The class
Mendelian randomization finds HDL-raising CETP variants also raise the risk of age-related macular degeneration (Ophthalmology 2017)
Original title: Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration
In a two-sample Mendelian randomization study using data from 33 526 individuals (16 144 cases, 17 832 controls) in the International Age-related Macular Degeneration Genomics Consortium, researchers tested 185 lipid-associated genetic variants, including those proxying specific lipid drug targets, for their association with age-related macular degeneration (AMD), alongside parallel analyses for coronary artery disease as a positive control and Alzheimer's disease as a negative control. HDL cholesterol was found to be a causal risk factor for AMD (odds ratio 1.22, 95% CI 1.03 to 1.44 per 1 standard deviation increase), with no causal effect found for LDL cholesterol or triglycerides. Variants in the CETP gene region that raise circulating HDL cholesterol were also associated with increased AMD risk, in contrast to LIPC-region variants that raise HDL cholesterol but show the opposite direction of association, leading the authors to conclude that raising HDL cholesterol, particularly via CETP inhibition, would likely increase AMD risk.
Original abstract
Purpose: Undertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk.
Design: Two-sample Mendelian randomization investigation using published data.
Participants: A total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium.
Methods: We consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD. We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy. We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk. We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison.
Main Outcome Measures: Diagnosis of AMD.
Results: We find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol. No causal effect of LDL-cholesterol or triglycerides was found. Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD.
Conclusions: Some genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.