Evaluating lipid-lowering drug targets for full-course diabetic retinopathy.

IF 3.7 2区医学 Q1 OPHTHALMOLOGY

British Journal of Ophthalmology Pub Date : 2025-04-21 DOI:10.1136/bjo-2024-325771

Jiahui Cao, Ting Su, Shuilian Chen, Zijing Du, Chunran Lai, Kaiyi Chi, Qinyi Li, Shan Wang, Qiaowei Wu, Yunyan Hu, Ying Fang, Yijun Hu, Zhuoting Zhu, Yu Huang, Xiayin Zhang, Honghua Yu

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Abstract

Background: Implementing lipid control in patients with diabetes is regarded as a potential strategy for halting the advancement of diabetic retinopathy (DR). This study seeks to use Mendelian randomisation (MR) to assess the causal relationship between lipid traits and lipid-lowering drug targets and full-course DR (background DR, severe non-proliferative DR (NPDR) and proliferative DR (PDR)).

Methods: A two-sample MR and drug target MR to decipher the causal effects of lipid traits and lipid-lowering drug targets on full-course DR, including background DR, severe NPDR and PDR, was conducted in the study. Genetic variants associated with lipid traits and genes encoding the protein targets of lipid-lowering drugs were extracted from the Global Lipids Genetics Consortium and UK Biobank. Summary-level data of full-course DR are obtained from FinnGen.

Results: No significant causal relationship was found between lipid traits and full-course DR. However, in drug target MR analysis, peroxisome proliferator-activated receptor gamma (PPARG) enhancement was associated with lower risks of background DR (OR=0.12, p=0.005) and PDR (OR=0.25, p=0.006). Additionally, mediation MR analysis showed that lowering fasting insulin (p=0.015) and HbA1c (p=0.005) levels mediated most of the association between PPARG and full-course DR.

Conclusions: This study reveals PPARG may be a promising drug target for full-course DR. The activation of PPARG could reduce the risk of full-course DR, especially background DR and PDR. The mechanism of the PPARG agonists' protection of full-course DR may be dependent on the glucose-lowering effect.

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评估糖尿病视网膜病变全程降脂药物靶点。

背景：在糖尿病患者中实施脂质控制被认为是阻止糖尿病视网膜病变（DR）进展的潜在策略。本研究旨在使用孟德尔随机化（MR）来评估脂质特征与降脂药物靶点和全程DR（背景DR、严重非增殖性DR （NPDR）和增殖性DR (PDR)）之间的因果关系。方法：采用双样本MR和药物靶点MR来解读脂质性状和降脂药物靶点对包括背景DR、重度NPDR和PDR在内的全程DR的因果关系。与脂质性状相关的遗传变异和编码降脂药物蛋白靶点的基因从全球脂质遗传学联盟和英国生物银行中提取。全程DR的汇总级数据来自FinnGen。结果：脂质特征与全程DR之间没有明显的因果关系。然而，在药物靶MR分析中，过氧化物酶体增殖物激活受体γ (PPARG)增强与背景DR （OR=0.12, p=0.005）和PDR （OR=0.25, p=0.006）的风险降低相关。此外，介导MR分析显示，降低空腹胰岛素（p=0.015）和HbA1c （p=0.005）水平介导了PPARG与全程DR之间的大部分关联。结论：本研究表明，PPARG可能是一个有希望的全程DR药物靶点，激活PPARG可以降低全程DR的风险，尤其是背景DR和PDR。PPARG激动剂对全程DR的保护机制可能依赖于其降糖作用。

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

British Journal of Ophthalmology 医学-眼科学

CiteScore

10.30

自引率

2.40%

发文量

213

审稿时长

3-6 weeks

期刊介绍： The British Journal of Ophthalmology (BJO) is an international peer-reviewed journal for ophthalmologists and visual science specialists. BJO publishes clinical investigations, clinical observations, and clinically relevant laboratory investigations related to ophthalmology. It also provides major reviews and also publishes manuscripts covering regional issues in a global context.