ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Clinical Diabetes
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1638661
This article is part of the Research TopicDiabetes Complications: Navigating Challenges and Unveiling New SolutionsView all 7 articles
The immune-related plasma protein LAT2 as a protective modulator in diabetic retinopathy: a Mendelian randomization study
Provisionally accepted
Ming Yang1
Weizhen Wu2*- 1Capital Medical University Affiliated Beijing Friendship Hospital Department of Ophthalmology, Beijing, China
- 2Department of Otolaryngology, Affiliated Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Background:Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Although numerous observational studies have explored candidate biomarkers, the causal contributions of circulating plasma proteins to DR pathogenesis remain largely unclear due to confounding and reverse causality.Methods:To address this, we performed a two-sample Mendelian randomization (MR) analysis using protein quantitative trait loci (pQTLs) derived from the UK Biobank Pharma Proteomics Project (n = 54,219) and DR outcome data from the FinnGen cohort (n = 96,429; 14,142 cases). Colocalization and transcriptome-based MR analyses were conducted to validate causal protein candidates. We further performed experimental validation in hyperglycemia-induced retinal cells and assessed immune mediation using MR-based mediation analysis. A phenome-wide MR (MR-PheWAS) was also conducted to evaluate disease specificity.Results:Among five significant proteins, we identified Linker for Activation of T Cells Family Member 2 (LAT2) as a robust protective factor for DR (OR = 0.358, 95% CI: 0.215–0.597, p < 0.001). Colocalization analysis (PP.H4 = 0.8546) and SMR analysis supported a shared genetic basis between LAT2 expression and DR. LAT2 expression was significantly upregulated under high-glucose stress in retinal cells. Mediation MR revealed that CD27⁺ switched memory B cells partially mediated the protective effect of LAT2 (mediation proportion: 6.2%, p = 0.047). The MR-PheWAS further confirmed the tissue-specific association of LAT2 with DR.Conclusions:LAT2 may be a potential protective factor for diabetic retinopathy, offering preliminary insight for future biomarker development and prevention strategies.
Keywords: Diabetic Retinopathy, Mendelian Randomization (MR), biomarker, Lat2, phenome-wide MR
Received: 31 May 2025; Accepted: 01 Jul 2025.
Copyright: © 2025 Yang and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Weizhen Wu, Department of Otolaryngology, Affiliated Beijing Friendship Hospital, Capital Medical University, Beijing, China
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