As specialists in ophthalmology are well aware, age-related macular degeneration (AMD) develops when there’s an accumulation of lipoprotein-rich deposits, known as drusen, in the extracellular area between the retinal pigment epithelium and Bruch’s membrane. However, while it has been established that drusen have lipoproteins, the class of lipoprotein involved in AMD progression is not well defined.1
Original Article published on Medpage Today .
Past studies have had differing results, with some finding an association between elevated high-density lipoprotein (HDL) levels, and others finding the opposite—either an inverse relationship or no relationship between elevated HDL levels and AMD risk. There are also studies showing little to no association between risk of AMD and low-density lipoprotein (LDL) levels and total cholesterol. Additionally, some genomic studies have demonstrated a positive association between several single nucleotide polymorphisms (SNPs) and AMD risk.1
With these disparities in mind, a team of 6 experts from the University of California San Diego, in La Jolla, Calif., recently examined the possible associations between the clinical and genetic-based factors of lipoprotein metabolism and risk of AMD.1
The eyes don’t lie: new associations with AMD
Using data from the National Institutes of Health’s All of Us Research Program, the investigators performed a cross-sectional, retrospective analysis.1
The data included demographics, lipid-associated laboratory data, and prior history of statin use. The mean age of the patients who had a diagnosis of AMD (n=2328) and controls who did not (n=5028) was approximately 75 years old; the majority of both cohorts—84.2% and 82.8%, respectively—were non-Hispanic White.
Using odds ratio curves, the authors demonstrated that both low and high levels of HDL had a statistically significant association with an increased risk of AMD (P < .001 for both). Gender, smoking history, statin use, AREDS vitamin use, and having a hyperlipidemia phenotype, including cardiovascular disease, did not affect these associations. In addition, no statistically significant associations between triglycerides or LDL levels and AMD were found (P = .43 and P =.10, respectively).
Adjusted multivariable logistic regression showed that low and high levels of HDL were significantly associated with greater risk of AMD, as were history of smoking and statin use (P < .001 for all). However, the multivariate analysis did not show a significant association with high or low LDL (P = .32 and P = .47, respectively).
In terms of genetic data regarding SNPs, CFH and ARMS2 were significantly associated with increased risk of AMD (both P < .001), as was the novel SNP lipoprotein(a) (LPA; P = .007). ABCA1 and LIPC, genes associated with HDL metabolism, showed negative associations with the risk of AMD (P = .04 and P= .001, respectively).
Limitations and clinical implications
There were several limitations to this study. First, as this was a retrospective study, there are inherent limitations, including selection bias. Additionally, all diagnoses were from billing codes, which could have included inaccurate documentation. Lastly, the investigators did not do a subgroup analysis by AMD severity due to insufficient data. This lack of information, they wrote, “highlights the need for improved severity coding in eye diseases, a gap which has also been discussed in other contexts, such as glaucoma.”
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In an interview with MedPage Today, the study’s corresponding author, Christopher Toomey, MD, PhD, of the Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, discussed the study’s clinical implications. “Both low and high HDL levels are linked to an increased risk of developing AMD, meaning that there is an ideal range for HDL and that being too low or too high may increase the risk of developing AMD.”
“Our lab,” he continued, “is focused on determining the precise mechanism of local trapping of HDL particles in the retina, which appears to be a major event in the early stages of AMD.”
In addition to noting the impact of systemic metabolism on ocular health, Dr. Toomey and his co-authors concluded their report by sharing another important finding: HDL-associated SNPs, including LPA, are linked to increased AMD risk, highlighting the genetic aspect of AMD and the potential for using genetic information going forward.
Published: April 04, 2025
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