Abstract
Purpose :
The complement system is a well-known modulator of risk for age-related macular degeneration (AMD), a progressive, blinding disease. But few treatments are available because the causal regulatory pathways connecting systemic inflammation, lipids, and AMD are poorly understood. In Mendelian Randomization (MR), reports from independent genome-wide association studies (GWAS) are jointly analyzed to discover exposures that have direct effects on an outcome, and which may not yet be known. Genetic proxies for cholesterol can be statistically tested at a large scale to pinpoint the causal effects of exposures on AMD.
Methods :
The MRC IEU OpenGWAS Database was mined for associations between exposure phenotypes containing cholesterol keywords and outcome of advanced AMD from the 2016 International Age-related Macular Degeneration Consortium GWAS. The consortium encompassed 12,711 cases, including the Age-Related Eye Disease Studies (AREDS and AREDS2), and 14,590 controls of European descent. Two studies were used for three exposures (HDL and total cholesterol: 297,626 controls; LDL: 283,251 controls).
Results :
All cholesterol phenotypes were found to have strong effects on advanced AMD by MR Egger tests: 47 SNPs were reported for HDL association, 55 for LDL, and 43 for total cholesterol. Overall effect size for HDL was 1.83 (s.e. = 0.37, p = 1.21E-05). Each + mg/dL HDL in blood plasma approximately doubled risk of developing advanced AMD. LDL and total cholesterol were significant but moderated: -0.43 (s.e. = 0.19, p = 3.11E-02), -0.96 (s.e. = 0.35, p = 8.34E-03). One SNP was shared between HDL and LDL: rs429358 in APOE (Apolipoprotein E), an essential metabolizer of triglyceride-rich lipoprotein. In single-SNP MR (LDL, Wald test) this had an effect size of -1.78 (s.e. = 0.13, p = 1.35E-41).
Conclusions :
As reported from independent GWASes, genetic instrumental variables for high HDL conferred significant risk to develop advanced AMD, while lowering of LDL or total cholesterol reduced risk. Elevated HDL or too-low LDL may trigger a local inflammatory response causing irreparable macular damage over time. All three types are metabolically interrelated, and it is advisable to consider patient cholesterol levels when evaluating disease risk. MR can decipher the etiology of complex eye diseases by pointing to the most effective targets to lower risk of progression.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.