What lies behind the causal impact of body mass index level and change on human health? Added value from complementary study design and deep metabolom

体重指数水平及其变化对人类健康的因果影响背后隐藏着什么？

• 批准号: 1976206
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-1976206
• 关键词: What; lies; behind; causal; impact

This project aims to better understand how body mass index (BMI) exerts an effect on human health and disease using metabolomics in complementary study designs and through applied genetic epidemiology.RationaleThere is strong evidence that BMI causally influences a wide range of health outcomes, but there is little understanding of the mechanisms driving BMI effects and at the level of the population we are limited in our ability to alter BMI. Targeted lifestyle and pharmaceutical interventions have failed to deliver large reductions in BMI and the only effective intervention is surgery. The proposal here is that metabolomic measurements can be used to understand the mechanisms by which BMI contributes to disease. Circulating metabolites are the product of genetic and non-genetic factors and are a useful read-out of physiological function. Despite the similarity of metabolites to complex health outcomes, it remains possible to map metabolites to genotypes and translatable biological pathways. Consequently, identifying metabolites important in the link between BMI and disease is a promising approach to further understanding BMI as a risk factor. Aims and ObjectivesTo better understand how BMI exerts an effect on human health and disease using metabolomics in complementary study designs and through applied genetic epidemiology. This PhD will be coodrinated with a Wellcome Trust funded programme of research that explicitly seeks to use the most contemporary and powerful study designs, metabolic data capture and analytical techniques to explore BMI as a risk factor. MethodsWe will address five key research questions by testing the hypotheses that: 1. Specific circulating metabolites are affected by BMI change2. BMI has a causal effect on the human metabolite response to feeding 3. BMI has a causal effect on the on the human faecal microbiome4. It is possible to causally map the human faecal microbiome onto the metabolome to extend the study of the microbiome5. Metabolites identified through population based causal analysis of BMI, intervention studies of BMI change, the effect of BMI on metabolic response and investigation of the microbiome ("BMI-metabolites") have a causal effect on disease risk. Research summaryBMI, a measure of adiposity, is observationally associated with health outcomes including all-cause mortality, CVD, T2D, and cancer. We do not yet know the full story of why BMI is a risk factor, and altering BMI at the population level is challenging.Metabolic differences are present across BMI levels and this is reflected in circulating metabolites. The result of genetic and non-genetic factors, circulating metabolites provide information on physiological function and can be used to identify links between BMI and disease.

该项目旨在通过补充研究设计中的代谢组学和应用遗传流行病学，更好地了解体重指数 (BMI) 如何对人类健康和疾病产生影响。基本原理有强有力的证据表明 BMI 会因果影响广泛的健康结果，但对驱动 BMI 影响的机制知之甚少，而且在人群水平上，我们改变 BMI 的能力有限。有针对性的生活方式和药物干预措施未能大幅降低体重指数，唯一有效的干预措施是手术。这里的建议是，代谢组学测量可用于了解 BMI 导致疾病的机制。循环代谢物是遗传和非遗传因素的产物，是生理功能的有用读数。尽管代谢物与复杂的健康结果相似，但将代谢物映射到基因型和可翻译的生物途径仍然是可能的。因此，鉴定在 BMI 和疾病之间的联系中重要的代谢物是进一步了解 BMI 作为危险因素的一种有前途的方法。目的和目标利用补充研究设计中的代谢组学和应用遗传流行病学，更好地了解 BMI 如何对人类健康和疾病产生影响。该博士学位将与 Wellcome Trust 资助的研究项目相协调，该项目明确寻求使用最现代、最强大的研究设计、代谢数据捕获和分析技术来探索 BMI 作为风险因素。方法我们将通过检验以下假设来解决五个关键研究问题： 1. 特定循环代谢物受 BMI 变化的影响 2。 BMI 对人类代谢物对进食的反应有因果影响 3。BMI 对人类粪便微生物组有因果影响 4。可以将人类粪便微生物组因果映射到代谢组上，以扩展微生物组的研究5。通过基于人群的 BMI 因果分析、BMI 变化的干预研究、BMI 对代谢反应的影响以及微生物组研究（“BMI 代谢物”）确定的代谢物对疾病风险具有因果影响。研究摘要BMI（肥胖的衡量标准）与健康结果（包括全因死亡率、CVD、T2D 和癌症）密切相关。我们还不知道为什么 BMI 是一个风险因素，并且在人群水平上改变 BMI 具有挑战性。不同 BMI 水平之间存在代谢差异，这反映在循环代谢物中。作为遗传和非遗传因素的结果，循环代谢物提供了有关生理功能的信息，可用于识别 BMI 与疾病之间的联系。