University of California San Diego researchers have identified a U-shaped association between high-density lipoprotein (HDL) levels and age-related macular degeneration (AMD) risk, with lower incidence of AMD in the middle range and peaks in both the lower and upper ranges. The team also discovered specific genetic variants related to HDL metabolism as contributing factors to AMD.

AMD is the leading cause of legal blindness among older adults in industrialized nations, characterized by the accumulation of drusen, lipoprotein-rich deposits in the retina. AMD pathogenesis has been linked to dysregulation of lipid metabolism. Previous research showed conflicting associations between lipid levels and AMD, leaving questions about their role in disease progression.

The study, “High Density Lipoproteins Associate with Age-Related Macular Degeneration in the All of Us Research Program,” published in Ophthalmology, examines both clinical and genetic data to assess the impact of lipid metabolism on AMD risk utilizing data from the National Institutes of Health’s All of Us Research Program.

Researchers conducted a cross-sectional, retrospective analysis of 7,356 participants, including 2,328 AMD patients and 5,028 controls matched by age, race, and gender. Clinical data included smoking status, hyperlipidemia history, and statin use. Laboratory measures of low-density lipoprotein (LDL), HDL, and triglycerides were analyzed, excluding outliers.

Single nucleotide polymorphisms (SNPs) associated with HDL and LDL metabolism were extracted using the PLINK toolkit. Logistic regression models evaluated associations between these variables and AMD risk.

Multivariable regression analyses revealed that both low and high HDL levels were significantly associated with increased AMD risk, forming the U-shaped relationship. Smoking and statin use were also linked to higher AMD risk. No significant correlations were seen between AMD and LDL or triglyceride levels.

Genetic analyses showed that SNPs involved in HDL metabolism, including variants in the ABCA1 and LIPC genes, were protective against AMD. LPA, a gene associated with lipoprotein(a), emerged as a novel risk factor for AMD. This is the first study to link LPA to AMD, suggesting a role in drusen formation.

Reliance on retrospective data and diagnostic codes limited the subgroup analyses of AMD severity due to insufficient data. Future research could validate these findings in prospective studies and explore the role of LPA and other lipid-modulating therapies in AMD prevention and treatment.

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