Thyroid Eye Disease (TED) is a complex condition that affects some people with Graves’ disease, but not everyone. Understanding how genetics contributes to TED can shed light on why certain individuals are more susceptible, guiding more personalized approaches to diagnosis and treatment.
Thyroid Eye Disease (TED), also known as Graves’ ophthalmopathy or Graves’ eye disease, is an autoimmune disorder affecting tissues around the eye (orbital fat, muscles, connective tissue). Not all those afflicted with Graves’ disease show eye involvement, and so it is important to understand the genetic underpinnings and contribution of the genetic component in the development of TED. Several recent studies have helped to identify genes and gene networks that may increase susceptibility or influence the severity of TED.
TED occurs due to the inflammation and tissue destruction caused by the infiltration of the immune cells into the orbital tissues. By studying the changes in the gene expression in those immune cells, it is possible to decipher the gene networks involved in the susceptibility to TED. Some of the ways to identify these gene networks include RNA sequencing and microarray analyses, as well as undertaking biomarker discovery based on the known function to uncover candidate genes. This article summarizes the key findings, the strengths and limitations, and how this evolving field may impact diagnosis, risk stratification, and therapy.
Evidence Found in Genes That Link to Thyroid Eye Disease
In a recent comprehensive study from 2025 (1), gene expression analyses were performed on immune cells from patients with TED and compared to immune cells taken from ‘control’ Graves’ disease patients without eye involvement. The results pinpointed about 10 “hub” genes whose expression was strongly associated with TED status. These genes were specifically found in TED patients compared to their Graves’ disease counterparts, who lacked eye involvement. These genes include:
- MMP9 (matrix metallopeptidase 9) is involved in extracellular matrix remodeling and tissue invasion. Its upregulation is a well-known observation in many inflammatory diseases.
- MPO (myeloperoxidase) is an enzyme found in neutrophils that contributes to oxidative stress and inflammation. In fact, TED patients show an elevated level of neutrophils in their blood as opposed to the control patients.
- CEACAM1 / CEACAM8 (Carcinoembryonic antigen-related cell adhesion molecules 1/8) are cell adhesion molecules that regulate immune cell interactions.
- SLPI (secretory leukocyte protease inhibitor) modulates protease activity in white blood cells (leukocytes) and inflammation.
- AZU1 (azurocidin 1) and BPI (bactericidal/permeability-increasing protein) are granule-derived, neutrophil-related proteins.
- KCNJ15 (Potassium Inwardly Rectifying Channel Subfamily J Member 11) is a potassium channel gene, which may affect cell signaling or ionic homeostasis in immune cells.
- TNFRSF10C (tumor necrosis factor receptor superfamily) is a death receptor (a decoy receptor for TRAIL) involved in cell survival/apoptosis regulation.
Additional Genetics and Biomarker Studies
Apart from the above hub-gene approach, there are several other studies that have employed microarray data, literature mining, and network analyses to further ascertain the genetic linkage in developing TED.
- A 2021 (2) study analyzed published gene sets from existing studies and computational predictions from microarrays to identify 22 gene biomarkers for TED, then constructed a regulatory network with >1,000 interactions.
- A 2025 (3) paper showed extracellular proteins as potential biomarkers in TED and identified candidates that may serve as secreted markers or therapeutic targets.
- A 2024 (4) review synthesizes many of these findings and also discusses dysregulations in apoptosis, inflammatory signaling and regulation of autoimmunity in TED pathogenesis.
As a whole, multiple lines of genomic and transcriptomic evidence support the notion of a strong genetic component, particularly in immune, inflammatory, and extracellular matrix–related genes, with the presence and severity of TED.
Relevance of Genetic Preponderance
The discovery of genetic signatures associated with TED carries potential clinical and translational implications, such as:
Risk Stratification and Prediction Relating to Graves’ Ophthalmopathy
Certain gene expression signatures or variants may be able to reliably distinguish those with Graves disease who will develop TED from those who will not. This can assist clinicians in better predicting risks in newly diagnosed patients. For example, someone with a “pro-TED” gene signature can be observed more closely or receive early intervention.
Biomarkers and Monitoring
Elevated expression of hub genes might serve as biomarkers to monitor disease activity, predict flare-ups, relapse or response to therapy. Since these biomarkers have been identified in immune cells harvested from peripheral blood, they can offer a convenient way of screening.
Understanding Pathophysiology and Newer Therapeutic Targets
Mechanistic insights show that neutrophil activation, oxidative stress, ECM remodeling, and immune cell–stromal interactions may play more central roles than previously concurred. This can lead to new therapeutic interventions targeting those pathways. Other hub genes or related pathways might be targetable by drugs such as MMP inhibitors, modulators of oxidative stress, or inhibitors of adhesion molecules.
While promising, the genetics of TED is still an emerging field with many challenges, and it is important to know that expression and correlation do not equal causation. Also, larger controlled studies with bigger sample sizes need to be carried out to affirm these conclusions. In addition, most studies have been performed with immune cells harvested from peripheral blood, and an attempt has been made to compare these findings with orbital tissues, such as samples procured during surgery. Apart from mere gene expression, variant identification is also important in establishing the role of genetic variants and potential mutations in increasing the predisposition to developing TED.
Concerned About TED? Schedule a Consultation Today
To wrap up, there is strong evidence for the existence of a genetic component in determining the risk of developing TED. This risk is polygenic and multifactorial, i.e., more than one gene or pathway is involved. These genetic associations may ultimately help improve risk prediction, biomarker monitoring, and therapeutic targeting, but are still in their incipient stage. Further research combining gene variants, expression, functional validation, and longitudinal design will further clarify which genes truly drive TED and also help decide interventions.
If you suspect or are having signs and symptoms of TED (bulging eyes, inflammation) or are interested in learning more about the disease and emerging treatment options, do not hesitate to schedule an appointment with Dr. Raymond Douglas.
References
- Lin H, Duan H, Zheng J, Jiang Z, Xu Y, Huang H. Clinical characteristics of thyroid eye disease and expression profile of peripheral blood immune cells. Sci Rep. 2025;15(1):28666. Epub 20250806. doi: 10.1038/s41598-025-08904-4. PubMed PMID: 40764715; PMCID: PMC12325906.
- Zou H, Xu W, Wang Y, Wang Z. A data-driven approach for the discovery of biomarkers associated with thyroid eye disease. BMC Ophthalmol. 2021;21(1):166. Epub 20210409. doi: 10.1186/s12886-021-01903-9. PubMed PMID: 33832456; PMCID: PMC8034124.
- He S, Nie H, Yin X, Zhong Z. Identification of key extracellular proteins as the potential biomarkers in thyroid eye disease. PLoS One. 2025;20(4):e0322415. Epub 20250429. doi: 10.1371/journal.pone.0322415. PubMed PMID: 40299971; PMCID: PMC12040256.
- Kulbay M, Tanya SM, Tuli N, Dahoud J, Dahoud A, Alsaleh F, Arthurs B, El-Hadad C. A Comprehensive Review of Thyroid Eye Disease Pathogenesis: From Immune Dysregulations to Novel Diagnostic and Therapeutic Approaches. Int J Mol Sci. 2024;25(21). Epub 20241029. doi: 10.3390/ijms252111628. PubMed PMID: 39519180; PMCID: PMC11546489.
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