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

本项目旨在通过代谢组学的互补研究设计和应用遗传流行病学，更好地了解身体质量指数（BMI）如何对人类健康和疾病产生影响。理由：有强有力的证据表明，BMI会对一系列健康结果产生因果影响，但人们对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未能大幅降低BMI，唯一有效的干预措施是手术。这里的建议是，代谢组学测量可以用来理解BMI导致疾病的机制。循环代谢产物是遗传和非遗传因素的产物，是生理功能的有用解读。尽管代谢物与复杂的健康结果相似，但仍有可能将代谢物与基因型和可翻译的生物学途径联系起来。因此，确定在BMI和疾病之间的联系中重要的代谢物是进一步理解BMI作为危险因素的一个有希望的方法。目的和目的利用代谢组学和应用遗传流行病学在互补研究设计中更好地了解BMI对人类健康和疾病的影响。该博士学位将与Wellcome Trust资助的研究项目合作，该项目明确寻求使用最现代和最强大的研究设计，代谢数据捕获和分析技术来探索BMI作为风险因素。我们将通过测试假设来解决五个关键的研究问题：1。特定的循环代谢物受到BMI变化的影响2。体重指数对人体对喂养的代谢物反应有因果关系。体重指数对人体粪便微生物群有因果关系。有可能将人类粪便微生物组因果映射到代谢组，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的调查（“BMI-代谢物”）确定的代谢物对疾病风险有因果影响。研究总结：bmi是一种衡量肥胖的指标，在观察中与健康结果相关，包括全因死亡率、心血管疾病、糖尿病和癌症。我们还不知道为什么BMI是一个危险因素的全部原因，而且在人口水平上改变BMI是具有挑战性的。BMI水平之间存在代谢差异，这反映在循环代谢物中。遗传和非遗传因素的结果，循环代谢物提供了生理功能的信息，并可用于确定BMI与疾病之间的联系。

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.