Tan Yao, Yan Zuyun, Yin Jiayang, Cao Jiamin, Xie Bingyu, Zhang Feng, Zhang Wenhua, Xiong Wei
Department of Ophthalmology, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Yuelu District, Changsha City, 410013, Hunan Province, China.
Postdoctoral Station of Clinical Medicine, The Third Xiangya Hospital, Central South University, Changsha City, 410013, Hunan Province, China.
Acta Diabetol. 2025 Feb;62(2):193-203. doi: 10.1007/s00592-024-02345-7. Epub 2024 Aug 1.
Diabetic retinopathy (DR) results from complex genetic and metabolic interactions. Unraveling the links between blood metabolites and DR can advance risk prediction and therapy.
Leveraging Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC), we analyzed 10,413 DR cases and 308,633 controls. Data was sourced from the Metabolomics GWAS server and the FinnGen project.
Our research conducted a comprehensive MR analysis across 486 serum metabolites to investigate their causal role in DR. After stringent selection and validation of instrumental variables, we focused on 480 metabolites for analysis. Our findings revealed 38 metabolites potentially causally associated with DR. Specifically, 4-androsten-3beta,17beta-diol disulfate 2 was identified as significantly associated with a reduced risk of DR (OR = 0.471, 95% CI = 0.324-0.684, p = 7.87 × 10), even after rigorous adjustments for multiple testing. Sensitivity analyses further validated the robustness of this association, and linkage disequilibrium score regression analyses showed no significant genetic correlation between this metabolite and DR, suggesting a specific protective effect against DR.
Our study identifies 4-androsten-3beta,17beta-diol disulfate 2, a metabolite of androgens, as a significant protective factor against diabetic retinopathy, suggesting androgens as potential therapeutic targets.
糖尿病视网膜病变（DR）由复杂的遗传和代谢相互作用导致。阐明血液代谢物与DR之间的联系可推动风险预测和治疗。
利用孟德尔随机化（MR）和连锁不平衡评分回归（LDSC），我们分析了10413例DR病例和308633例对照。数据来源于代谢组学全基因组关联研究服务器和芬兰基因项目。
我们的研究对486种血清代谢物进行了全面的MR分析，以研究它们在DR中的因果作用。在对工具变量进行严格筛选和验证后，我们聚焦于480种代谢物进行分析。我们的研究结果揭示了38种代谢物可能与DR存在因果关联。具体而言，即使在对多重检验进行严格校正后，4-雄烯-3β,17β-二醇二硫酸酯2被确定与DR风险降低显著相关（OR = 0.471，95%CI = 0.324 - 0.684，p = 7.87×10）。敏感性分析进一步验证了这种关联的稳健性，连锁不平衡评分回归分析表明该代谢物与DR之间不存在显著的遗传相关性，提示其对DR具有特定的保护作用。
我们的研究确定了雄激素的一种代谢物4-雄烯-3β,17β-二醇二硫酸酯2是预防糖尿病视网膜病变的重要保护因素，提示雄激素可能是潜在的治疗靶点。
