Purpose

Thyroid associated orbitopathy (TAO) is mostly associated with autoimmune thyroid disease (AITD). Early diagnosis is crucial, but clinical practice lacks reliable biomarkers. Evidence for lacrimal gland involvement with altered protein composition in tears has been reported. We investigated the total tear protein and miRNA profile of TAO patients to identify potential biomarkers specific for active TAO.

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Methods

Tear fluid samples were collected from 30 TAO patients with CAS-score ≥4, 32 patients with AITD, and 39 control subjects (NC). All participants were euthyroid. Small RNA-seq and LC-MS/MS was performed to identify significantly differentially expressed (DE) miRNAs and proteins, respectively. Reactome and KEGG and miRNA target lists were used to explore enriched miRNAs, proteins, and their pathway interactions.

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Results

Small RNA-seq captured 305 miRNAs, from which 10 significantly DE miRNAs were identified, including upregulation of hsa-miR-184 in TAO vs. both AITD and NC. LC-MS/MS analysis captured 4141 proteins, including 4 DE proteins. Sorcin (SRI) was downregulated in TAO vs. NC, whereas the comparison of TAO and AITD groups pointed todownregulation of glutathione S-transferase Mu 1 (GSTM1) and 2 (GSTM2) and upregulation of keratin, type I cytoskeletal 15 (KRT15). Targets of hsa-miR-184 show a trend to be downgregulated in proteomics. DE miRNA are associated with immune, inflammatory, metabolic, stress related and several signal transduction pathways. DE proteins in TAO are associated with immune, inflammatory, metabolic and biosynthesis.

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Conclusion

We included TAO patients and compared them with AITD patients and normal controls by analalyzing their tear fluid samples both with small RNA sequencing and LC-MS/MS. Several differentially expresse miRNA and proteins were found, linked to immune resones and several signal transduction pathways. This study provides possible key targets for further research on the exact mechanism of TAO pathogenesis and may help provide reliable biomarkers for early detection of disease.

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Additional Authors

First name	Last name	Base Hospital / Institution
Emma	Delanote	Ghent University
María del Rocío	Pérez Baca	Ghent University
Hanne	Lenaerts	Ghent University
Gabrielle	Holtappels	Ghent University
Caroline	Van Cauwenbergh	Ghen University
Manon	Van Haute	Ghent University
Julie	Van Puyvelde	Ghent University Hospital
Pieter	Mestdagh	Ghent University
Bruno	Lapauw	Ghent University Hospital
Bart P	Leroy	Ghent University Hospital
Daria	Fijalkowska	Ghent University
Frauke	Coppieters	Ghent University

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