Abstract
Disruption of metabolic homeostasis is an important factor in many diseases. Various metabolites have been linked to higher risk of morbidity and all-cause mortality using metabolomics in large population-based cohorts. In these studies, baseline metabolite levels were compared across subjects to identify associations with health outcomes, implying the existence of ‘healthy’ concentration ranges that are equally applicable to all individuals. Here, we focused on intra-individual changes in metabolite levels over time and their link to mortality, potentially allowing more personalized risk assessment. We analysed targeted metabolomics data for 134 blood metabolites from 1409 participants in the population-based CARLA cohort at baseline and after four years. Metabotypes of the majority of participants (59%) were extremely stable over time indicated by high correlation between the subjects’ metabolite profiles at the two time points. Metabotype instability and, in particular, decrease of valine were associated with higher risk of all-cause mortality in 7.9 years of follow-up (hazard ratio (HR) = 1.5(95%CI = 1.0–2.3) and 0.2(95%CI = 0.1–0.3)) after multifactorial adjustment. Excluding deaths that occurred in the first year after metabolite profiling showed similar results (HR = 1.8(95%CI = 1.1–2.8)). Lower metabotype stability was also associated with incident cardiovascular disease (OR = 1.2(95%CI = 1.0–1.3)). Therefore, changes in the personal metabotype might be a valuable indicator of pre-clinical disease.
Highlights
Diseases linked to metabolic imbalance such as cardiovascular diseases (CVD) and diabetes are among the 10 leading causes of death in developed countries[1]
Out of 1779 individuals examined at baseline, for 1409 participants, blood samples were available for the follow-up visit after 4 years (Supplementary Figure 1)
Metabolomics measurements were performed in serum samples collected at baseline and at 4-years follow-up using the AbsoluteIDQ p150 kit for targeted mass spectrometry based quantification of 163 metabolites comprising mainly amino acids and lipids
Summary
Diseases linked to metabolic imbalance such as cardiovascular diseases (CVD) and diabetes are among the 10 leading causes of death in developed countries[1]. Using non-targeted metabolomics technology in a cohort of African Americans, Yu et al.[7] recently, identified nine metabolites from diverse metabolic pathways, such as steroids, bile acids, amino acids, dipeptides, and xenobiotics, that correlated with all-cause mortality In these studies, metabolite levels measured in samples from a single time point were used to test their association with prevalent and incident diseases or mortality, i.e., levels were compared across subjects to identify metabolites that indicate higher risk of disease or mortality if their levels are not within the ‘normal’ range The primary goal of our present study was to investigate whether changes in the levels of metabolites over several years and the overall stability of the personal metabotype in this period are linked to subsequent cardiovascular events and all-cause mortality To this end, we performed quantitative profiling of 163 metabolites, including acylcarnitines, amino acids, phospholipids and hexose, in blood samples from 1409 participants enrolled in the CARLA study at two time points separated by 4 years. Data on cardiovascular events and all-cause mortality were available for a mean follow-up time of 7.9 years from baseline
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