Graves' ophthalmopathy (GO) is a debilitating autoimmune disorder that affects the orbital and periorbital tissues. It occurs in about 30 % of patients with Graves' disease, a type of autoimmune thyroid eye disease (TED). The clinical manifestations of GO are varied, ranging from mild symptoms, such as ocular irritation and swelling, to more severe features, including exophthalmos, diplopia, and, in rare cases, vision loss due to optic nerve compression (Bartalena and Tanda, 2022; Gontarz-Nowak et al., 2020). These clinical features significantly impact patients' quality of life. Despite extensive research, the pathophysiological mechanisms underlying GO are not fully understood, although both environmental and genetic factors are recognized as contributors (Bartalena et al., 2020). These clinical features are primarily driven by immune-mediated inflammation of orbital tissues (Shu et al., 2024). While the pathogenesis of GO remains complex, genetic susceptibility plays a crucial role.

Genetic susceptibility, particularly involving immune-related genes, have increasingly been recognized as key determinants in the development of GO (Fang et al., 2021). Co-stimulatory molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), cluster of differentiation 28 (CD28), tumor necrosis factor superfamily, member 4 (TNFSF4), programmed cell death protein 1 (PD-1), inducible T cell costimulator (ICOS), CD80, CD86, inducible T cell co-stimulator (ICOSL), CD40, and programmed cell death ligand 1 (PD-L1) are pivotal in the modulation of T-cell activation, maintaining immune tolerance and preventing excessive immune responses (Zhang and Vignali, 2016). Polymorphisms in the genes encoding these co-stimulatory molecules have been implicated in various autoimmune diseases, including systemic lupus erythematosus (Chen et al., 2023a), rheumatoid arthritis (Chen et al., 2023b), and type 1 diabetes (Gootjes et al., 2022). In GO, single nucleotide polymorphisms (SNPs) in these genes are thought to influence disease susceptibility and clinical severity, potentially by altering T-cell activation and immune regulation within orbital tissues (Wang and Smith, 2014).

Several studies have reported associations between co-stimulatory molecule SNPs and the development of GO (Wang and Smith, 2014). However, the relationship between these SNPs and specific clinical characteristics of GO, such as the degree of exophthalmos, severity of diplopia, or extent of soft tissue involvement, remains poorly understood. Given the phenotypic variability observed in GO, identifying genetic markers associated with distinct clinical features may provide valuable insights into disease mechanisms and help refine treatment approaches.

This study aims to investigate the correlation between SNPs in co-stimulatory molecules and the clinical characteristics of GO, with a particular focus on laterality, orbital pain, eyelid inflammation (swelling and erythema), diplopia, exophthalmos, conjunctival inflammation (redness and chemosis), and eyelid retraction. By exploring these associations, this research seeks to enhance the understanding of the genetic factors contributing to the heterogeneity of GO, with the potential to identify novel therapeutic targets.