Predicting the early risk of ophthalmopathy in Graves' disease patients using TCR repertoire.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC7641174 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
Publications
Predicting the early risk of ophthalmopathy in Graves' disease patients using TCR repertoire.
Wang Yue Y Liu Yufeng Y Yang Xiaofei X Guo Hui H Lin Jiadong J Yang Jinkui J He Mingqian M Wang Jingya J Liu Xiaomei X Shi Tingting T Wu Liping L Zhang Chengsheng C Ye Kai K Shi Bingyin B
Clinical and translational medicine 20201101 7
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Project description:Thyroid-associated ophthalmopathy (TAO) is a common and debilitating manifestation of Graves disease (GD). Presently little is known about factors that may increase the risk of developing TAO among patients with GD.To identify risk factors associated with the development of TAO among individuals with newly diagnosed GD.In this longitudinal cohort study, all beneficiaries 18 years of age or older with newly diagnosed GD who were continuously enrolled in a large nationwide US managed care network and who visited an eye care professional 1 or more times from 2001 to 2009 were identified. International Classification of Diseases, Ninth Revision, Clinical Modification billing codes were used to identify those who developed manifestations of TAO. Multivariable Cox regression was used to determine the hazard of developing TAO among persons with newly diagnosed GD, with adjustment for sociodemographic factors, systemic medical conditions, thyrotropin levels, and medical and surgical interventions for management of hyperthyroidism.Manifestations of TAO measured by hazard ratios (HRs) with 95% CIs.Of 8404 patients with GD who met the inclusion criteria, 740 (8.8%) developed TAO (mean follow-up, 374 days since initial GD diagnosis). After adjustment for potential confounders, surgical thyroidectomy, alone or in combination with medical therapy, was associated with a 74% decreased hazard for TAO (adjusted HR, 0.26 [95% CI, 0.12-0.51]) compared with radioactive iodine therapy alone. Statin use (for ?60 days in the past year vs <60 days or nonuse) was associated with a 40% decreased hazard (adjusted HR, 0.60 [CI, 0.37-0.93]). No significant association was found for the use of nonstatin cholesterol-lowering medications or cyclooxygenase 2 inhibitors and the development of TAO.If prospective studies can confirm our finding that a thyroidectomy and statin use are associated with substantially reduced hazards for TAO among patients with GD, preventive measures for this burdensome manifestation of GD may become a reality.
| S-EPMC4495733 | biostudies-literature
Project description:BackgroundGraves' ophthalmopathy (GO) significantly impairs the quality of life of affected individuals and the most severe cases can be sight threatening. Given the limited therapeutic options, a strong emphasis should be placed on disease prevention to diminish the significant morbidity associated with this disease.SummaryGO is most prevalent in women and most severe in men. Although some genetic differences between GO patients and Graves' disease patients without ophthalmopathy have been identified, none of the polymorphisms identified to date impart a high enough risk of GO to justify genetic testing to guide therapy or preventive strategies. Poorly defined mechanical factors that appear also to play a role in GO susceptibility will likely be better elucidated with advances in imaging techniques. Tobacco smoking has been consistently linked to development or deterioration of GO. Smokers who receive radioactive iodine have the highest incidence of unfavorable GO outcome, which is proportional to the number of cigarettes smoked per day. Several studies have reported an association between radioactive iodine treatment for Graves' disease and worsening or development of GO. Observational studies suggest that the same appears to be true for thyroid dysfunction, including both hyper- and hypothyroidism. While thyrotropin receptor antibody levels appear to be useful in predicting the course of disease and response to therapy, it is not known whether they are predictive of GO development. The puzzling scenarios of euthyroid or clinically unilateral GO, the large number of nonsmoking GO patients, and the occasional development of GO years after thyroid dysfunction has been treated all underline the multifactorial etiology of this disorder in which no single factor determines the clinical outcome.ConclusionsGO appears to have a complex genetic basis with multiple susceptibility alleles that act in combination with nongenetic factors to contribute to disease expression.
| S-EPMC3357079 | biostudies-literature
Project description:Graves' ophthalmopathy (GO) is an inflammatory autoimmune disease that affects the eyes. It can significantly alter the quality of life in patients because of its distinctive pathological appearance and the effect on vision. To date, the exact pathological mechanism of GO has not been explicitly discovered. However, several studies have associated autophagy with this disease. Autophagy is a catabolic process that helps maintain homeostasis in all organisms by protecting the cells and tissues from various endogenous and exogenous stress factors. Based on our results, patients affected with GO have comparatively elevated levels of autophagy, which critically affects the pathological mechanism of the GO. In this review, we have summarized the autophagy mechanism in the pathogenesis of GO.
| S-EPMC10140433 | biostudies-literature
Project description:BackgroundA large gene region, called GD-1, was first described by this laboratory as linked to Graves' disease (GD) and included the gene for the thyroid-stimulating hormone receptor (TSHR). Recent studies have now suggested an association of TSHR intronic polymorphisms with GD. We have taken the opportunity to examine a population of well-characterized patients with autoimmune thyroid disease (AITD) typed for an additional thyroid susceptibility gene, the immunoregulatory gene for cytotoxic T-lymphocyte antigen 4 (CTLA-4), to examine its relationship with the susceptibility to GD endowed by TSHR gene polymorphisms.MethodsWe used TSHR-SNP-rs2268458, located in intron 1 of the TSHR gene, measured using standard PCR-RFLP procedures, as our marker for the TSHR gene association. We genotyped 200 patients with GD, 83 patients with Hashimoto's thyroiditis (HT), and 118 healthy controls (all female Caucasians).ResultsThe allele and genotype frequencies from GD patients, but not HT patients, were significantly different from controls. The frequency of the combined genotype (allele) CC + TC was significantly higher in GD patients versus controls, suggesting that the C-containing genotype increased the risk for GD in a dominant manner (p = 0.018, odds ratio [OR] = 1.8). When compared with CTLA-4 (A/G)(49) single-nucleotide polymorphism (SNP), we were unable to demonstrate additive risk in patients with established AITD. Further, subsetting the patients (n = 120) into those with clinically significant Graves' ophthalmopathy (GO) showed no association with the TSHR SNP.ConclusionsThese results demonstrated that the intronic TSHR-SNP-rs2268458 was associated with GD, but not with HT, thus indicating that the TSHR gene has the potential to increase susceptibility to GD. However, we were not able to demonstrate any additive risk with the CTLA-4 (A/G)(49) SNP, which is, therefore, an independent risk factor for AITD. This suggested that, within the limits of the study population, each of these two genes provided a small contribution to GD susceptibility and that neither was essential. In addition, there was no evidence for the TSHR gene association adding to the risk of developing GO. Direct functional analyses are now needed to help explain the mechanisms of this TSHR gene susceptibility to GD.
| S-EPMC2857451 | biostudies-literature
Project description:BACKGROUND: Graves disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism, diffuse goiter, autoantibodies against thyroid-specific antigens, and dermopathy. Studies of GD have demonstrated the importance of the Th2 and Th17 immune responses in mediating disease progression. In the present study, we investigated the role of a Th2 cytokine, thymic stromal lymphopoietin (TSLP), in GD and Th17 differentiation. METHODS: In this study, we genotyped 470 patients with GD at 3 single nucleotide polymorphisms (SNPs) in TSLP. In addition, the serum concentrations of TSLP were determined in 432 patients and 272 controls. Ten patients and controls each were further screened using in vitro Th17 differentiation assays. The SNPs were genotyped using ABI TaqMan® SNP genotyping assays. For the Th17 differentiation assays, peripheral blood mononuclear cells (PBMCs) isolated from the patients and controls were placed into Th17 differentiation media, and interleukin 17 expression levels were determined. RESULTS: Haplotype analysis indicated that patients with the Ht3 (TCC) haplotype have a 3.28-fold higher risk of developing GD (p = 0.007), whereas those with the Ht5 (TCG) haplotype had a 0.03-fold, reduced risk of developing GD (p = 1 × 10-14). SNP rs3806933 (p = 0.007) was associated with female Graves ophthalmopathy (GO). TSLP expression levels were higher in GD patients than in control subjects, and TLSP was also shown to promote the differentiation of Th17 cells in GD patients. CONCLUSIONS: These results suggest that polymorphisms in TSLP may be used as genetic markers for the diagnosis and prognosis of GD. Furthermore, TLSP may be a target for treating GD.
| S-EPMC3582428 | biostudies-literature
Project description:Graves' disease (GD) is the most common cause of thyrotoxicosis and often involves the orbits. Graves' ophthalmopathy (GO), also known as Thyroid Eye Disease (TED), can be clinically significant and advance to sight-threatening stages. Our knowledge of the immunogenetic pathophysiology of GO is rapidly expanding. The present review is an attempt to summarize the current state of knowledge on the immunogenetics of GO. First we briefly review the epidemiology and clinical importance of GO, and then we describe in detail the macromolecular pathogenesis and finally immunogenetics of GO. Discrepancies between the results from various reports and the limitations of the available data are discussed. In particular, there is a scarcity of data from non-Asian populations. While several studies have demonstrated significant associations between polymorphisms in certain genes (especially CTLA-4, HLA-DRB-1, and TNF-?), there is a need for studies that investigate the relationship between polymorphisms and both serum and local concentrations of the resulting proteins. A complete understanding of GO susceptibility and pathogenesis has not been yet possible due to a number of important knowledge gaps that need to be filled by future research.
| S-EPMC3271309 | biostudies-literature
Project description:BackgroundGraves' disease (GD), including Graves' ophthalmopathy or orbitopathy (GO), is an autoimmune disease with an environmental and genetic component to its etiology. The genetic contribution to the GO clinical phenotype remains unclear. Previous data from our laboratory and others have suggested that GO has no specific genetic component distinct from GD itself, while other reports have occasionally appeared suggesting that polymorphisms in genes such as CTLA4 and IL23R specifically increase the risk for GO. One of the criticisms of all these reports has been the clinical definition of the GO phenotype as distinct from hyperthyroid GD devoid of clinically significant eye involvement. The objective of this study was to take advantage of a phenotypically pure group of GD patients with GO and examine a series of genes associated with GD to determine if any were more definitively associated with GO rather than Graves' thyroid disease itself.MethodsTo further examine whether specific susceptibility genes are associated with GO, we have performed further genetic association studies using highly characterized GO patients, many of whom had undergone orbital decompression surgery for their exophthalmos. We genotyped HLA, CTLA4, IL23R, and TSHR genes in a group of 256 Caucasian patients with severe GO (n=199) and less severe GO (n=57), and 90 patients with GD but no clinically apparent GO.ResultsWe found that the allele and genotype frequencies were not statistically different between GO and non-GO patients for any of the genes and gene combinations assessed.ConclusionsThese results provide further evidence that patients with GO do not have a distinct genetic susceptibility to their eye disease and again suggest that environmental and/or epigenetic influences are at play.
| S-EPMC3387758 | biostudies-literature
Project description:The macrophage migration inhibitory factor (MIF)/cluster of differentiation 74 (CD74) plays a role in immunological functions. The present study aims to investigate whether single-nucleotide polymorphisms (SNPs) in the MIF and CD74 are risk factors for developing Graves ophthalmopathy (GO) in patients with Graves disease (GD). A case-control study enrolled 484 patients with GD (203 with and 281 without GO) and 1000 healthy individuals. SNPs were discriminated using real-time polymerase chain reaction. Hardy-Weinberg equilibrium, as well as frequencies of allele and genotype between GD patients with and without GO, were estimated using the Chi-square test. The effects of CD74 on adipocyte proliferation and differentiation were evaluated using 3T3-L1 preadipocytes. Quantitative DNA-immunoprecipitation was used to detect the binding capacity of NR3C1 and FOXP3 to A/G oligonucleotides. The results showed that individuals carrying the GG genotype at rs2569103 in the CD74 had a decreased risk of developing GD (P=3.390 × 10-11, odds ratio (OR) = 0.021, 95% confidence interval (CI) = 0.003-0.154); however, patients with GD carrying the AG genotype at rs2569103 in the CD74 had an increased risk of developing GO (P=0.009, OR = 1.707, 95% CI = 1.168-2.495). The knockdown of CD74 reduced adipocyte proliferation and differentiation. NR3C1 had a higher affinity for A, whereas FOXP3 had a higher affinity for G of rs2569103. The results suggested the existence of a link between the genetic variation of CD74 promoter and the risk for developing GD and GO, which should be considered in clinical practice.
| S-EPMC7432997 | biostudies-literature
Project description: Not available
| S-EPMC11250345 | biostudies-literature
Project description:ContextGraves disease (GD) is one of the most common autoimmune disorders. Recent literature has shown an immune response involving several different inflammatory related proteins in these patients.ObjectiveThis work aimed to characterize the kynurenine pathway, activated during interferon-γ (IFN-γ)-mediated inflammation and cellular (T-helper type 1 [Th1] type) immunity, in GD patients with and without thyroid eye disease (TED).MethodsWe analyzed 34 biomarkers by mass spectrometry in serum samples from 100 patients with GD (36 with TED) and 100 matched healthy controls. The analytes included 10 metabolites and 3 indices from the kynurenine pathway, 6 microbiota-derived metabolites, 10 B-vitamers, and 5 serum proteins reflecting inflammation and kidney function.ResultsGD patients showed significantly elevated levels of 7 biomarkers compared with healthy controls (omega squared [ω2] > 0.06; P < .01). Of these 7, the 6 biomarkers with the strongest effect size were all components of the kynurenine pathway. Factor analysis showed that biomarkers related to cellular immunity and the Th1 responses (3-hydroxykynurenine, kynurenine, and quinolinic acid with the highest loading) were most strongly associated with GD. Further, a factor mainly reflecting acute phase response (C-reactive protein and serum amyloid A) showed weaker association with GD by factor analysis. There were no differences in biomarker levels between GD patients with and without TED.ConclusionThis study supports activation of IFN-γ inflammation and Th1 cellular immunity in GD, but also a contribution of acute-phase reactants. Our finding of no difference in systemic activation of the kynurenine pathway in GD patients with and without TED implies that the local Th1 immune response in the orbit is not reflected systemically.
| S-EPMC10188306 | biostudies-literature