High Density Lipoproteins Associate with Age-Related Macular Degeneration in the All of Us Research Program.

Objective: Extracellular lipoprotein aggregation is a critical event in AMD pathogenesis. In this study, we sought to analyze associations between clinical and genetic-based factors related to lipoprotein metabolism and risk for age-related macular degeneration (AMD) in the All of Us research program.

Design: Cross-sectional retrospective data analysis.

Subjects: 5028 healthy and 2328 AMD patients from All of Us.

Methods: Participants with and without AMD were age, race, and gender-matched in a 1:2 ratio respectively. Smoking status, history of hyperlipidemia, and statin use were extracted in a binary manner. Statin use was further subcategorized into hepatically vs. non-hepatically metabolized statins. Laboratory values for low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) were also extracted, and outliers were excluded from analysis. The PLINK toolkit was used to extract single-nucleotide polymorphisms (SNPs) associated with LDL and HDL dysregulation, as published in prior work. Odds ratio curves were computed to assess the risk between LDL, TG, and HDL versus AMD. All clinical and genetic variables were input into a multivariable logistic regression model, and odds ratios and p-values were generated.

Main outcome measures: Statistical significance of risk factors for AMD, thresholded at p ≤ 0.05.

Results: On multivariable regression analysis, statin use, and low and high HDL were significantly associated with increased AMD risk (p <0.001, <0.001, 0.004, <0.001 respectively). Additionally, the multivariable regression implicated HDL associated SNPs increased risk for AMD. Lastly, LPA was identified (p =0.007) as a novel SNP associated with increased AMD risk.

Conclusions: There exists a U-shaped relationship between HDL and AMD risk, such that high and low HDL are significantly associated with increased AMD risk. Additionally, SNPs associated with HDL metabolism are associated with AMD risk. This analysis further establishes the role of HDL in AMD pathogenesis.