Genetics
First Mendelian randomisation of lipid drug targets and diabetic retinopathy finds a PCSK9 signal but no CETP association (J Lipids 2024)
Original title: Genetic Association between Lipid-Regulating Drug Targets and Diabetic Retinopathy: A Drug Target Mendelian Randomization Study
A two-sample Mendelian randomisation study tested the causal effect of eight lipid-regulating drug targets, covering LDL-C (HMGCR, PCSK9, NPC1L1), HDL-C (CETP, SCARB1, PPARG) and triglycerides (PPARA, LPL), on diabetic retinopathy (DR) risk, using IEU OpenGWAS exposure data and FinnGen outcome data. PCSK9-mediated LDL-C showed suggestive evidence of a positive association with DR (odds ratio 1.34, 95% CI, 1.02 to 1.77). No significant association was found for HMGCR- or NPC1L1-mediated LDL-C, for CETP-, SCARB1- or PPARG-mediated HDL-C, or for PPARA- or LPL-mediated triglycerides, with DR risk. Described as the first study of its kind, the authors conclude PCSK9 inhibition may reduce DR risk; the CETP-mediated HDL-C pathway showed no genetic association with this diabetic eye complication.
Original abstract
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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.