Ribosomal DNA copy number: a novel genetic factor associated with body mass index in humans?

核糖体 DNA 拷贝数：与人类体重指数相关的新型遗传因素？

• 批准号: MR/X009661/1
• 负责人: Michelle Holland
• 金额: $ 37.45万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX009661%2F1
• 关键词: Ribosomal; DNA; copy; number; novel

Obesity rates have skyrocketed in the last three decades and represent a serious public health problem in the United Kingdom and globally. Although factors such as calorie dense diets and more sedentary lifestyles are responsible for this increase, genes also play a significant role in how an individual responds to their environment. With the exception of rare syndromes, regulation of body weight is under the influence of many genes, each with a relatively small effect. Over the last 15 years, there have been extensive efforts to identify such genes, but currently, a large proportion of heritability of body weight is yet to be identified. Our previous work has identified a part of our DNA (known as ribosomal DNA or rDNA) to respond to dietary exposures. rDNA contains instructions for making key components of the molecular machines that make proteins. These genes have been overlooked in most studies of human genetics due to technical issues with understanding their organisation within the DNA. Importantly, we have many copies of these genes (~100-600) and the number of copies varies across individuals. Building on this, we looked at whether rDNA may be contributing to obesity risk. In the work leading to this proposal, we identified that obese individuals had less copies of the rDNA genes. Here, we wish to verify this finding in a much larger population (~half a million subjects) using a resource that has both genetic data as well as measurements of weight, height, amount of body fat, among others. This will allow us to validate that the number of copies of rDNA an individual has is a previously unknown genetic factor contributing to body weight regulation, to identify how this relates to other predisposing genetic factors and also to other measurements that are associated with body weight regulation and some of the health conditions associated with obesity. We will also perform a similar analysis on tissues from mice that have been fed diets that cause obesity-this is a common model for understanding how specific genes function to control body weight. Together the proposed work will result in understanding the role of rDNA copy number in body weight regulation. This will allow us to use this, together with what is already known about genetic risk for obesity to build a more accurate tool to be able to assess an individual's genetic predisposition towards weight gain. Such tools allow clinicians to identify individuals at risk of a disease and intervene to prevent the disease occurring. In addition, we will verify whether the contribution of rDNA to genetic risk represents a previously unknown pathway. In combination with the work to establish the validity of the mouse model, this will pave the way to future work to understand how this contributes to body weight regulation. Besides improving our understanding of human biology in relation to obesity, this could also progress towards the development of novel therapeutic agents.

在过去的三十年里，肥胖率急剧上升，在英国和全球范围内都是一个严重的公共卫生问题。虽然高热量饮食和久坐不动的生活方式等因素是导致这种增加的原因，但基因在个人如何应对环境方面也发挥着重要作用。除了罕见的综合征，体重的调节受到许多基因的影响，每个基因的影响相对较小。在过去的15年里，人们已经做出了大量的努力来识别这些基因，但目前，体重的大部分遗传性尚未被确定。我们以前的工作已经确定了我们DNA的一部分（称为核糖体DNA或rDNA）对饮食暴露的反应。rDNA含有制造蛋白质分子机器关键组件的指令。这些基因在大多数人类遗传学研究中被忽视，因为理解它们在DNA中的组织存在技术问题。重要的是，我们有这些基因的许多拷贝（约100-600），拷贝数因个体而异。在此基础上，我们研究了rDNA是否可能导致肥胖风险。在导致这一提议的工作中，我们发现肥胖个体的rDNA基因拷贝较少。在这里，我们希望在更大的人群（约50万受试者）中验证这一发现，使用的资源既有遗传数据，也有体重，身高，体脂量等测量数据。这将使我们能够验证一个人的rDNA拷贝数是一个以前未知的遗传因素，有助于体重调节，以确定这与其他易感遗传因素以及与体重调节相关的其他测量和与肥胖相关的一些健康状况。我们还将对那些被喂食导致肥胖的食物的老鼠的组织进行类似的分析这是一个了解特定基因如何控制体重的常见模型。这项工作将有助于理解rDNA拷贝数在体重调节中的作用。这将使我们能够利用这一点，以及已经知道的肥胖遗传风险，建立一个更准确的工具，能够评估个人的遗传倾向对体重增加。这些工具允许临床医生识别处于疾病风险中的个体，并进行干预以预防疾病的发生。此外，我们将验证rDNA对遗传风险的贡献是否代表了一种以前未知的途径。结合建立小鼠模型的有效性的工作，这将为未来的工作铺平道路，以了解这如何有助于体重调节。除了提高我们对人类生物学与肥胖相关的理解外，这也可能有助于开发新的治疗药物。