gene and susceptibility to Graves' disease (GD). METHODS: Case-control studies with information on the associations between the rs3761547, rs3761548, and rs3761549 FOXP3 SNPs and GD published before 01 May 2020 were identified in the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases. Data from the studies were analyzed using RevMan version 5.3. RESULTS: Seven independent case-control studies including 4051 GD patients and 4569 controls were included in the meta-analysis. The overall pooled analysis indicated that FOXP3/rs3761548 and FOXP3/rs3761549 polymorphisms were significantly associated with GD susceptibility (rs3761548: A vs. C, odds ratio [OR] = 1.32, 95% confidence interval [CI] 1.05-1.67; rs3761549: TT vs. CC, OR = 1.98, 95%CI 1.49-2.65; (TT + TC) vs. CC, OR = 1.44, 95%CI 1.11-1.88). In contrast, the FOXP3/rs3761547 polymorphism was not associated with GD susceptibility. Subgroup analysis according to ethnicity showed that rs3761548 was associated with GD in Asians but not in Caucasians, whereas rs3761549 was associated in both Asians and Caucasians. CONCLUSION: This meta-analysis demonstrated that FOXP3/rs3761548 and FOXP3/rs3761549 SNPs were significantly associated with susceptibility to GD, at least in Asian populations.

The association between genetic polymorphisms of interleukin 23 receptor gene and the risk of rheumatoid arthritis: An updated meta-analysis.

This meta-analysis was conducted to confirm whether seven single nucleotide polymorphisms (SNPs) of interleukin-23 receptor (IL23R) gene are associated with rheumatoid arthritis (RA) susceptibility. RevMan version 5.3 was used to calculate statistical data. Sixteen articles involving 11,816 RA patients and 14,268 healthy controls were included in this meta-analysis. A significant association was identified between the rs11209026 polymorphism and RA susceptibility in Caucasians (AA vs. GG: OR = 1.78, 95% CI = 1.02-3.10, P = .04; AA vs. AG + GG: OR = 1.77, 95% CI = 1.02-3.08, P = .04). Additionally, our result showed that the G allele of IL23R/rs10489629 had a significantly increased frequency in RA patients of Caucasians and Asians (A vs. G: OR = 0.92, 95% CI = 0.88-0.97, P = .002; OR = 0.62, 95% CI = 0.44-0.87, P = .006, respectively). Furthermore, the meta-analysis revealed a significant association between the rs1343151 polymorphism and RA susceptibility in Caucasians (C vs. T: OR = 0.91, 95% CI = 0.87-0.96, P = .0004). Our meta-analysis confirmed the IL23R gene might be treated as a susceptible factor for RA.