Enabling precision management of glaucoma through discovery of underlying biological pathways and clinical prediction tool development

人们害怕失去视力，就像害怕患上痴呆或癌症一样。青光眼是全球无法治愈的失明的主要原因，影响着8000多万人。在青光眼的早期阶段，通常没有症状，人们也不知道自己得了这种病。等到视力明显丧失时，已经造成了相当大的不可逆转的损害。因此，早期发现青光眼对预防失明至关重要。在英国，当人们去社区验光师那里做视力检查时，青光眼是偶然发现的。由于目前的筛查试验不足，没有正式的筛查方案。一旦确诊，治疗通常是终身的，青光眼是医疗保健服务的主要负担，在英国，每年有超过100万的国民健康服务（NHS）门诊就诊。我们目前无法预测哪些青光眼患者最需要强化治疗，这意味着尽管接受了治疗，一些患者仍会失明，而其他患者可能被过度治疗。我们也无法预测，在众多的治疗方案中，哪一种对个别患者来说是最佳的，目前的治疗标准是反复试验。所有这些挑战，再加上人口老龄化导致青光眼患者人数迅速增加，使青光眼成为一项重大的公共卫生挑战。我们迫切需要创新检测和治疗青光眼的方法，以预防失明，并充分利用我们有限的资源。青光眼是一种遗传性疾病，但它是“复杂的”，这意味着它是由大量遗传因素共同作用引起的。我最近利用全球14项研究的数据，发现了100多种青光眼的遗传因素。在一个预测模型中，这些因素有助于预测人群中谁会患上青光眼。需要发现更多的因素，但这为有针对性的人群筛查提供了可能性，从而能够更早地诊断和预防不可逆的视力丧失。我的研究目的是：1。进一步发现新的遗传因素，以更好地了解青光眼的复杂本质，并更好地预测人群中哪些人患该疾病的风险最高。发现与血液中不同蛋白质和代谢物水平变化相关的其他青光眼致病生物学过程3。发现易患青光眼的非遗传因素，如饮食、运动和药物使用，并确定这些因素是否能改变一个人患病的遗传风险。建立一项青光眼患者的研究，收集他们随时间发展的数据，并将其与基因数据相结合。确定确定的遗传因素是否可以预测哪些青光眼患者失明的风险最高，并预测个体对不同治疗的反应。如果成功，我提出的研究将具有相当大的潜在影响。仅凭基因检测就能识别青光眼高风险人群，这将有助于对这些个体进行有针对性的筛查，从而实现早期诊断和预防不可修复的视力丧失。如果遗传因素能预测疾病的发展过程，就有可能帮助确定哪些患者需要最密集的治疗来预防失明，哪些患者的风险较低，以避免过度治疗。同样，利用遗传信息为每个病人选择最有效的治疗方法也可能成为可能。总之，基因检测可以让我们对青光眼患者进行个性化护理，并将有限的资源用于最需要的患者。诸如此类的创新方法对于处理数量迅速增加的青光眼患者至关重要。此外，确定青光眼背后的关键生物学过程将有助于开发新的药物治疗方法。

People fear losing their vision as much as developing dementia or cancer. Glaucoma is the leading cause of incurable blindness globally, affecting over 80 million people. In the early stages of glaucoma, there are usually no symptoms and people are unaware they have the disease. By the time vision loss is apparent, there has already been considerable irreversible damage. Therefore, early detection of glaucoma is critical for preventing blindness. In the UK, glaucoma is detected opportunistically at community optometrists when people attend for eye checks. There is no formal screening programme as current screening tests are inadequate. Once diagnosed, treatment is usually for life and glaucoma is a major burden on healthcare services with over 1 million National Health Service (NHS) outpatient visits per year in the UK. We are currently unable to predict which glaucoma patients need most intensive therapy, meaning some patients still develop blindness despite treatment and other patients are likely overtreated. We are also unable to predict which of the many treatment options will be optimal for individual patients and the current standard of care is trial and error. All these challenges, in combination with the rapidly increasing number of glaucoma sufferers due to the ageing population, makes glaucoma a major public health challenge. We urgently need to innovate how we detect and treat glaucoma to prevent blindness and make best use of our limited resources.Glaucoma is a hereditary condition but is "complex", meaning that it is caused by large number of genetic factors acting together. I recently discovered over 100 of these genetic factors for glaucoma using data combined from 14 studies globally. Put together in a prediction model, these factors helped predict who in a population will develop glaucoma. Many more factors need to be discovered, but this opens up the possibility of targeted population screening to enable earlier diagnosis and prevention of irreversible sight loss.The aims of my research are to:1. Discover further new genetic factors to better understand the complex nature of glaucoma and better predict which people in a population are at highest risk of the disease2. Discover other glaucoma-causing biological processes related to variation in levels of different proteins and metabolites in the blood3. Discover non-genetic factors that predispose to glaucoma, such as diet, exercise and medication use, and to determine if these factors can alter a person's genetic risk for disease4. Establish a study of glaucoma patients which collects data on their progress over time and combines this with genetic data5. Determine whether the identified genetic factors can predict which glaucoma patients are at highest risk of blindness and predict individual response to different treatmentsIf successful, my proposed research will have considerable potential impact. Being able to identify people at high risk of glaucoma on the basis of a genetic test alone will allow targeted screening of these individuals, enabling earlier diagnosis and prevention of irreparable vision loss. If genetic factors predict the course of the disease, it will be possible to help decide which patients need most intensive treatment to prevent blindness and which patients are at low risk to avoid overtreating them. Similarly, it may become possible to select the most effective treatment for each individual patient using genetic information. Put together, genetic testing may allow us to personalise the care of glaucoma patients and direct our limited resources to the patients that need it most. Innovative approaches such as this are essential to deal with the rapidly increasing numbers of glaucoma patients. Additionally, the work identifying the key biological processes that underlie glaucoma will help the development of new drug treatments.