A Transcriptome-Based Molecular Taxonomy for Non-Surgical Thyroid Eye Disease: A Cross-Sectional Cohort Study with Unsupervised Clustering_Vol. 4 No. 1 (JMHS 2026)_Journal of Medicine and Health Science (ISSN: 2959-0639)

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A Transcriptome-Based Molecular Taxonomy for Non-Surgical Thyroid Eye Disease: A Cross-Sectional Cohort Study with Unsupervised Clustering

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DOI: https://doi.org/10.62517/jmhs.202605127

Author(s)

Tianyi Zhu1,2,3,4,†, Weijin Qian1,2,3,4,†, Jin Liu1,2,3,4,†, Qiang Huang5, Lianfei Fang1,2,3,4, Li Yang1,2,3,4, Runchuan Li1,2,3,4, Xuefei Song1,2,3,4, Liang Chen5, Huifang Zhou1,2,3,4,*

Affiliation(s)

1Department of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China 3Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai, China 4Chinese Consortium for Thyroid Eye Disease (CCTED), Shanghai, China 5State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, School of Medicine, Shanghai University, Shanghai, China †These authors contributed equally to this work and share first authorship. *Corresponding Author

Abstract

An autoimmune condition affecting the orbit, known as thyroid eye disease (TED), commonly presents in conjunction with Graves’ hyperthyroidism (GH). Current severity and activity assessments do not effectively inform treatment regimens, particularly the selection of target therapies for non-surgical TED. Our research aimed to develop a new TED classifier to improve the diagnosis and to aid in the precise treatment. A three-arm cohort of 224 participants including patients with TED and GH, as well as healthy controls was collected at baseline before treatment for RNA sequencing. Differential analysis revealed gene expression signatures that were unique to TED. Unsupervised clustering based on ophthalmopathy-specific genes and most variable genes was conducted in TED. This classification was validated by bootstrap resampling and refined using biological hub genes for clinical applications. Clinical manifestations, immune infiltration, and drug sensitivity were analysed in different TED subtypes. In TED, autoantigens were elevated, immune responses were activated, and both cellular proliferation and metabolic disorders were observed. A new molecular taxonomy was established and validated that is complementary to the severity and activity in guidelines. C1 (n=93) was the "adaptive and proliferative" subtype, characterised by an increased number of adaptive lymphocytes and represented by six hub genes (DDR2, LRP1B, NTRK2, PALB2, PTPRD and SLC25A6). In contrast, C2 (n=59) was the "inflammatory and destructive" subtype, exhibiting greater pain and reflex epiphora symptom, and represented by three hub genes (MON2, SNORA74B and STX16). There were significant differences in clinical characteristics, risk factors, ocular pain and reflex epiphora. Drug sensitivity analysis revealed distinct therapeutic vulnerabilities for the two subtypes: C1 showed sensitivity to kinase inhibitors, while C2 showed sensitivity to glucocorticoids and anti-inflammatory agents. We profiled the genes of TED and developed a hub gene-based molecular classification, which provides a framework for subtype-guided therapeutic selection.

Keywords

Thyroid Eye Disease; Molecular Taxonomy; Unsupervised Clustering; Transcriptome Sequencing; Targeted Therapy.

References

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