| Title: | Decoding Gene-Lifestyle Synergy in Diabetic Retinopathy Development: A Transethnic Prospective Cohort Study |
| Journal: | Ophthalmology |
| Published: | 27 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42055347/ |
| DOI: | https://doi.org/10.1016/j.ophtha.2026.04.017 |
Publication 17820
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Abstract
PURPOSE: To develop a machine learning (ML)-driven polygenic risk score (PRS) for DR and evaluate the extent to which lifestyle may mitigate genetic risk.</p>
METHODS: This multicenter, multiethnic cohort study included 91,691 participants with DR-free prediabetes/diabetes from the UK Biobank (UKB); and 1,119 participants with DR-free diabetes from the Guangzhou Diabetic Eye Study (GDES) for independent validation. A systematic literature review was conducted to identify candidate DR loci in PubMed, EMBASE, Web of Science, and WHO databases until 1 May 2025. An ML-driven PRS for DR was constructed by integrating 182 literature-derived single nucleotide polymorphisms, which was subsequently applied to two multiethnic, prospective cohorts. Lifestyle adherence was determined using a scoring system based on four behavioral factors (no smoking, optimal weight control, regular physical activity, and healthy sleep) and were categorized as favorable (3-4 factors), intermediate (2 factors) and unfavorable (0-1 factor).</p>
RESULTS: Participants at high genetic risk had a 37% higher risk of developing incident DR than those at low genetic risk, regardless of lifestyle (HR = 1.37, 95% CI: 1.18 to 1.60; P < 0.001). An unfavorable lifestyle was associated with a 49% higher risk than a favorable lifestyle, regardless of genetic risk (HR = 1.49, 95% CI: 1.34 to 1.65; P < 0.001). High genetic risk combined with an unfavorable lifestyle more than doubled the DR risk (HR = 2.09, 95% CI: 1.67 to 2.60; P < 0.001). Among participants at high genetic risk, a favorable lifestyle was associated with a 44% lower DR risk (HR = 0.56, 95% CI: 0.42 to 0.75; P < 0.001), corresponding to a reduction in the standardized DR rates from 7.5% (95% CI: 7.4% to 7.6%) to 4.6% (95% CI: 4.5% to 4.7%). The gene-lifestyle synergistic associations were confirmed by replication in the GDES.</p>
CONCLUSIONS: Both genetic risk and modifiable lifestyles demonstrated independent and joint impacts on DR risk. While risk reduction was greatest among those with high genetic risk, our findings support universal behavioral interventions for DR prevention, regardless of genetic background.</p>
10 Authors
- Shaopeng Yang
- Zhuoyao Xin
- Baichen Liu
- Yu Huang
- Zhuoting Zhu
- Shaoying Tan
- Mingguang He
- Yih-Chung Tham
- Ching-Yu Cheng
- Wei Wang
1 Application
| Application ID | Title |
|---|---|
| 105658 | Multi-omics for subphenotyping and predicting of the ocular and systemic age-related diseases |
Enabling scientific discoveries that improve human health