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Biomarker identification of thyroid associated ophthalmopathy using microarray data.

ABSTRACT: AIM:To uncover the underlying pathogenesis of thyroid associated ophthalmopathy (TAO) and explore potential biomarkers of this disease. METHODS:The expression profile GSE9340, which was downloaded from Gene Expression Omnibus database, included 18 specimens from 10 TAO patients and 8 hyperthyroidism patients without ophthalmopathy. The platform was HumanRef-8 v2 Expression BeadChip. Raw data were normalized using preprocess. Core package and the differentially expressed genes (DEGs) were identified based on t-test with limma package of R. Functional enrichment analyses were performed recruiting the DAVID tool. Based on STRING database, a protein-protein interaction (PPI) network was constructed, from which a module was extracted. The functional enrichment for genes in the module was performed by the BinGO plugin. RESULTS:In total, 861 DEGs (433 up-regulated and 428 down-regulated) between TAO patients and hyperthyroidism patients without ophthalmopathy were identified. Crucial nodes in the PPI network included TPX2, CDCA5, PRC1, KIF23 and MKI67, which were also remarkable in the module and all enriched in cell cycle process. Additionally, MKI67 was highly correlated with TAO. Besides, the DEGs of GTF2F1, SMC3, USF1 and ZNF263 were predicted as transcription factors (TFs). CONCLUSION:Several crucial genes are identified such as TPX2, CDCA5, PRC1 and KIF23, which all might play significant roles in TAO via the regulation of cell cycle process. Regulatory relationships between TPX2 and CDCA5 as well as between PRC1 and KIF23 may exist. Additionally, MKI67 may be a potent biomarker of TAO, and SMC3 and ZNF263 may exert their roles as TFs in TAO progression.

SUBMITTER: Yang HB

PROVIDER: S-EPMC6133893 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Biomarker identification of thyroid associated ophthalmopathy using microarray data.

Yang Hong-Bin HB Jiang Jie J Li Lu-Lu LL Yang Huang-Qiang HQ Zhang Xiao-Yu XY

International journal of ophthalmology 20180918 9

<h4>Aim</h4>To uncover the underlying pathogenesis of thyroid associated ophthalmopathy (TAO) and explore potential biomarkers of this disease.<h4>Methods</h4>The expression profile GSE9340, which was downloaded from Gene Expression Omnibus database, included 18 specimens from 10 TAO patients and 8 hyperthyroidism patients without ophthalmopathy. The platform was HumanRef-8 v2 Expression BeadChip. Raw data were normalized using preprocess. Core package and the differentially expressed genes (DEG ...[more]

PMID: 30225222

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Project description:BACKGROUND:Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy. METHODS:We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ?3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed. RESULTS:In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes. CONCLUSIONS:In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997 .).

Project description:Thyroid associated ophthalmopathy (TAO) is an orbital autoimmune inflammatory disease that is commonly associated with thyroid dysfunction. Although the etiology of TAO is unclear, ROS accumulation and oxidative stress have been closely linked to the pathogenesis of TAO. Ferroptosis is an iron-dependent programmed cell death characterized by intracellular labile iron levels, excessive accumulation of reactive oxygen species (ROS) and lipid peroxidation. Currently, there are few reports regarding the role of ferroptosis in TAO. This article aimed to identify ferroptosis-related genes (FRGs) with diagnostic and therapeutic potential in TAO and explore their relationship with immune cells and lncRNAs. GSE58331 was downloaded from Gene Expression Omnibus (GEO) database. A total of 162 DEGs were identified between 27 TAO samples and 22 health samples from GSE58331, among which six FRGs (CYBB, CTSB, SLC38A1, TLR4, PEX3, and ABCC1) were obtained. The AUC of SLC38A1, TLR4, PEX3 in lacrimal gland tissues was greater than 80 which suggested high diagnostic value in TAO. The result of immune cell infiltrate analysis indicated increased infiltration of monocytes (p < 0.001), macrophages M0(p = 0.039), mast cells activated (p = 0.008), and neutrophils (p = 0.045) in orbital tissues from TAO patients. Meanwhile, mast cells resting (p = 0.043) and macrophages M2 (p = 0.02) showed reduced infiltration in TAO samples. There were no gender differences in immune cell infiltration in the TAO patients. Two differentially expressed lncRNAs, LINC01140 and ZFHX4-AS1, in TAO groups were identified as ferroptosis-related lncRNAs. CYBB-LINC01140-TLR4, CYBB- LINC01140- SLC38A1, TLR4- LINC01140- SLC38A1, and CTSB- ZFHX4-AS1- CYBB may be potential RNA regulatory pathways in TAO. Targeted drugs and transcription factors for differential expressed FRGs were also screened out in our study. In vitro, experiments revealed that CTSB, PEX3, ABCC1 and ZFHX4-AS1(lncRNA) were differentially expressed in orbital fibroblasts (OFs) between TAO groups and healthy controls at the transcriptional level.

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Biomarker identification of thyroid associated ophthalmopathy using microarray data.

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Biomarker identification of thyroid associated ophthalmopathy using microarray data.

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