Metabolomic profiling for improved understanding of cardiovascular diseases in type 2 diabetes

Cardiovascular diseases (CVD) remain a leading cause of death in type 2 diabetes (T2D). This is in part through associations with known risk factors (e.g. hypertension, dyslipidaemia, co-morbid chronic renal disease). However, these provide an incomplete explanation of the elevated risk and typically more severe pathology of CVD in T2D. Moreover, they cannot fully explain differences between populations, including notably high T2D-associated CVD risks in the Mexican population.  

Reflecting influences of genetic, epigenetic and environmental factors, the metabolome provides an integrated measure of biologic status. In combination with genetic data it can provide a tool for understanding the molecular basis of disease, and metabolomic investigation of CVD in T2D would be expected to provide novel mechanistic insights to inform CVD prediction, prevention and treatment. 

This project applies this approach using data from 150,000 adults in the Mexico City Prospective Study (MPCS). At recruitment in 1998-2004 from two areas of Mexico City, participants completed electronic questionnaires, physical measurements were taken, and blood samples were collected. Genome-wide genotype data, plasma NMR metabolomic profiling data and HbA1c levels are available for all participants. Follow-up is on-going for cause-specific mortality through death registry linkage, and for major non-fatal diseases through interviewer-administered surveys. 

Using these data, the project aims to characterise the metabolomic profile of CVD and CVD subtypes, and examine the influence of T2D and HbA1c on these associations. Mendelian randomisation (MR), including approaches such as multivariable MR (capable of addressing challenges posed by metabolomics data e.g. multicollinearity), will be used to understand the likely causality of observed associations and their relevance for mechanistic pathways underlying CVD risks in T2D.