Mendelian randomization implicates high-density lipoprotein cholesterol–associated mechanisms in aetiology of age-related macular degeneration

Objective: 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: 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 one 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 pharmacological agents for
10 lipid therapy. We then conduct a two-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 (viewed as a positive control) and Alzheimer’s disease (a negative control) for comparison.
Main outcome measures: Age-related macular degeneration diagnosis.
Results: We find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio estimate of 1.22 (95% confidence interval 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 coronary artery disease.
Conclusions: There is some genetic evidence to suggest that HDL-cholesterol is a causal risk factor for AMD risk, and that raising HDL-cholesterol (particularly via cholesteryl ester transfer protein [CETP] inhibition) will increase AMD risk.