Genetic Association between Lipid-Regulating Drug Targets and Diabetic Retinopathy: A Drug Target Mendelian
Shengnan Chen1,2, Ming Zhang3, Peng Yang1
1Department of Joint Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi, China.
Background:
Diabetic retinopathy (DR) is a diabetic microvascular complication and a leading cause of vision loss. However, there is a lack of effective strategies to reduce the risk of DR currently. The present study is aimed at assessing the causal effect of lipid-regulating targets on DR risk using a two-sample Mendelian randomization (MR) study.
Method:
Genetic variants within or near drug target genes, including eight lipid-regulating targets for LDL-C (HMGCR, PCSK9, and NPC1L1), HDL-C (CETP, SCARB1, and PPARG), and TG (PPARA and LPL), were selected as exposures. The exposure data were obtained from the IEU OpenGWAS project. The outcome dataset related to DR was obtained from the FinnGen research project. Inverse-variance-weighted MR (IVW-MR) was used to calculate the effect estimates by each target. Sensitivity analyses were performed to verify the robustness of the results.
Results:
There was suggestive evidence that PCSK9-mediated LDL-C levels were positively associated with DR, with OR (95% CI) of 1.34 (1.02-1.77). No significant association was found between the expression of HMGCR- and NPC1L1-mediated LDL-C levels; CETP-, SCARB1-, and PPARG-mediated HDL-C levels; PPARA- and LPL-mediated TG levels; and DR risk.
Conclusions:
This is the first study to reveal a genetically causal relationship between lipid-regulating drug targets and DR risk. PCSK9-mediated LDL-C levels maybe positively associated with DR risk at the genetic level. This study provides suggestive evidence that PCSK9 inhibition may reduce the risk of DR.
Insights
This study investigated lipid targets and diabetic retinopathy (DR) risk. Genetic analysis suggests PCSK9 inhibition may lower DR risk, offering a potential new strategy for this vision-threatening complication.
Area of Science:
- Genetics
- Ophthalmology
- Metabolic Disorders
Background:
- Diabetic retinopathy (DR) is a major cause of vision loss and a complication of diabetes.
- Current strategies to prevent DR are limited.
- Understanding the genetic links between lipid regulation and DR is crucial for developing new interventions.
Purpose of the Study:
- To assess the causal effect of lipid-regulating drug targets on the risk of diabetic retinopathy (DR).
- To explore potential genetic pathways linking lipid metabolism to DR pathogenesis.
- To identify novel therapeutic targets for DR prevention.
Main Methods:
- A two-sample Mendelian randomization (MR) study design was employed.
- Genetic variants for eight lipid-regulating targets (LDL-C, HDL-C, TG) were used as exposures.
- DR outcome data were obtained from the FinnGen research project; IEU OpenGWAS project provided exposure data.
Main Results:
- Suggestive evidence indicated a positive association between PCSK9-mediated LDL-C levels and DR risk (OR: 1.34, 95% CI: 1.02-1.77).
- No significant causal associations were found for other investigated lipid targets (HMGCR, NPC1L1, CETP, SCARB1, PPARG, PPARA, LPL) with DR risk.
- Sensitivity analyses were conducted to ensure the robustness of the findings.
Conclusions:
- This study is the first to suggest a genetically causal link between lipid-regulating targets and DR risk.
- PCSK9-mediated LDL-C levels may be positively associated with DR risk at the genetic level.
- PCSK9 inhibition presents a potential therapeutic strategy to reduce DR risk.
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