Elucidating the role of genetically determined metabolites in Diabetic Retinopathy: insights from a mendelian randomization analysis.

IF 3.1 3区医学 Q2 ENDOCRINOLOGY & METABOLISM Acta Diabetologica Pub Date : 2024-08-01 DOI:10.1007/s00592-024-02345-7

Yao Tan, Zuyun Yan, Jiayang Yin, Jiamin Cao, Bingyu Xie, Feng Zhang, Wenhua Zhang, Wei Xiong

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Abstract

Aims: Diabetic retinopathy (DR) results from complex genetic and metabolic interactions. Unraveling the links between blood metabolites and DR can advance risk prediction and therapy.

Methods: 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.

Results: 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^- 5), 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.

Conclusions: 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.

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阐明由基因决定的代谢物在糖尿病视网膜病变中的作用：孟德尔随机分析的启示。

目的：糖尿病视网膜病变（DR）是复杂的遗传和代谢相互作用的结果。揭示血液代谢物与糖尿病视网膜病变之间的联系可以促进风险预测和治疗：利用孟德尔随机化（Mendelian Randomization，MR）和连锁不平衡评分回归（Linkage Disequilibrium Score Regression，LDSC），我们分析了 10,413 例 DR 病例和 308,633 例对照。数据来源于代谢组学 GWAS 服务器和 FinnGen 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。经过对工具变量的严格筛选和验证，我们重点分析了 480 种代谢物。我们的研究结果显示，38种代谢物可能与DR存在因果关系。特别是 4-雄烯-3beta,17beta-二醇二硫酸盐 2 被确定与降低 DR 风险显著相关（OR = 0.471，95% CI = 0.324-0.684，p = 7.87 × 10-5），即使经过严格的多重测试调整也是如此。敏感性分析进一步验证了这种关联的稳健性，连锁不平衡得分回归分析表明，这种代谢物与DR之间没有显著的遗传相关性，这表明对DR有特殊的保护作用：我们的研究发现雄激素的代谢产物 4-雄烯-3beta,17beta-二醇二硫酸盐 2 是糖尿病视网膜病变的重要保护因素，这表明雄激素是潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Diabetologica 医学-内分泌学与代谢

CiteScore

7.30

自引率

2.60%

发文量

180

审稿时长

2 months

期刊介绍： Acta Diabetologica is a journal that publishes reports of experimental and clinical research on diabetes mellitus and related metabolic diseases. Original contributions on biochemical, physiological, pathophysiological and clinical aspects of research on diabetes and metabolic diseases are welcome. Reports are published in the form of original articles, short communications and letters to the editor. Invited reviews and editorials are also published. A Methodology forum, which publishes contributions on methodological aspects of diabetes in vivo and in vitro, is also available. The Editor-in-chief will be pleased to consider articles describing new techniques (e.g., new transplantation methods, metabolic models), of innovative importance in the field of diabetes/metabolism. Finally, workshop reports are also welcome in Acta Diabetologica.