A recent study published in Ophthalmology evaluated the associations between clinical and genetic-based factors related to lipoprotein metabolism and risk for age-related macular degeneration (AMD) among patients participating in a national research program.
Let’s start with some background on this.
A growing body of literature has implicated lipoprotein metabolism pathways in AMD pathogenesis, though associations studied between serum lipoprotein levels and AMD risk are inconsistent.
Case in point:
- Previous studies have suggested that elevated high-density lipoprotein (HDL)—but not total cholesterol or low-density lipoprotein (LDL)—is associated with increased AMD risk
- Conversely, other studies have suggested an inverse or lack of relationship between high HDL and AMD risk
What about studies on genes associated with lipoprotein metabolism?
Separately, genomic studies have indicated a positive association between AMD risk and several single nucleotide polymorphisms (SNPs) associated with lipoprotein metabolism, such as:
However: Not all of these SNPs were reported as significantly associated with AMD across multiple genome-wide association studies (GWAS).
- Meaning: There remains a knowledge gap regarding the inconsistent associations between various laboratory and genomic factors linked to lipoprotein metabolism and AMD risk.
Now talk about the study.
In this cross-sectional retrospective study, investigators included 2,328 AMD patients and 5,028 health controls from the All of Us patient population who were age-, race-, and gender-matched in a 1:2 ratio.
- Quick rundown: All of Us is a research program sponsored by the National Institutes of Health (NIH) that includes survey, clinical, and genetic data for 1 million people from groups historically underrepresented in U.S. health research.
The research team analyzed key characteristics between cohorts, including:
- Smoking status
- History of hyperlipidemia
- Statin use
- Hepatically metabolized statins
- Non-hepatically metabolized statins
- Laboratory values for:
- LDL
- HDL
- TG
Main outcome measure: Statistical significance of risk factors for AMD—thresholded at p ≤ 0.05
Anything else?
Researchers used the PLINK tool set to extract single-nucleotide polymorphisms (SNPs) associated with LDL and HDL dysregulation, as published in prior work.
Note: PLINK is an open-source whole genome association analysis toolset designed to perform a range of basic, large-scale analyses of genetic data.
Findings?
Statin use as well as low and high HDL were significantly associated with increased AMD risk (p < 0.001, < 0.001, < 0.004, respectively).
- However: TG and LDL were not associated with increased AMD risk.
Bring in the genetic analyses.
SNPS associated with HDL metabolism were also associated with an increased risk of AMD.
LPA was identified as a novel SNP associated with increased AMD risk (p = 0.007).
- Some background on LPA: Lipoprotein(a) plasma concentrations are highly heritable and largely controlled by the LPA gene, which is a well-known genetically determined risk factor for cardiovascular disease.
Expert opinion?
Despite conflicting evidence regarding the relationship between elevated HDL and AMD risk, the authors noted that—to their knowledge—this was the first time a U-shaped relationship between low and high HDL and AMD had been described.
They added that a U-shaped relationship may explain inconsistencies in prior analyses comparing mean HDL levels in AMD and control populations while also mirroring a similar U-shaped relationship between low and high HDL and cardiovascular disease risk.
Interesting … any notable limitations?
These included:
- The study's retrospective design
- All diagnoses were extracted through billing codes, which may be prone to inaccurate documentation
- There was no subgroup analysis of the data by AMD severity because over a third of the diagnosis codes did not specify the severity or were insufficient for certain stages of AMD
Finally: Tie it all together for me.
These findings suggest that a U-shaped relationship between HDL and AMD risk exists, such that high and low HDL are significantly associated with increased AMD risk.
Further: SNPs associated with HDL metabolism (ex., LPA) were associated with AMD risk—highlighting the role of HDL in AMD pathogenesis.