A Big Data investigation of the influence of life-long metabolic factors that contribute to age-related eye diseases

大数据调查导致年龄相关眼病的终生代谢因素的影响

• 批准号: 2749295
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2749295
• 关键词: Big; Data; investigation; influence; life

There is a body of evidence linking age-related eye diseases (AREDs), and in particular age-related macular degeneration (AMD), glaucoma and age-related cataract to metabolic dysfunction. Previous metabolomic studies of AREDs have performed metabolome-wide analyses in different cohorts with a range of different metabolite evaluation techniques. However, many cohorts were clinic-based, underpowered and used a variety of platforms and there has been little convergence in the literature. For example, a meta-review of 13 AMD studies(1) revealed that a broad range of potential biomarkers, including phenylalanine, adenosine, hypoxanthine, tyrosine, creatine, citrate, carnitine, proline and maltose, and that lipid, carbohydrate, amino acid and nucleotide metabolism may be dysregulated in affected individuals. The lack of convergence of results from the studies in the meta-analysis supports the need for further studies to select and validate metabolite biomarkers of AMD with higher confidence. In glaucoma, a recent review of 18 metabolomics studies(2) suggested that hydroxyproline and methionine were consistently increased in plasma, while results from aqueous humour revealed alanine, creatine, glycine and lysine increased in glaucoma. The authors argued that plasma-based findings were less consistent than those using aqueous humour. Since plasma is the only practical and relatively non-invasive source of data for large population studies, there is therefore need for further improvements in plasma metabolomics studies of AREDs. The supervisors of this project published a 2019 study(3) from TwinsUK of 313 metabolites and found a vitamin C metabolite O-methylascorbate is associated with and causally lowers IOP, the main risk factor for glaucoma, highlighting the power of antioxidants in combating photooxidative stress. This particular study also sets an example for the methodological approach in this project by using random forest machine learning to identify the most influential metabolites, and Mendelian randomization to investigate a causal effect of metabolites on IOP. Age-related cataract has to date received less attention, with few high-throughput metabolomic studies: a search for plasma-based metabolomic profiling returned no published data except for one article on glaucoma where sex-matched controls with cataract were used. While there is an effective surgical remedy, revealing metabolic signatures of cataract patients would improve understanding of molecular mechanisms and if an intervention could delay cataract, then significant surgical volume reduction and cost savings could follow. The supervisors of this project have access to data from four large cohorts of over 500,000 people, including the UK Biobank, meaning that this study has the power to identify novel associations to further understand the pathophysiology of age-related eye diseases, to potentially examine for causality raising the prospect of novel therapies, and to use machine learning models to predict those at risk of disease using metabolomics platforms. Hou XW et al. (2020) Metabolomics in Age-Related Macular Degeneration: A Systematic Review. Invest Ophthalmol Vis Sci. 61, 13-13 Tang Y et al. (2022) Metabolomics in Primary Open Angle Glaucoma: A Systematic Review and Meta-Analysis. Front Neurosci. 16, 835736 Hysi PG et al. (2019) Ascorbic acid metabolites are involved in intraocular pressure control in the general population. Redox Biol. 20, 349-353

有大量证据将年龄相关性眼病（ARED），特别是年龄相关性黄斑变性（AMD）、青光眼和年龄相关性白内障与代谢功能障碍联系起来。先前的ARED代谢组学研究已经使用一系列不同的代谢物评价技术在不同的队列中进行了代谢组范围的分析。然而，许多队列是基于临床的，动力不足，使用各种平台，文献中几乎没有融合。 例如，13项AMD研究的荟萃综述（1）显示，广泛的潜在生物标志物，包括苯丙氨酸、腺苷、次黄嘌呤、酪氨酸、肌酸、柠檬酸盐、肉毒碱、脯氨酸和麦芽糖，以及受影响个体的脂质、碳水化合物、氨基酸和核苷酸代谢可能失调。荟萃分析中研究结果的缺乏一致性支持了进一步研究的需要，以更高的置信度选择和验证AMD的代谢物生物标志物。 在青光眼中，最近对18项代谢组学研究的综述（2）表明，血浆中的羟脯氨酸和甲硫氨酸持续增加，而房水的结果显示，青光眼中的丙氨酸、肌酸、甘氨酸和赖氨酸增加。作者认为，基于血浆的结果不如使用房水的结果一致。由于血浆是大人群研究中唯一实用且相对非侵入性的数据来源，因此需要进一步改进ARED的血浆代谢组学研究。 该项目的主管发表了一项来自TwinsUK的2019年研究（3），研究了313种代谢物，发现维生素C代谢物O-甲基抗坏血酸盐与青光眼的主要风险因素IOP相关并降低IOP，突出了抗氧化剂在对抗光氧化应激方面的作用。这项特殊的研究还为该项目中的方法学方法树立了一个榜样，即使用随机森林机器学习来识别最有影响力的代谢物，并使用孟德尔随机化来研究代谢物对IOP的因果影响。 迄今为止，青光眼相关的白内障受到的关注较少，几乎没有高通量代谢组学研究：对基于血浆的代谢组学分析的搜索没有返回已发表的数据，除了一篇关于青光眼的文章，其中使用了性别匹配的白内障对照。虽然有一种有效的手术治疗方法，但揭示白内障患者的代谢特征将提高对分子机制的理解，如果干预可以延迟白内障，那么可以显著减少手术量并节省成本。 该项目的主管可以访问包括英国生物银行在内的四个超过50万人的大型队列的数据，这意味着该研究有能力确定新的关联，以进一步了解年龄相关性眼病的病理生理学，潜在地检查因果关系，提高新疗法的前景，并使用机器学习模型来预测那些使用代谢组学平台的疾病风险。Hou XW et al.（2020）代谢组学在视网膜相关黄斑变性：系统性综述。投资眼科维斯科学61，13-13 Tang Y et al.（2022）原发性开角型青光眼的代谢组学：系统性综述和荟萃分析。前线神经科学16，835736 Hysi PG et al.（2019）抗坏血酸代谢物参与一般人群的眼内压控制。氧化还原生物学20，349-353