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Evaluating lipid-lowering drug targets for full-course diabetic retinopathy
Jiahui Cao1, Ting Su1,2, Shuilian Chen1
1Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
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.
Insights
Peroxisome proliferator-activated receptor gamma (PPARG) activation may reduce risks for diabetic retinopathy (DR), particularly background DR and proliferative DR (PDR). This effect appears linked to improved glucose control, suggesting PPARG as a potential therapeutic target.
Area of Science:
- Genetics and Precision Medicine
- Ophthalmology
- Metabolic Diseases
Background:
- Diabetic retinopathy (DR) progression is linked to lipid control.
- Investigating causal links between lipid traits, drug targets, and DR is crucial.
Purpose of the Study:
- To assess the causal relationship between lipid traits and lipid-lowering drug targets with full-course diabetic retinopathy (DR).
- To evaluate background DR, severe non-proliferative DR (NPDR), and proliferative DR (PDR) in relation to these factors.
Main Methods:
- Employed two-sample Mendelian randomization (MR) and drug target MR analyses.
- Utilized genetic data from the Global Lipids Genetics Consortium, UK Biobank, and FinnGen for DR data.
Main Results:
- No significant causal link was found between lipid traits and full-course DR.
- PPARG enhancement showed reduced risks for background DR (OR=0.12) and PDR (OR=0.25).
- Mediation analysis indicated fasting insulin and HbA1c levels mediate the PPARG-DR association.
Conclusions:
- PPARG emerges as a promising drug target for full-course DR.
- PPARG activation may lower risks for background DR and PDR.
- The protective mechanism of PPARG agonists likely involves glucose-lowering effects.
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