Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Ophthalmology and Visual Sciences Academic Clinical Programme, Duke-NUS Medical School, Singapore.
Ophthalmology. 2022 Mar;129(3):285-294. doi: 10.1016/j.ophtha.2021.09.013. Epub 2021 Sep 28.
We hypothesized that the effect of blood lipid-related metabolites on primary open-angle glaucoma (POAG) would differ according to specific lipoprotein particles and lipid sub-fractions. We investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG.
Cross-sectional study.
Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n = 8503).
All participants underwent detailed standardized 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 2 stages. First, we investigated whether and which lipid-related metabolites were directly associated with POAG using regression analyses followed by Bayesian network modeling. Second, we investigated if any causal relationship exists between the identified lipid-related metabolites, if any, and POAG using 2-sample Mendelian randomization (MR) analysis. We performed genome-wide association studies (GWAS) on high-density lipoprotein (HDL) 3 cholesterol (after inverse normal transformation) and used the top variants associated with HLD3 cholesterol as instrumental variables (IVs) in the MR analysis.
Primary open-angle glaucoma.
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 (odds ratio [OR], 0.72 per 1 standard deviation increase in HDL3 cholesterol; 95% confidence interval [CI], 0.61-0.84), independently of age, gender, intraocular pressure (IOP), body mass index (BMI), education level, systolic blood pressure, axial length, and statin medication. Using 5 IVs identified from the GWAS and with the inverse variance weighted MR method, we found that higher levels of HDL3 cholesterol were associated with a decreased odds of POAG (OR, 0.91; 95% CI, 0.84-0.99, P = 0.021). Other MR methods, including weighted median, mode-based estimator, and contamination mixture methods, derived consistent OR estimates. None of the routine lipids (blood total, HDL, or low-density lipoprotein [LDL] cholesterol) were associated with POAG.
Overall, these results suggest that the relationship between HDL3 cholesterol and POAG might be causal and specific, and that dysregulation of cholesterol transport may play a role in the pathogenesis of POAG.
我们假设血脂相关代谢物对原发性开角型青光眼（POAG）的影响因特定脂蛋白颗粒和脂质亚组分而异。我们研究了血脂蛋白颗粒和脂质亚组分水平与 POAG 的关系。
横断面研究。
招募了参加基于人群的新加坡眼病流行病学研究（n=8503）基线检查的个体。
所有参与者均接受详细的标准化眼部和全身检查。使用核磁共振代谢组学平台定量测定了 130 种血脂相关代谢物。分析分 2 个阶段进行。首先，我们使用回归分析和贝叶斯网络建模来研究血脂相关代谢物是否以及哪些与 POAG 直接相关。其次，我们使用两样本孟德尔随机化（MR）分析来研究鉴定出的血脂相关代谢物与 POAG 之间是否存在任何因果关系。我们对高密度脂蛋白（HDL）3 胆固醇（经逆正态变换）进行全基因组关联研究（GWAS），并将与 HDL3 胆固醇关联最强的变异作为 MR 分析中的工具变量（IVs）。
原发性开角型青光眼。
在参与者中，175 人（2.1%）患有 POAG。首先，逻辑回归模型显示总 HDL3 胆固醇（负相关）和非常大的 HDL 中的磷脂（正相关）与 POAG 相关。进一步使用贝叶斯网络分析表明，只有总 HDL3 胆固醇与 POAG 直接相关（优势比[OR]，每增加 1 个标准偏差的 HDL3 胆固醇增加 0.72；95%置信区间[CI]，0.61-0.84），独立于年龄、性别、眼内压（IOP）、体重指数（BMI）、教育程度、收缩压、眼轴和他汀类药物的使用。使用 GWAS 确定的 5 个 IVs，并采用倒数方差加权 MR 方法，我们发现 HDL3 胆固醇水平较高与 POAG 的患病风险降低相关（OR，0.91；95%CI，0.84-0.99，P=0.021）。其他 MR 方法，包括加权中位数、基于模式的估计量和污染混合物方法，得出了一致的 OR 估计值。常规血脂（血液总胆固醇、HDL 或低密度脂蛋白[LDL]胆固醇）均与 POAG 无关。
总的来说，这些结果表明，HDL3 胆固醇与 POAG 之间的关系可能是因果关系和特异性的，胆固醇转运的失调可能在 POAG 的发病机制中起作用。
