Transcriptome Analysis of Orbital Adipose Tissue in Active Thyroid Eye Disease Using Next Generation RNA Sequencing Technology

Bradford W. Lee1, 2, 4, Virender B. Kumar2, Pooja Biswas2, Audrey C. Ko1, 2, Ramzi M. Alameddine1, 2, David B. Granet, M.D. 2, Radha Ayyagari2, Don O. Kikkawa1, 2, 3, *, Bobby S. Korn1, 2, 3, *
1 Department of Ophthalmology, Division of Ophthalmic Plastic and Reconstructive Surgery, University of California, San Diego, La Jolla, CA
2 Department of Ophthalmology, University of California, San Diego, La Jolla, CA
3 Division of Plastic Surgery, Department of Surgery, University of California, San Diego, La Jolla, CA
4 Division of Oculofacial Plastic and Reconstructive Surgery, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL

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© 2018 Lee et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: ( This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence can be addressed to the co-corresponding authors Bobby S. Korn and Don O. Kikkawa at Shiley Eye Institute, University of California San Diego, 9415 Campus Point Drive, La Jolla, CA 92093, USA; Tel: +1 858-246-0424; E-mails:,



This study utilized Next Generation Sequencing (NGS) to identify differentially expressed transcripts in orbital adipose tissue from patients with active Thyroid Eye Disease (TED) versus healthy controls.


This prospective, case-control study enrolled three patients with severe, active thyroid eye disease undergoing orbital decompression, and three healthy controls undergoing routine eyelid surgery with removal of orbital fat. RNA Sequencing (RNA-Seq) was performed on freshly obtained orbital adipose tissue from study patients to analyze the transcriptome. Bioinformatics analysis was performed to determine pathways and processes enriched for the differential expression profile. Quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) was performed to validate the differential expression of selected genes identified by RNA-Seq.


RNA-Seq identified 328 differentially expressed genes associated with active thyroid eye disease, many of which were responsible for mediating inflammation, cytokine signaling, adipogenesis, IGF-1 signaling, and glycosaminoglycan binding. The IL-5 and chemokine signaling pathways were highly enriched, and very-low-density-lipoprotein receptor activity and statin medications were implicated as having a potential role in TED.


This study is the first to use RNA-Seq technology to elucidate differential gene expression associated with active, severe TED. This study suggests a transcriptional basis for the role of statins in modulating differentially expressed genes that mediate the pathogenesis of thyroid eye disease. Furthermore, the identification of genes with altered levels of expression in active, severe TED may inform the molecular pathways central to this clinical phenotype and guide the development of novel therapeutic agents.

Keywords: Orbital adipose tissue, Thyroid eye disease, Transcriptome, Next generation sequencing, RNA sequencing technology, IGF-1 signaling.