HDL3 Cholesterol Transport Dysregulation May Correlate with Glaucoma Onset

Eye Exam
HINES, IL – NOVEMBER 05: William Weiser has his eyes examined at the Central Blind Rehabilitation Center at the Edward Hines Jr. VA Hospital November 5, 2009 in Hines, Illinois. The Blind Rehabilitation Center offers various programs to help blind veterans develop the skills they need for independent living. Weiser, an Air Force veteran, began losing his eyesight about five years ago when he was diagnosed with Macular Degeneration. (Photo by Scott Olson/Getty Images)
A study shows patients with glaucoma had lower blood levels of total HDL3 cholesterol than those without glaucoma.

The relationship between HDL3 cholesterol and primary open-angle glaucoma (POAG) may be causal and specific, according to findings published in Ophthalmology. This dysregulation of cholesterol transport may play a role in the pathogenesis or POAG, researchers suggest.

Researchers conducted a cross-sectional study to investigate the associations of blood levels of lipoprotein particles and lipid subfractions with POAG. The study’s participants, who were recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n=8503), underwent standardized ocular and systemic examinations. Using a nuclear magnetic resonance metabolomics platform, a total of 130 blood lipid-related metabolites were quantified.

During the first stage of a 2-step process, the researchers used regression analysis to investigate whether and which lipid-related metabolites were directly associated with POAG. During the second stage, a 2-sample mendelian randomization (MR) was used to investigate if any causal relationship exists between the identified lipie-related metabolites, if any, and POAG. Subsequently, genome-wide association studies (GWAS) were performed on HDL3 cholesterol, after inverse normal transformation, and the top variants associated with it were used as instrumental variables (IVs) in the MR analysis. 

Of the study’s participants, 2.1% (n = 175) had POAG. A logistic regression model showed that POAG was associated with total HDL3 cholesterol (negatively) and phospholipids in very large HDL (positively). A subsequent Beyesian network analysis showed that, independently of age, gender, intraocular pressure (IOP), body mass index (BMI), education level, systolic blood pressure, axial length, and statin medication, POAG was only associated with total HDL3 (cholesterol odds ratio = .72 per 1 standard deviation increase in HDL cholesterol; 95%CI .61-.84). Finally, higher levels of HDL3 cholesterol were associated with a decreased odds of POAG, using 4 IVs identified from the GWAS and with the inverse variance weighted MR method (odds ratio = .91; 95%CI .84-.98; P =.016). 

The study’s use of Bayesian network modeling was a strength due to its allowance of the discovery and quantifying of complex relationships among lipid-related metabolites, clinical risk factors, and glaucoma. Its implementation was able to show that only the “level of HDL3 cholesterol was directly associated with POAG, in contrast to level of phospholipids in very large HDL that were indirectly associated, possibly through BMI, IOP and age,” according to the study.


Nusinovici S, Li H, Thakur S, et al. High-density lipoprotein 3 cholesterol and primary open-angle glaucoma: metabolomics and mendelian randomization analyses. Ophthalmol. Published online September 27, 2021. doi:10.1016/j.ophtha.2021.09.013