Purpose

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.

Design

Cross-sectional study.

Participants

Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n = 8503).

Methods

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.

Main Outcome Measure

Primary open-angle glaucoma.

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 (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.

Conclusions

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.

中文翻译：

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高密度脂蛋白 3 胆固醇和原发性开角型青光眼

目的

我们假设血脂相关代谢物对原发性开角型青光眼 (POAG) 的影响会因特定的脂蛋白颗粒和脂质亚组分而异。我们研究了脂蛋白颗粒和脂质亚组分的血液水平与 POAG 的关系。

设计

横断面研究。

参与者

为基于人群的新加坡眼病流行病学研究的基线访问招募的个人（n = 8503）。

方法

所有参与者都接受了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对总共 130 种血脂相关代谢物进行了量化。分析分两个阶段进行。首先，我们使用回归分析和贝叶斯网络建模研究了是否以及哪些脂质相关代谢物与 POAG 直接相关。其次，我们使用 2 样本孟德尔随机化 (MR) 分析调查了已鉴定的脂质相关代谢物（如果有）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（在逆正态变换后）进行了全基因组关联研究 (GWAS)，并在 MR 分析中使用与 HLD3 胆固醇相关的顶级变体作为工具变量 (IV)。

主要成果衡量标准

原发性开角型青光眼。

结果

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）和超大 HDL 中的磷脂（正）与 POAG 相关。使用贝叶斯网络分析的进一步分析表明，只有总 HDL3 胆固醇与 POAG 直接相关（优势比 [OR]，HDL3 胆固醇每增加 1 个标准差增加 0.72；95% 置信区间 [CI]，0.61-0.84），独立于年龄、性别、眼压 (IOP)、体重指数 (BMI)、教育程度、收缩压、眼轴长度和他汀类药物。使用从 GWAS 确定的 5 个 IV 和逆方差加权 MR 方法，我们发现较高水平的 HDL3 胆固醇与 POAG 几率降低相关（OR，0.91；95% CI，0.84-0.99，P =0.021)。其他 MR 方法，包括加权中值、基于模式的估计和污染混合方法，得出一致的 OR 估计。常规血脂（总血脂、HDL 或低密度脂蛋白 [LDL] 胆固醇）均与 POAG 无关。

结论

总体而言，这些结果表明 HDL3 胆固醇和 POAG 之间的关系可能是因果关系和特异性的，并且胆固醇转运的失调可能在 POAG 的发病机制中发挥作用。