Leveraging genetic differences and Mendelian randomization to dissect the causal link and shared etiology between diabetic nephropathy and diabetic retinopathy
10.3980/j.issn.1672-5123.2025.11.20
- VernacularTitle:基于遗传差异与孟德尔随机化分析糖尿病肾病与糖尿病视网膜病变的因果关系及共同机制
- Author:
Guoxin DING
1
;
Jing WANG
1
;
Xian WANG
1
;
Zhou ZHANG
1
;
Xin XIAO
1
;
Yingqi LI
1
Author Information
1. Guizhou Medical University, Guiyang 550001, Guizhou Province, China; Department of Ophthalmology, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
- Publication Type:Journal Article
- Keywords:
diabetic nephropathy;
diabetic retinopathy;
Mendelian randomization;
single nucleotide polymorphism;
differential gene expression
- From:
International Eye Science
2025;25(11):1838-1847
- CountryChina
- Language:Chinese
-
Abstract:
AIM: To investigate the genetic association and potential causal relationship between diabetic nephropathy(DN)and diabetic retinopathy(DR), and to elucidate their shared molecular mechanisms through differential gene expression analysis and Mendelian randomization(MR).METHODS: Transcriptomic data of DN and DR were obtained from the Gene Expression Omnibus(GEO)database and analyzed for differentially expressed genes(DEGs). Genes meeting the significance threshold(log2FC>1, P<0.05)were identified, followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis to explore shared biological pathways. Using genome-wide association study(GWAS)summary statistics for DN and DR, two-sample MR analysis was performed, with DN as the exposure and DR as the outcome. The causal effect was primarily estimated with the inverse-variance weighted(IVW)method, and sensitivity analyses were conducted to assess robustness.RESULTS: MR analysis revealed that DN significantly increased the risk of DR. IVW estimates indicated that the odds ratio(OR)for non-proliferative DR(NPDR)was 3.23(95% CI: 2.12-4.95, P<0.001), and the OR for proliferative DR(PDR)was 1.10(95% CI: 1.06-1.15, P<0.001). DEG analysis identified several key genes, including FN1, COL1A2, and THBS2. FN1 and COL1A2 are involved in extracellular matrix remodeling and fibrosis, contributing to vascular permeability alterations and microvascular damage in diabetic complications. THBS2 is closely associated with angiogenesis and vascular homeostasis, suggesting its potential role in DR. KEGG enrichment analysis showed that these DEGs were mainly enriched in advanced glycation end products(AGEs)-RAGE signaling, extracellular matrix degradation, and oxidative stress pathways, all of which are highly relevant to the pathogenesis of DN and DR.CONCLUSION: This study demonstrates the genetic association between DN and DR using MR and DEGs analyses. The shared mechanisms, particularly involving extracellular matrix remodeling, inflammatory response, and angiogenesis, may serve as novel therapeutic targets and provide a theoretical basis for the early diagnosis and targeted treatment of diabetic complications.
