Triglyceride-driven pathogenesis in thyroid-associated ophthalmopathy: a dual approach of clinical correlation and genetic causality

AIM: To clarify the clinical correlations and causal relationships between lipid metabolism and the progression of thyroid-associated ophthalmopathy (TAO). METHODS: This case-control study retrieved clinical data from 2018 to 2023. A total of 2591 patients were enrolled, including 197 patients with TAO (case group) and 2394 patients with hyperthyroidism without TAO (control group). Serum lipid parameters, including triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and the HDL/total cholesterol ratio, as well as thyroid function markers, were compared between the two groups. Correlation analyses were performed to evaluate the associations between serum lipid levels and key ocular manifestations of TAO, including exophthalmos degree, clinical activity score, and disease severity. Furthermore, Mendelian randomization (MR) analysis was conducted using genome-wide association study (GWAS) datasets, with hyperthyroidism as the exposure variable and serum lipid parameters as the outcome variables, to infer the causal relationship between hyperthyroidism, lipid metabolism, and TAO progression. RESULTS: The TAO group consisted of 101 males and 96 females, while the hyperthyroidism group included 706 males and 1688 females. Compared with the control group, patients with TAO had significantly higher levels of triglycerides (1.83±1.21 vs 1.40±1.08 mmol/L, P0.1). MR analysis confirmed that hyperthyroidism exerted a causal effect in reducing serum triglycerides [inverse-variance weighting odds ratio (OR)=0.035, 95% confidence interval (CI): 0.01-0.12] and total cholesterol (OR=0.085, 95%CI: 0.02-0.34), with no evidence of horizontal pleiotropy (MR-PRESSO P>0.05). CONCLUSION: Elevated serum triglyceride levels are an independent risk factor for TAO severity, especially exophthalmos, and triglyceride metabolism is inversely regulated by thyroid function.