Circulating plasma metabolites, lifestyle, adiposity, and biochemical exposures and risk of major chronic diseases and their co-occurence

The prevalence of cardiovascular diseases (CVD), type 2 diabetes (T2D), cancer and dementia/Alzheimer’s disease (AD) has risen partially due to the aging of the Western populations and also to increases in shared risk factors. Although increasing evidence has linked unhealthy lifestyle, adiposity and abnormal biochemical measures to the risk of these diseases, the underlying mechanisms remain unclear yet. Metabolomics, through a systematic evaluation of small-molecule metabolites in biological samples such as blood, may help to study these exposures and health outcomes because it integrates information from genetic and environmental factors. To our knowledge, few studies have identified early biomarkers of common diseases and even less evidence exist on metabolic signatures of a number of exposures, simultaneously, in relation to diseases. Metabolomics, would allow the discovery of biomarkers and identification of novel metabolic pathways of exposures involved in the development of common diseases and thus advance our understanding on the underlying biological mechanisms by which the exposure is acting. We propose, for the duration of three years, to perform a prospective analysis by using large-scale metabolite, genetic, exposure, and clinical data from the UK Biobank. In this project, we will: 1) examine associations between baseline metabolites and risk of CVD, T2D, several types of cancer and dementia/AD; 2) investigate associations of lifestyle, circadian rhythm, adiposity and biochemical exposures with risk of these diseases; 3) try to identify metabolite signatures of each exposure and associate them with the risk of these diseases; 4) estimate the extent to which the identified metabolite signatures mediate the associations between the exposures and diseases; 5) examine causality of the associations between the identified metabolites or metabolite signatures and risk of diseases; 6) investigate the role of the identified exposures, metabolites and metabolite signatures in the risk of progressing from one of these diseases to multimorbidity. The results of this project will be useful to elucidate the underlying mechanisms in the relationship between exposures to highly prevalent diseases risk. The identified metabolites and metabolomics signatures related with these diseases and their co-occurrence could be used as target for prevention or treatment of both single disease and multimorbidity.