Kang Tianyi, Zhou Yi, Fan Cong, Zhang Yue, Yang Yu, Jiang Jian
Eye Center of Xiangya Hospital, Central South University, Changsha, 410008 Hunan China.
Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, 410008 Hunan China.
EPMA J. 2024 Jul 13;15(3):511-524. doi: 10.1007/s13167-024-00373-5. eCollection 2024 Sep.
Glaucoma is the leading cause of irreversible blindness worldwide. Normal tension glaucoma (NTG) is a distinct subtype characterized by intraocular pressures (IOP) within the normal range (< 21 mm Hg). Due to its insidious onset and optic nerve damage, patients often present with advanced conditions upon diagnosis. NTG poses an additional challenge as it is difficult to identify with normal IOP, complicating its prediction, prevention, and treatment. Observational studies suggest a potential association between NTG and abnormal lipid metabolism, yet conclusive evidence establishing a direct causal relationship is lacking. This study aims to explore the causal link between serum lipids and NTG, while identifying lipid-related therapeutic targets. From the perspective of predictive, preventive, and personalized medicine (PPPM), clarifying the role of dyslipidemia in the development of NTG could provide a new strategy for primary prediction, targeted prevention, and personalized treatment of the disease.
In our study, we hypothesized that individuals with dyslipidemia may be more susceptible to NTG due to a dysregulation of microvasculature in optic nerve head. To verify the working hypothesis, univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were utilized to estimate the causal effects of lipid traits on NTG. Drug target MR was used to explore possible target genes for NTG treatment. Genetic variants associated with lipid traits and variants of genes encoding seven lipid-related drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). GWAS data for NTG, primary open angle glaucoma (POAG), and suspected glaucoma (GLAUSUSP) were obtained from FinnGen Consortium. For apolipoproteins, we used summary statistics from a GWAS study by Kettunen et al. in 2016. For metabolic syndrome, summary statistics were extracted from UK Biobank participants. In the end, these findings could help identify individuals at risk of NTG by screening for lipid dyslipidemia, potentially leading to new targeted prevention and personalized treatment approaches.
Genetically assessed high-density cholesterol (HDL) was negatively associated with NTG risk (inverse-variance weighted [IVW] model: OR per SD change of HDL level = 0.64; 95% CI, 0.49-0.85; = 1.84 × 10), and the causal effect was independent of apolipoproteins and metabolic syndrome (IVW model: OR = 0.29; 95% CI, 0.14-0.60; = 0.001 adjusted by ApoB and ApoA1; OR = 0.70; 95% CI, 0.52-0.95; = 0.023 adjusted by BMI, HTN, and T2DM). Triglyceride (TG) was positively associated with NTG risk (IVW model: OR = 1.62; 95% CI, 1.15-2.29; = 6.31 × 10), and the causal effect was independent of metabolic syndrome (IVW model: OR = 1.66; 95% CI, 1.18-2.34; = 0.003 adjusted by BMI, HTN, and T2DM), but not apolipoproteins (IVW model: OR = 1.71; 95% CI, 0.99-2.95; = 0.050 adjusted by ApoB and ApoA1). Genetic mimicry of apolipoprotein B (APOB) enhancement was associated with lower NTG risks (IVW model: OR = 0.09; 95% CI, 0.03-0.26; = 9.32 × 10).
Our findings supported dyslipidemia as a predictive causal factor for NTG, independent of other factors such as metabolic comorbidities. Among seven lipid-related drug targets, APOB is a potential candidate drug target for preventing NTG. Personalized health profiles can be developed by integrating lipid metabolism with life styles, visual quality of life such as reading, driving, and walking. This comprehensive approach will aid in shifting from reactive medical services to PPPM in the management of NTG.
The online version contains supplementary material available at 10.1007/s13167-024-00373-5.
青光眼是全球不可逆性失明的主要原因。正常眼压性青光眼（NTG）是一种独特的亚型，其特征是眼压（IOP）在正常范围内（<21 mmHg）。由于其发病隐匿且会导致视神经损伤，患者在确诊时往往已处于疾病晚期。NTG带来了额外的挑战，因为眼压正常时很难识别，这使其预测、预防和治疗变得复杂。观察性研究表明NTG与脂质代谢异常之间可能存在关联，但缺乏确立直接因果关系的确凿证据。本研究旨在探讨血清脂质与NTG之间的因果联系，同时确定与脂质相关的治疗靶点。从预测、预防和个性化医学（PPPM）的角度来看，阐明血脂异常在NTG发生发展中的作用可为该疾病的一级预测、靶向预防和个性化治疗提供新策略。
在我们的研究中，我们假设血脂异常的个体可能由于视神经乳头微血管调节异常而更容易患NTG。为验证该工作假设，我们采用单变量孟德尔随机化（UVMR）和多变量孟德尔随机化（MVMR）来估计脂质性状对NTG的因果效应。药物靶点孟德尔随机化用于探索NTG治疗的可能靶点基因。从全球脂质遗传学联盟全基因组关联研究（GWAS）中提取与脂质性状相关的基因变异以及编码七个脂质相关药物靶点的基因变异。NTG、原发性开角型青光眼（POAG）和疑似青光眼（GLAUSUSP）的GWAS数据来自芬兰基因组联盟。对于载脂蛋白，我们使用了Kettunen等人在2016年进行的一项GWAS研究的汇总统计数据。对于代谢综合征，汇总统计数据来自英国生物银行的参与者。最后，这些发现有助于通过筛查脂质代谢异常来识别NTG风险个体，可能会带来新的靶向预防和个性化治疗方法。
经基因评估的高密度脂蛋白（HDL）与NTG风险呈负相关（逆方差加权[IVW]模型：HDL水平每标准差变化的OR = 0.64；95% CI，0.49 - 0.85；P = 1.84×10），且因果效应独立于载脂蛋白和代谢综合征（IVW模型：OR = 0.29；95% CI，0.14 - 0.60；经载脂蛋白B和载脂蛋白A1调整后的P = 0.001；OR = 0.70；95% CI，0.52 - 0.95；经体重指数、高血压和2型糖尿病调整后的P = 0.023）。甘油三酯（TG）与NTG风险呈正相关（IVW模型：OR = 1.62；95% CI，1.15 - 2.29；P = 6.31×10），且因果效应独立于代谢综合征（IVW模型：OR = 1.66；95% CI，1.18 - 2.34；经体重指数、高血压和2型糖尿病调整后的P = 0.003），但不独立于载脂蛋白（IVW模型：OR = 1.71；95% CI，0.99 - 2.95；经载脂蛋白B和载脂蛋白A1调整后的P = 0.050）。载脂蛋白B（APOB）增强的基因模拟与较低的NTG风险相关（IVW模型：OR = 0.09；95% CI，0.03 - 0.26；P = 9.32×10）。
我们的研究结果支持血脂异常是NTG的一个预测性因果因素，独立于代谢合并症等其他因素。在七个脂质相关药物靶点中，APOB是预防NTG的一个潜在候选药物靶点。通过将脂质代谢与生活方式、阅读、驾驶和行走等视觉生活质量相结合，可以制定个性化的健康档案。这种综合方法将有助于在NTG管理中从反应性医疗服务转向PPPM。
在线版本包含可在10.1007/s13167 - 024 - 00373 - 5获取的补充材料。
