High-density lipoprotein 3 cholesterol and primary open-angle glaucoma: metabolomics and mendelian randomization analyses.

Abstract Objective We hypothesized that the effect of blood lipid-related metabolites on POAG would differ according to specific lipoprotein particles and lipid sub-fractions. We thus investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG. Design Cross-sectional study. Participants Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n=8,503). Methods All participants underwent detailed standardised ocular and systemic examinations. A total of 130 blood lipid-related metabolites were quantified using a nuclear magnetic resonance metabolomics platform. The analyses were conducted in two stages. First, we investigated whether and which lipid-related metabolites were directly associated with POAG, using regression analyses followed by Bayesian network modelling. Second, we investigated if any causal relationship exists between the identified lipid-related metabolites, if any, and POAG, using two-sample mendelian randomization (MR) analysis. We performed genome-wide association studies (GWAS) on HDL3 cholesterol (after inverse normal transformation) and used the top variants associated with HLD3 cholesterol as instrumental variables (IVs) in the MR analysis. Main outcome measure POAG Results Of the participants, 175 (2.1%) had POAG. First, a logistic regression model showed that total HDL3 cholesterol (negatively) and phospholipids in very large HDL (positively) were associated with POAG. Further analyses using a Bayesian network analysis showed that only total HDL3 cholesterol was directly associated with POAG (OR = 0.72 per 1 standard deviation increase in HDL3 cholesterol; 95 % confidence interval [CI]: 0.61, 0.84), independently of age, gender, IOP, BMI, education level, systolic blood pressure, axial length, and statin medication. Using 4 IVs identified from the GWAS and with the inverse variance weighted MR method, we found that higher levels of HDL3 cholesterol was associated with a decreased odds of POAG (OR = 0.91, 95% CI: 0.84 - 0.98, P = 0.016). Other MR methods, including weighted median, mode-based estimator, and contamination mixture methods derived consistent OR estimates. Finally, none of the routine lipids (blood total, HDL or LDL cholesterol) were associated with POAG. Conclusion Overall, these results suggest that the relationship between HDL3 cholesterol and POAG might be causal and specific, and that dysregulation of cholesterol transport may thus play a role in the pathogenesis of POAG.