High iodine promotes autoimmune thyroid disease by activating hexokinase 3 and inducing polarization of macrophages towards M1.

Autoimmune thyroid disease (AITD), the most common autoimmune disease, includes Graves' disease (GD) and Hashimoto's thyroiditis (HT). Currently, the pathogenesis of AITD is not fully understood. Our study aimed to examine the presence of macrophage polarization imbalance in AITD patients, to investigate whether high iodine can cause macrophage polarization imbalance, and to investigate the role of key genes of metabolic reprogramming in macrophage polarization imbalance caused by high iodine. We synergistically used various research strategies such as systems biology, clinical studies, cell culture and mouse disease models. Gene set enrichment analysis (GSEA) revealed that M1 macrophage hyperpolarization was involved in the pathogenesis of AITD. In vitro and in vivo experiments showed that high iodine can affect the polarization of M1 or M2 macrophages and their related cytokines. Robust rank aggregation (RRA) method revealed that hexokinase 3 (HK3) was the most aberrantly expressed metabolic gene in autoimmune diseases. In vitro and in vivo studies revealed HK3 could mediate macrophage polarization induced by high iodine. In summary, hyperpolarization of M1-type macrophages is closely related to the pathogenesis of AITD. High iodine can increase HK3 expression in macrophages and promote macrophage polarization towards M1. Targeting HK3 can inhibit M1 polarization induced by high iodine.

Polymorphisms of ATG5 Gene Are Associated with Autoimmune Thyroid Diseases, Especially Thyroid Eye Disease.

Objective: To explore the association of ATG5 gene polymorphisms with autoimmune thyroid diseases (AITDs) including Hashimoto's thyroiditis (HT) and Graves' illness (GD) as well as their clinical features. Methods: rs6568431, rs548234, and rs6937876 were selected to investigate the correlation of single-nucleotide polymorphisms of ATG5 gene with AITDs. Their frequencies in 824 AITD patients, including 271 HT patients and 553 GD patients, and 764 healthy controls were tested using both ligase detection reaction and multiplex polymerase chain reaction. Results: Allele A frequency of rs6568431 in AITDs patients (p = 0.016, OR = 1.201, 95% CI = 1.034 - 1.394) and allele G frequency of rs6937876 in AITDs patients (p = 0.009, OR = 1.223, 95% CI = 1.052 - 1.422) and in GD patients (p = 0.009, OR = 1.247, 95% CI = 1.056 - 1.473) were significantly higher than those in the healthy controls. The frequency of G allele (p = 5.42E - 18, OR = 0.242, 95% CI = 0.173 - 0.339) of rs6937876 was significantly higher in GD patients with ophthalmopathy. However, no relationship was found between family history, age onset, and the three SNPs. Conclusion: The study is the first to reveal the association between AITDs and ATG5 polymorphisms, and ATG5 gene is considered as a predisposing gene to AITDs, especially GDs.

High-throughput T cell receptor sequencing reveals differential immune repertoires in autoimmune thyroid diseases.

BACKGROUND: Autoimmune thyroid diseases (AITDs) are chronic autoimmune diseases specific to thyroid and mainly include Graves' disease (GD) and Hashimoto' thyroiditis (HT). The adaptive immunoreactivity of CD4+ T cells plays a crucial role in the pathogenesis of AITDs, but very little has been known about its changes in disease status. METHODS: We collected peripheral CD4+ T cells from 12 GD patients, including 6 newly diagnosed GD (NGD) and 6 refractory GD (RGD) patients, 6 HT patients and 6 healthy controls, and examined the gene expression profiles and colon types of T cells receptor (TCR) ß chain complementarity determining region 3 (CDR3) using high-throughput sequencing. RESULTS: The TCR repertoire were significantly expanded in AITDs groups, and some TCR genes were expressed more preferentially in AITDs group than in the healthy control group, including TRBV15 (P = 0.001), TRBV4-2 (P = 0.003), TRBV9 (P = 0.007), TRBV3-2 (P = 0.012), TRBV7-8 (P = 0.015), TRBV25-1 (P = 0.019), TRBV12-4 (P = 0.019) and TRBV27 (P = 0.02) in GD patients as well as TRBV29-1 (P = 0.004), TRBV12-4 (P = 0.004), TRBV6-5 (P = 0.011), TRBV7-2 (P = 0.012), TRBV27 (P = 0.012), TRBV9 (P = 0.031) and TRBV4-2 (P = 0.032) in HT patients. Moreover, subgroup analysis showed that the difference in the TCR spectrum between the normal group and NGD was not obvious, but a large number of differential genes appeared in the RGD group. CONCLUSION: TCR spectrum has changed in patients with AITDs with expanded repertoire and many upregulated TRBV genes. Moreover, this difference is not apparent in GD patients at the initial stage, but as the disease progresses, the differences in TCR profiles became more pronounced.

T cell receptor revision and immune repertoire changes in autoimmune diseases.

Autoimmune disease (AID) is a condition in which the immune system breaks down and starts to attack the body. Some common AIDs include systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus and so forth. The changes in T-cell receptor (TCR) repertoire have been found in several autoimmune diseases, and may be responsible for the breakdown of peripheral immune tolerance. In this review, we discussed the processes of TCR revision in peripheral immune environment, the changes in TCR repertoire that occurred in various AIDs, and the specifically expanded T cell clones. We hope our discussion can provide insights for the future studies, helping with the discovery of disease biomarkers and expanding the strategies of immune-targeted therapy.HighlightsRestricted TCR repertoire and biased TCR-usage are found in a variety of AIDs.TCR repertoire shows tissue specificity in a variety of AID diseases.The relationship between TCR repertoire diversity and disease activity is still controversial in AIDs.Dominant TCR clonotypes may help to discover new disease biomarkers and expand the strategies of immune-targeted therapy.

Psoriasis Susceptibility 1 Candidate 1 (PSORS1C1) Polymorphism is Associated with Autoimmune Thyroid Disease in a Chinese Han Population.

BACKGROUND: Autoimmune thyroid disease (AITD) is an inherited, complex gene- and immune-related disorder that mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT). Psoriasis susceptibility 1 candidate 1 (PSORS1C1) is a susceptibility gene associated with many autoimmune diseases, but its role in an individual's predisposition to AITD is unknown. METHODS: This study included 1065 Chinese Han patients with AITD and 943 matched healthy individuals. The rs3130983, rs3778638, rs3815087, and rs4959053 single nucleotide polymorphisms (SNPs) in PSORS1C1 were determined using multiplex polymerase chain reaction technology. RESULTS: Of the four SNPs, only the distribution of the rs3778638 genotypes was different between the AITD (AA, 2.67%; AG, 19.15%; and GG, 78.18%) and control (AA, 1.52%; AG, 22.2%; and GG, 75.87%) groups (P = .046). An association between rs3778683 and GD was observed (p = .039) but not with HT. No linkage disequilibrium was observed for rs3130983, rs3815087, rs3778638, and rs4959053 in PSORS1C1 among the patients with AITD and controls. CONCLUSION: This study suggests the influence of PSORS1C1 rs3778638 on the susceptibility to GDs, supporting this locus as a common autoimmunity risk factor.

Identification of lncRNA and mRNA Expression Profile in Relapsed Graves' Disease.

Background: Graves' disease (GD) is a common autoimmune disease, and its pathogenesis is unclear. Studies have found that the occurrence of GD is related to the immune disorder caused by the interaction of genetic susceptibility and environmental factors. The CD4+ T cell subset is closely related to the immune disorder of GD. LncRNAs are RNA molecules with a length of more than 200 nt and are involved in a variety of autoimmune diseases. However, the roles of lncRNAs in recurrent GD are still elusive. The purpose of this study is to identify lncRNA and mRNA expression profile in relapsed Graves' disease. Method: CD4+ T cells from 12 recurrent GD and 8 healthy controls were collected for high-throughput sequencing. The gene-weighted co-expression network analysis (WGCNA) was used to construct the co-expression module relevant to recurrent GD, and the key genes in the module were verified by RT-PCR. Results: There are 602 upregulated lncRNAs and 734 downregulated lncRNAs in CD4+ T cells in recurrent GD patients compared with the healthy controls. The module most relevant to GD recurrence was constructed using WGCNA, and the key genes in the module were verified by RT-PCR. We found that the expression of RPL8, OAS2, NFAT5, DROSHA, NONHSAT093153.2, NONHSAT118924.2, and NONHSAT209004.1 was significantly decreased in GD group (p < 0.001, p < 0.001, p < 0.01, p < 0.05, p < 0.001, p < 0.05, and p < 0.01, respectively). Conclusion: LncRNAs are closely related to the recurrence of GD. For the first time, we constructed the expression profile of lncRNAs and mRNAs in CD4+ T cells in recurrent GD patients.

METTL3 Is Involved in the Development of Graves' Disease by Inducing SOCS mRNA m6A Modification.

Objective: Epigenetic modifications in RNA are known to play critical roles in cell differentiation through regulating expressions of some key genes including members of the suppressor of cytokine signaling (SOCS) family. The present study aimed to unveil the relationship of SOCS mRNA methylation induced by methyltransferase like 3 (METTL3) with Graves' disease (GD). Methods: Differently expressed genes (DEG) in GD tissues were identified using microarray analysis and further validated using CD4+ T cell microarray of GD tissues and isolated peripheral blood mononuclear cells (PBMCs). Furthermore, expressions of METTL3 targeted genes were detected using METTL3 knock-down experiment in RAW264.7 cells. Results: High throughput microarrays revealed that METTL3 and SOCS molecules were aberrantly expressed in thyroid tissues and CD4+T cells of GD compared to the controls. Bioinformatic analysis was undertaken by searching databases of found genes of the SOCS family that possessed many mRNA m6A modification loci. METTL3 knock-down experiment revealed that expressions of SOCS family members SOCS1, SOCS2, SOCS4, SOCS5, and SOCS6 were increased after METTL3 knock-down. Conclusions: For the first time, the present study revealed the relationship between m6A modification and GD and indicated that METTL3 may be involved in the development of GD by inducing mRNA m6A methylation modification of SOCS family members.

Systemic Proteomic Analysis Reveals Distinct Exosomal Protein Profiles in Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a complex disease with unknown pathogenesis. In recent years, fewer have paid attention to the broad spectrum of systemic markers of RA. The aim of this study was to identify exosomal candidate proteins in the pathogenesis of RA. METHODS: Totally, 12 specimens of plasma from 6 RA patients and 6 age- and gender-matched controls from the Chinese population were obtained for nanoscale liquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS) analysis to identify exosomal profiles. RESULTS: A total of 278 exosomal proteins were detected. Among them, 32 proteins were significantly upregulated (FC ≥ 2.0 and P < 0.05) and 5 proteins were downregulated (FC ≤ 0.5 and P < 0.05). Bioinformatics analysis revealed that transthyretin (TTR), angiotensinogen (AGT), lipopolysaccharide-binding protein (LBP), monocyte differentiation antigen CD14 (CD14), cartilage oligomeric matrix protein (COMP), serum amyloid P (SAP/APCS), and tenascin (TNC) can interact with each other. Subsequently, these cross-linked proteins may be mainly involved in the inflammatory-related pathways to mediate the onset of RA. Noteworthy, the LBP/CD14 complex can promote the expression of IL-8 and TNF-α, eventually leading to the development of RA. CONCLUSIONS: Our findings suggest distinct plasmatic exosomal protein profiles in RA patients. These proteins not only take important parts in the vicious circle in the pathogenic process of RA but also serve as novel biomarkers in RA diagnosis and prognosis.

Inclusion of ALKBH5 as a candidate gene for the susceptibility of autoimmune thyroid disease.

PURPOSE: RNA demethylase AlkB homolog 5 (ALKBH5) gene is pivotal in N6-methyladenosine (m6A) modification. Therefore, this study aimed to explore the potential relationship between polymorphisms of ALKBH5 gene and the development of autoimmune thyroid disease (AITD). MATERIAL AND METHODS: A case-control study of 979 AITD patients, including 620 Graves' disease (GD) and 359 Hashimoto's thyroiditis (HT), and 732 normal controls of the Chinese Han population was performed using high-throughput sequencing (HiSeq) genotyping method for detecting 5 variants in ALKBH5 gene (rs12936694, rs2124370, rs4925144, rs8068517, and rs9913266). In addition, the associations between ALKBH5 single nucleotide polymorphisms (SNPs) and clinical phenotypes of AITD were investigated. RESULTS: Compared to normal controls, rs9913266 displayed significant differences in allele and genotype distributions in AITD and GD. rs12936694 also showed significantly different frequencies of alleles in AITD and GD. The link of these 2 loci polymorprhisms to AITD and GD also existed after adjusting for age and gender. When stratified by sex, the minor allele of rs9913266 was associated with the risk of female AITD and HT development before and after adjusting for age and gender. There was a significant association between rs8068517 locus and GD in females after adjusting for the confounders. Finally, we observed significant correlations of haplotypes CGACA and CAGCG to the susceptibility of AITD and GD. CONCLUSIONS: Our results provided evidence of association of polymorphisms in ALKBH5 gene with AITD, GD, and HT patients, and hence ALKBH5 might be the candidate gene for susceptibility to AITD.

Identifying and Validating Differentially Methylated Regions in Newly Diagnosed Patients with Graves' Disease.

This research used combined bioinformatic methods to identify differentially methylated regions (DMRs) in newly diagnosed patients with Graves' disease (GD). Peripheral blood from six GD patients and controls was collected and methyl-DNA immunoprecipitation (MeDIP), and NimbleGen Human DNA Methylation 3 × 720 K promoter plus CpG island microarrays were further analyzed. DMRs were categorized into low-methylated genes and high-methylated genes, which were mapped into a protein-protein interaction (PPI) network constructed by a dataset. Then, six candidate genes were validated in an expanded population with 32 GD patients and 30 controls using bisulfite amplicon sequencing. Top 10 hub genes revealed by PPI analysis were CRHR1, CAMK2A, SERPINA1, RANBP9, ICAM1, ADRB2, KRTAP13-1, PTPRA, S100A2, and KPRP. Five CpG sites of CDKN2C (51436061), SERPINA1 (94856657), B3GNT2 (62422532 and 62422689), and IRS4 (107979477) were validated, having significantly different methylation levels between GD patients and controls. Based on gender stratification, nine significant CpG sites of CDKN2C (51436061), SERPINA1 (94855831), and B3GNT2 (62422301, 62422327, 62422356, 62422365, 62422374, 62422532, and 62422689) were detected between female GD patients and controls. The methylation level of 62422532 of B3GNT2 was significantly associated with levels of serum TGAb and TRAb. In addition, the methylation level of 62422689 of B3GNT2 showed significant correlation with the age of GD patients. In the analysis of prediction of transcription factor binding at specific CpG sites in B3GNT2 promoter region, paired box protein 5 (Pax-5) and CCAAT/enhancer-binding protein (C/EBP ß) might be under the influence of methylation at CpG sites 62422365 and 62422532, respectively. CDKN2C, SERPINA1, IRS4, and especially B3GNT2 were potential aberrantly methylated genes related to GD. These findings might supply the latest information of DNA methylation in the GD disease.

An Update Evolving View of Copy Number Variations in Autoimmune Diseases.

Autoimmune diseases (AIDs) usually share possible common mechanisms, i.e., a defect in the immune tolerance exists due to diverse causes from central and peripheral tolerance mechanisms. Some genetic variations including copy number variations (CNVs) are known to link to several AIDs and are of importance in the susceptibility to AIDs and the potential therapeutic responses to medicines. As an important source of genetic variants, DNA CNVs have been shown to be very common in AIDs, implying these AIDs may possess possible common mechanisms. In addition, some CNVs are differently distributed in various diseases in different ethnic populations, suggesting that AIDs may have their own different phenotypes and different genetic and/or environmental backgrounds among diverse populations. Due to the continuous advancement in genotyping technology, such as high-throughput whole-genome sequencing method, more susceptible variants have been found. Moreover, further replication studies should be conducted to confirm the results of studies with different ethnic cohorts and independent populations. In this review, we aim to summarize the most relevant data that emerged in the past few decades on the relationship of CNVs and AIDs and gain some new insights into the issue.

METTL3 gene polymorphisms contribute to susceptibility to autoimmune thyroid disease.

PURPOSE: Autoimmune thyroid disease (AITD) is a classic autoimmune disorder that mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT). In this study, we explored the potential relationship between single-nucleotide polymorphisms (SNPs) of methyltransferase like 3 (METTL3) gene and the development of AITD. METHODS: The distribution of METTL3 genotypes at seven loci (rs1139130, rs1263790, rs1263791, rs17197156, rs2242526, rs3752411, and rs4417466) in 960 AITD (599 GD and 361 HT) patients and 732 unrelated healthy volunteers was examined using high-throughput sequencing technology in a case-controlled manner and their correlations with AITD development were statistically analyzed. RESULTS: METTL3 genotypes at these seven SNPs were not correlated with both GD and HT except a borderline association between rs3752411and GD after adjusted for age, sex, and thyroid function under the recessive model. Subgroup analysis demonstrated that the minor allele frequencies of rs2242526 and rs4417466 were higher in male AITD patients than in healthy volunteers before adjusted for confounding factors and the genotype distribution of rs4417466 was significantly different between the two groups. Additionally, the genotype frequencies of rs1139130, rs1263791, rs2242526, and rs4417466 were positively related with GD in male patients. Likewise, the allele distribution of rs1263791, rs2242526, and rs4417466 in male GD patients differed significantly from that in male controls. Multivariate logistic regression analyses revealed a significant association between allele frequencies of these three loci and GD in male patients after adjusted for the confounding factors. Moreover, the genotype of rs3752411 was strongly associated with GD in females as well. Furthermore, distribution of rs3752411 genotype was significantly associated with hypothyroidism in HT patients. CONCLUSION: Our study for the first time revealed a strong correlation between METTL3 mutations and AITD predisposition, implying that METTL3 may be a new candidate gene for AITD treatment.

Proteomics Screening of Differentially Expressed Cytokines in Tears of Patients with Graves' Ophthalmopathy.

BACKGROUND: The current study aimed at exploring the cytokine profile in the tears of patients with Graves' ophthalmopathy (GO). METHODS: Tears were sampled from the eyes of 7 patients with active GO and 7 healthy volunteers using filter paper. Then the levels of up to 34 cytokines in the tears of each subject were detected using high-throughput protein microarray technology in line with the introduction. RESULTS: The results of cytokine protein microarray screening showed that 10 proteins, namely, CD40, CD40 Ligand, GITR, IL-12p70, IL-1 beta, IL-2, IL-21, IL-6, MIP-3 alpha and TRANCE, were overexpressed (with fold change >1.20) and 3 proteins, namely, GM-CSF, IL-1 sRI and IL-13 were downregulated (with fold change < 0.83) in GO patients. In addition, the protein levels of CD40 and CD40 ligand (CD40L) were significantly different between GO patients and healthy controls (P=0.028 and 0.011, respectively). Further Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of differently expressed proteins showed that these proteins were involved in biological functions including biological processes (positive regulation of cytokine production, JAK-STAT cascade and leukocyte proliferation), molecular functions (cytokine and growth factor receptors binding and cytokine activity), and other important pathways (cytokine-cytokine receptor interaction, JAK-STAT signaling pathway, IL-17 signaling pathway, NF-kappa B signaling pathway, Th17 cell differentiation, and intestinal immune network for IgA production), all of which might be involved in the pathology of GO. CONCLUSION: Our cytokine protein microarray analysis indicated that several proteins were differentially expressed in GO patients, which provides potential targets for GO prevention.

The Impact of Obesity on Thyroid Autoimmunity and Dysfunction: A Systematic Review and Meta-Analysis.

Background: To help inform decision making in the clinical setting, we carried out a systematic review and meta-analysis to estimate the association of thyroid disease risks with obesity. Methods: Pubmed, Embase, Web of Science, Cochrane database and Google Scholar electronic databases were searched from inception to October 31, 2018 without language restrictions to explore the relationship between thyroid disorders and obesity. The relative risk (RR) or odds risk (OR) for thyroid disorders were pooled using the SPSS and STATA software. Results: A total of 22 studies were included in the study. (1) Meta-analysis showed that obesity was significantly associated with an increased risk of hypothyroidism (RR = 1.86, 95% CI 1.63-2.11, P < 0.001). Meta-analyses after stratification further showed that obese population had increased risks of overt hypothyroidism (RR = 3.21, 95% CI 2.12-4.86, P < 0.001) and subclinical hypothyroidism (RR = 1.70, 95% CI 1.42-2.03, P < 0.001). (2) Further meta-analysis also showed obesity was clearly associated with Hashimoto's thyroiditis (RR = 1.91, 95% CI 1.10-3.32, P = 0.022), but not with Graves' disease. (3) In the meta-analysis of antibodies, obesity was correlated with positive thyroid peroxidase antibody (TPOAb) (RR = 1.93, 95% CI 1.31-2.85, P = 0.001), but not with positive thyroglobulin antibody (TGAb). Conclusions: Obesity was significantly related to hypothyroidism, HT, and TPOAb, implying that prevention of obesity is crucial for thyroid disorders. Systematic Review Registration: PROSPERO: CRD42018096897.

Risk of Thyroid Disorders in Patients with Gout and Hyperuricemia.

The risk of thyroid autoimmunity and thyroid dysfunction among patients with gout and hyperuricemia has not been well defined. This study was undertaken to examine the impact of gout and hyperuricemia on risk of thyroid disorders including thyroid autoimmunity and thyroid dysfunction. A population-based cross-sectional study was conducted to assess the risk of thyroid autoimmunity and thyroid dysfunction related to gout and hyperuricemia, which included 115 gout patients, 439 hyperuricemic patients, and 2 254 individuals without gout and hyperuricemia. A systematic review and meta-analysis of 14 observational studies was also done to systematically evaluate the risk of thyroid dysfunction among patients with gout and hyperuricemia. Findings from the cross-sectional study suggested a significantly increased risk of hypothyroidism among female gout patients (OR=2.44, 95% CI 1.15-5.17, p=0.02). Besides, gout could also substantially increase risk of Hashimoto's thyroiditis in women (OR=3.15, 95% CI 1.53-6.49, p=0.002). The meta-analysis proved a considerably increased risk of hypothyroidism among both gout patients (OR=1.51, 95% CI 1.23-1.85, p<0.001) and hyperuricemic patients (OR=1.34, 95% CI 1.11-1.61, p=0.002). Moreover, this meta-analysis also suggested that gout could also significantly increase the risk of hyperthyroidism (OR=1.25, 95% CI 1.06-1.48, p=0.01). The findings from the study suggest increasing risk of hypothyroidism and Hashimoto's thyroiditis among gout patients. Moreover, gout but not hyperuricemia is linked to increased risk of hyperthyroidism. More studies are warranted to elucidate the influence of gout and hyperuricemia on thyroid disorders.

Thyroid disorders in patients with myasthenia gravis: A systematic review and meta-analysis.

BACKGROUND: Our purpose was to determine the prevalence of thyroid disorders in myasthenia gravis (MG) or whether MG was associated with an increased risk of thyroid disorders. METHODS: Pubmed, Embase, Web of Science, Cochrane database, Google Scholar and the Chinese Biomedical Databases were searched about the relationship between thyroid disorders and myasthenia gravis up to November 30, 2018, without language restrictions. The prevalence and relative risk (RR) for thyroid disorders were pooled by the R and STATA software. RESULTS: 39 papers with 24,927 MG patients were ultimately included for analysis in this meta-analysis. The pooled estimate of thyroid autoimmunity prevalence in MG patients was 10.1% (95%CI 6.7%-15.1%). Subgroups in patients with thyroid autoimmunity showed the prevalence of positive TGAb was the highest in MG patients (12.6%, 95%CI 8.1%-19.1%), followed by GD (6.0%, 95%CI 4.2%-8.5%), HT (4.6%, 95%CI 1.9%-10.5%). Moreover, the pooled estimated prevalence of thyroid dysfunction in MG patients was 6.8% (95%CI 4.6%-9.8%). After stratification, the results showed the prevalence of hyperthyroidism and hypothyroidism in MG cases were 5.6% (95%CI 3.9%-8.0%) and 2.6% (95%CI 1.7%-4.1%), respectively. In addition, meta-analysis of 2 studies showed that MG was significantly associated with the increased risk of thyroid autoimmunity (OR = 2.86; 95%CI 1.54-5.28, P = .001). CONCLUSIONS: This systemic review and meta-analysis provides reliable evidence that thyroid disorders are prevalent in MG, especially TGAb positivity, GD, hyperthyroidism, and HT, and MG is associated with increased risk for thyroid autoimmunity.

Aberrant Histone Methylation in Patients with Graves' Disease.

BACKGROUND: Graves' disease (GD) is an organ-specific autoimmune disease. Accumulated data have indicated that aberrant epigenetic modifications are associated with many autoimmune disorders. However, it remains unknown whether histone methylation plays a role in the pathogenesis of GD. In the present study, we aimed to assess histone modification patterns in peripheral blood mononuclear cells (PBMCs) from GD patients. The rate (degree) of H3K4 and H3K9 methylation and the expressions of histone-modifying genes were investigated. METHODS: A total of 68 GD patients and 32 healthy controls were enrolled in this study. Global histone H3K4/H3K9 methylation of PBMCs was evaluated by the EpiQuik™ global histone H3K4/H3K9 methylation assay kit. The expressions of histone methyltransferases (HMTs) and histone demethylases (HDMs) at the mRNA level were determined by real-time quantitative polymerase chain reaction. RESULTS: Global histone H3K9 methylation in PBMCs of GD patients was significantly decreased compared with that in the healthy controls (P=0.007). The expressions of HMTs (SUV39H1 and SUV39H2) at the mRNA level were significantly decreased in PBMCs from GD patients compared with healthy controls (P<0.001), whereas the SETD1A expression at the mRNA level was significantly increased in GD patients compared with healthy controls (P=0.004). In addition, the expressions of HDMs, including JHDM2A and JMJD2A, at the mRNA level were significantly increased in GD patients compared with healthy controls (P<0.001; P=0.007). Moreover, the mRNA expression levels of JARID1A and LSD1 did not significantly differ in GD patients and healthy controls (P>0.05). CONCLUSIONS: These findings firstly suggested that the histone methylation was aberrant in PBMCs of GD patients, which could be possibly attributed to the deregulation of epigenetic modifier genes. Abnormal histone methylation modification may be involved in the pathogenesis of GD.

U-shaped relationship between iodine status and thyroid autoimmunity risk in adults.

BACKGROUND: Iodine status has long been regarded as an environmental determinant for thyroid dysfunction, but its relationship with thyroid autoimmunity (TAI) is still controversial. Our study aimed to elucidate the relationship between iodine status and TAI through both a population-based study and a dose-response meta-analysis of eligible epidemiological studies. METHODS: A population-based, cross-sectional study was firstly carried out, which enrolled a total of 2808 Chinese adults. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated through logistic regression analysis. A dose-response meta-analysis of eligible epidemiological studies was also carried out. RESULTS: The cross-sectional study showed an U-shaped relationship between iodine intake and TAI in adults. Compared with those with more than adequate iodine status, individuals with iodine deficiency, adequate iodine status and iodine excess all had higher risk of TAI, and the adjusted ORs were 1.50 (95% CI 1.03-2.17, P = 0.032), 1.50 (95% CI 1.09-2.07, P = 0.013) and 1.68 (95% CI 1.11-2.53, P = 0.014), respectively. The dose-response meta-analysis included 22 epidemiological studies with a total of 69,987 participants and further validated the U-shaped relationship between iodine intake and TAI in adults, which proved the significantly increased risk of TAI among individuals with either iodine deficiency or iodine excess. Stratified analysis of studies with low risk of confounding bias also identified similar findings. CONCLUSION: The study suggests an U-shaped relationship between iodine intake and TAI in adults, and both iodine deficiency and iodine excess are risk factors of TAI in adults. The underlying mechanisms need to be elucidated in future studies.

Aberrant Expressions of Co-stimulatory and Co-inhibitory Molecules in Autoimmune Diseases.

Co-signaling molecules include co-stimulatory and co-inhibitory molecules and play important roles in modulating immune responses. The roles of co-signaling molecules in autoimmune diseases have not been clearly defined. We assessed the expressions of co-stimulatory and co-inhibitory molecules in autoimmune diseases through a bioinformatics-based study. By using datasets of whole-genome transcriptome, the expressions of 54 co-stimulatory or co-inhibitory genes in common autoimmune diseases were analyzed using Robust rank aggregation (RRA) method. Nineteen array datasets and 6 RNA-seq datasets were included in the RRA discovery study and RRA validation study, respectively. Significant genes were further validated in several autoimmune diseases including Graves' disease (GD). RRA discovery study suggested that CD160 was the most significant gene aberrantly expressed in autoimmune diseases (Adjusted P = 5.9E-12), followed by CD58 (Adjusted P = 5.7E-06) and CD244 (Adjusted P = 9.5E-05). RRA validation study also identified CD160 as the most significant gene aberrantly expressed in autoimmune diseases (Adjusted P = 5.9E-09). We further found that the aberrant expression of CD160 was statistically significant in multiple autoimmune diseases including GD (P < 0.05), and CD160 had a moderate role in diagnosing those autoimmune diseases. Flow cytometry confirmed that CD160 was differentially expressed on the surface of CD8+ T cells between GD patients and healthy controls (P = 0.002), which proved the aberrant expression of CD160 in GD at the protein level. This study suggests that CD160 is the most significant co-signaling gene aberrantly expressed in autoimmune diseases. Treatment strategy targeting CD160-related pathway may be promising for the therapy of autoimmune diseases.

IRF7 Gene Variations Confer Susceptibility to Autoimmune Thyroid Diseases and Graves' Ophthalmopathy.

The objective of this study was to investigate whether IRF7 polymorphisms are associated with autoimmune thyroid diseases (AITDs). We selected three single nucleotide polymorphisms (SNPs) of IRF7, namely, rs1061501, rs1131665, and rs1061502 for genotyping using PCR-based ligase detection reaction (LDR) method in a total of 1659 participants (592 with Graves' disease, 297 with Hashimoto's thyroiditis, and 770 healthy controls). Gene-disease and genotype-clinical phenotype associations were evaluated for the three SNPs. Our results showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in AITD patients were both higher than those of the controls (rs1131665: AG genotype: P = 0.017, OR = 1.968; allele G: P = 0.018, OR = 1.946; rs1061502: AG genotype: P = 0.029, OR = 1.866; allele G: P = 0.031, OR = 1.847). Subgroup analysis also showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in Graves' disease patients were both higher than those of the controls (rs1131665: AG genotype: P = 0.015, OR = 2.074; allele G: P = 0.016, OR = 2.048; rs1061502: AG genotype: P = 0.034, OR = 1.919; allele G: P = 0.035, OR = 1.898). Furthermore, the allele G frequency of rs1061501 was associated with Graves' ophthalmopathy (P = 0.035, OR = 1.396). No significant difference in IRF7 polymorphisms was found between Hashimoto's thyroiditis patients and controls. Our study has revealed for the first time that IRF7 is a susceptibility gene for AITD, especially for Graves' disease and Graves' ophthalmopathy.