Investigating the influence of genetic variation associated with age-related macular degeneration on plasma levels of complement regulatory proteins

研究与年龄相关性黄斑变性相关的遗传变异对补体调节蛋白血浆水平的影响

• 批准号: MR/P025838/1
• 负责人: Richard Unwin
• 金额: $ 66.42万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP025838%2F1
• 关键词: Investigating; influence; genetic; variation; associated

Age-related Macular Degeneration (AMD) is the leading cause of blindness in the Western world. Recently, it has become clear that the genetic make-up of an individual has a strong influence on their risk of developing AMD. Gene variants have been found which are 'protective', i.e. individuals with these variants have lower risk of AMD, and which are 'causative', i.e. their presence results in increased risk. There are two main genetic regions that modify AMD risk. One, on chromosome 10, is poorly understood. The other, on chromosome 1, provides the code for a series of proteins called Complement Factor H (FH), Factor H-Like Protein 1 (FHL-1), and five proteins called Factor H-Related 1-5 (FHR1-5). These proteins are involved in regulating part of the immune system called the complement cascade. It is thought that genetic variations on chromosome 1 alter the amounts of these proteins, resulting in inflammation in the eye and ultimately to the development of AMD. This is supported by a number of studies where the absence of one of these proteins, or a change in its sequence (hence function) can be shown to change the risk of AMD occurring.While it is assumed that these AMD-associated genetic variants change the levels of FH, FHL1 and FHR1-5 present in the body, this has been difficult to confirm. These proteins are very similar (indeed FHL-1 is identical to the first half of FH, with the exception of a very small tag at one end). This means that standard methods, which recognise and measure a protein based on its shape are fraught with problems, as it is very difficult to prove exactly which form is being measured. In this project, we will take a different approach - mass spectrometry (MS). MS works by 'weighing' the molecules of interest, then counting how many of each are present. Since we know the structure of these proteins, we can calculate their mass and detect them with very high confidence. Indeed, MS is now routinely used for testing blood levels of many compounds as part of routine clinical care. We have developed an MS-based method which can measure the levels of all seven proteins of interest in plasma at the same time. This method will be of great value. We will use it to analyse blood samples where we have already used standard methods and see how the results match, showing which methods are reliable. Secondly, we will measure the levels of these seven proteins in plasma collected as part of a large genetic study of AMD. The donors of these blood samples have already had their genetic profile determined. By measuring the amounts of protein, we can compare with the genetic data and see for the first time how the genetics impacts on the levels of each protein, and in turn how the levels of these proteins confer AMD risk. This research will provide new understanding as to how AMD develops, will improve our ability to define risk, and may allow the development or monitoring of new treatments.This assay will also be useful for research into other diseases. These proteins are known to be important for certain kidney diseases and reliable ways to measure them will be important both for research and clinical care. There is also evidence that they contribute to other conditions such as Alzheimer's disease.

视网膜相关性黄斑变性（AMD）是西方世界失明的主要原因。最近，人们已经清楚地认识到，个体的遗传组成对他们患AMD的风险有很大的影响。已经发现基因变体是“保护性的”，即具有这些变体的个体具有较低的AMD风险，并且是“致病性的”，即它们的存在导致风险增加。有两个主要的遗传区域可以改变AMD的风险。其中之一位于10号染色体上，人们对此知之甚少。另一个位于1号染色体上，为一系列称为补体因子H（FH）、H因子样蛋白1（FHL-1）的蛋白质和五种称为H因子相关1-5（FHR 1 -5）的蛋白质提供代码。这些蛋白质参与调节免疫系统的一部分，称为补体级联反应。据认为，1号染色体上的遗传变异改变了这些蛋白质的数量，导致眼睛炎症，最终导致AMD的发展。这一点得到了许多研究的支持，其中一种蛋白质的缺失或其序列（因此功能）的改变可以改变AMD发生的风险。虽然假设这些AMD相关的遗传变异改变了体内存在的FH，FHL 1和FHR 1 -5的水平，但这很难证实。这些蛋白质非常相似（事实上，FHL-1与FH的前半部分相同，除了一端有一个非常小的标签）。这意味着基于其形状识别和测量蛋白质的标准方法充满了问题，因为很难确切证明测量的是哪种形式。在这个项目中，我们将采取不同的方法-质谱（MS）。MS的工作原理是“称量”感兴趣的分子，然后计算每种分子的数量。由于我们知道这些蛋白质的结构，我们可以计算它们的质量并以非常高的置信度检测它们。事实上，MS现在通常用于测试许多化合物的血液水平，作为常规临床护理的一部分。我们开发了一种基于MS的方法，可以同时测量血浆中所有七种感兴趣蛋白的水平。这种方法将有很大的价值。我们将使用它来分析血液样本，我们已经使用标准方法，看看结果如何匹配，显示哪些方法是可靠的。其次，我们将测量这七种蛋白质在血浆中的水平，这些血浆是作为AMD大型遗传研究的一部分收集的。这些血液样本的捐赠者已经确定了他们的遗传特征。通过测量蛋白质的量，我们可以与遗传数据进行比较，并首次看到遗传学如何影响每种蛋白质的水平，以及这些蛋白质的水平如何赋予AMD风险。这项研究将为AMD的发展提供新的理解，将提高我们定义风险的能力，并可能允许开发或监测新的治疗方法。这项测定也将有助于研究其他疾病。已知这些蛋白质对某些肾脏疾病很重要，测量它们的可靠方法对于研究和临床护理都很重要。也有证据表明，他们有助于其他条件，如阿尔茨海默氏症。

项目成果

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

• DOI: 10.1038/s41467-020-14499-3
• 发表时间: 2020-02-07
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Cipriani, Valentina;Lores-Motta, Laura;Clark, Simon J.
• 通讯作者: Clark, Simon J.

Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations.

• DOI: 10.1016/j.ajhg.2021.05.015
• 发表时间: 2021-08-05
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: Cipriani V;Tierney A;Griffiths JR;Zuber V;Sergouniotis PI;Yates JRW;Moore AT;Bishop PN;Clark SJ;Unwin RD
• 通讯作者: Unwin RD

The eye as a complement dysregulation hotspot.

• DOI: 10.1007/s00281-017-0649-6
• 发表时间: 2018-01
• 期刊: Seminars in immunopathology
• 影响因子: 9
• 作者: Clark SJ;Bishop PN
• 通讯作者: Bishop PN

Theranos's lesson for investors: speak to lab workers.

Theranos 给投资者的教训：与实验室工作人员交谈。

• DOI: 10.1038/d41586-022-00167-7
• 发表时间: 2022
• 期刊: Nature
• 影响因子: 64.8
• 作者: Unwin RD

Levels of soluble complement regulators predict severity of COVID-19 symptoms.

可溶性补体调节器的水平预测了199症状的严重程度。

• DOI: 10.3389/fimmu.2022.1032331
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3