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In the news: Low HDL3 Cholesterol Associated with a Higher Risk of Glaucoma

What is High Density Lipoprotein 3 (HDL3)?

A new study ePublished in the journal Ophthalmology reports that lower levels of HDL3 cholesterol is associated with a higher risk of primary open angle glaucoma (POAG)(1).

As background, LDL and HDL particles carry cholesterol in the blood. LDL particles are the major carriers, but they can be ingested by macrophages and then be trapped in blood wall vessels and contribute to atherosclerosis. In contrast, HDL particles transport cholesterol back to the liver for excretion through reverse cholesterol transport. HDLs remove cholesterol from macrophage foam cells, smooth muscle cells and endothelial cells in vessel walls.

HDLs can be separated into two major subfractions: larger, more-buoyant HDL2 particles and smaller, less-buoyant, HDL3 particles. HDL particles, especially small and dense HDL3, have a protective effect on vascular endothelium through anti-oxidative, anti-inflammatory, and anti-thrombotic activities.

Lipoproteins and Age-Related Diseases

Recent findings underscore the importance of lipo-protein structure, composition, and function in age-related diseases. A recent meta-analysis, for example, showed that free cholesterol in small HDL was associated with a lower risk of dementia and Alzheimer’s disease. Further, phospholipids and total lipids within extra-large HDL, and cholesterol in small VLDL (very large dense lipoprotein) particles were associated with age-related macular degeneration.

In terms of glaucoma, several epidemiological studies have reported that plasma lipid concentrations and hyperlipidemia have a significant association with the risk of POAG. However, the effects of plasma lipids or subfractions and the risk of POAG are still unclear. This uncertainty coupled with recent findings led researchers to investigate the relationship between lipoprotein particles, lipid sub-fractions and POAG.

Study Details and Results

The researchers analyzed blood lipids in a cohort of patients from the Singapore Epidemiology of Eye Disease study. A total of 130 blood lipid-related metabolites were quantified using an NMR metabolomics platform. To investigate whether/which lipid-related particles were directly linked with POAG, they used regression analyses followed by Bayesian network modelling. To assess whether any causal relationship existed between any identified lipid-related metabolite and POAG they conducted mendelian randomization and genome-wide association studies.

The results were as follows: • Only HDL3 was directly associated with POAG, with higher blood levels of total HDL3 cholesterol significantly associated with lower odds of POAG independently of age, gender, IOP, BMI, education, systolic blood pressure, axial length, and statin medication. • None of the routine lipids (blood total, HDL, or LDL cholesterol) were associated with POAG, suggesting the specificity of HDL3

Study participants with POAG had lower blood levels of total HDL3 vs those without POAG. The authors theorize that the low HDL3evels may indicate a less efficient transport of cholesterol through the reverse cholesterol transport. The absence of a link between OAG & routine lipids, and the mendelian randomization analysis suggest the causality of this association, although further studies are needed.

Lifestyle Approaches to Raising HDL3?

Should more research confirm this link, the question becomes can HDL3 levels be raised? Physical activity and weight loss, while healthy mainstays, primarily raise HDL2 and not HDL3. It has been reported that higher HDL3 is associated with both moderate alcohol intake and lower carbohydrate intake. In one random-ized trial, HDL-3 decreased in abstainers but not in drinkers, and the resumption of alcohol increased HDL3 without affecting HDL2. Another study found that replacing dietary carbohydrates with fat significantly increased HDL3 concentrations. In general, however, research regarding the impact of diet patterns on glaucoma development or progression is scarce.

References

1. Nusinovici S, et al. High-density lipoprotein 3 cholesterol and primary open-angle glaucoma: metabolomics and mendelian randomization analyses. Ophthalmol. ePub ahead of print Sept 27, 2021.