6 research outputs found
Recommended from our members
Microbiome and metabolome features of the cardiometabolic disease spectrum
Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-and co-morbid conditions or polypharmacy. Here in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis, and IHD cases at three distinct clinical stages; acute coronary syndrome, chronic IHD and IHD with heart failure, and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish IHD cases from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome may begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes, or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate IHD cases from healthy individuals or metabolically-matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features
Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits
We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue. Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care