[Association between lipid levels and the risk of Graves' ophthalmopathy: Mendelian randomization and clinical...

Objective: To investigate the association between lipid levels and the risk of Graves' ophthalmopathy (GO). Methods: This study employed Mendelian randomization (MR) with a retrospective cross-sectional analysis. Summary data for lipids and GO were obtained from the genome-wide association studies (GWAS) released between 2013 and 2023, and two-sample MR was used to explore the causal relationship between lipids and GO. Inverse-variance weighting (IVW) served as the primary estimator, with MR-Egger regression and the weighted median (WM) as auxiliary methods. A series of sensitivity analyses were conducted to ensure the validity and stability of the findings. In parallel, lipid data were collected from inpatients with GO and contemporaneous healthy controls in the Department of Ophthalmology, the Third Xiangya Hospital of Central South University, from April 2022 to November 2024, and differences in lipid levels were analyzed using independent-samples t tests and non-parametric tests. Results: In the forward MR analysis for HDL-C, two GWAS datasets were used. Both the ieu-b-109 data (OR=0.644,95%CI=0.388-1.070,P=0.089) and the ieu-b-4844 data (OR=1.349,95%CI=0.848-2.146,P=0.206) indicated that HDL-C had no significant causal association with the risk of GO. the low-density lipoprotein cholesterol (LDL-C) was evaluated using four GWAS data sources. The ieu-a-300 data (OR=0.686,95%CI=0.352-1.335,P=0.267), the ieu-a-781 data (OR=0.467,95%CI=0.116-1.886,P=0.285), the ieu-b-110 data (OR=0.734,95%CI=0.380-1.419,P=0.358), and the ieu-b-4846 data (OR=1.311,95%CI=0.634-2.714,P=0.465) were not statistically significant, and the effect directions were inconsistent, suggesting that LDL-C had no clear causal effect on the risk of GO. Triglycerides were evaluated using five data sources. The ieu-a-783 data (OR=1.101,95%CI=0.461-2.626,P=0.829), the ieu-b-4849 data (OR=0.657,95%CI=0.203-2.128,P=0.483), the ieu-b-4850 data (OR=1.144,95%CI=0.568-2.305,P=0.707), the met-d-Total_TG data (OR=1.630,95%CI=0.309-8.600,P=0.565), and the ukb-bub35-TRIG data (OR=0.906,95%CI=0.572-1.436,P=0.674) showed no causal association between triglyceride levels and the risk of GO. the total cholesterol was evaluated using the ieu-a-782 dataset (OR=0.672,95%CI=0.103-4.399,P=0.678), which suggested no significant causal effect on the risk of GO. The effect directions of all these analyses were consistent across IVW, MR-Egger, and WM methods, suggesting that the results were relatively robust. No clear causal relationship between lipids and GO was found. In the reverse MR analysis, no causal relationship was found between GO and HDL-C, triglycerides, or total cholesterol (P>0.05). Although the ieu-b-4846 data suggested a slight inverse association between Graves' ophthalmopathy and LDL-C (OR=0.983,95%CI=0.968-0.998,P=0.027), it was not significant after FDR correction (FDR=0.081). An observational study included 102 patients with GO, including 45 males (44.1%) and 57 females (55.9%), with an average age of 43.50 (33.00, 53.00) and a BMI of 23.55±3.50. There were 102 healthy controls, including 46 males (45.1%) and 56 females (54.9%), with an average age of 42.50 (34.00, 56.00) and a BMI of 23.20±3.67. The results showed no statistically significant differences in HDL-C (P=0.487), LDL-C (P=0.186), triglycerides (P=0.391), or total cholesterol (P=0.168) between the two groups. Conclusion: Both MR and observational studies indicate that lipid levels may not be significantly associated with the risk of GO. There is a need for large sample and in-depth clinical studies in China.