M5.1 Activin A and its role in pathophysiology of preeclampsia

Abstract

Preeclampsia is a complex syndrome with multiple biological pathways contributing to its etiology. Therefore, we have taken a holistic, data-driven, or “systems biology”, approach to identify a metabolic signature in plasma that is predictive of subsequent preeclampsia. Metabolomics, is a powerful strategy for investigating, in a single chemical snapshot, the low molecular weight (bio)chemicals (metabolites) present in the metabolome of a cell, tissue or organism. Its position as the final downstream product of gene expression makes the metabolome a sensitive measure of disease phenotype: an indicator of both genetic and environmental perturbations. Here I present my group’s ongoing work investigating the metabolic signature of preeclampsia. We have reported preliminary results of an anonymous metabolomic screen of plasma from women with established pre-eclampsia [1,2]. We described, and subsequently identified, highly discriminatory metabolites that effectively distinguished cases with disease from matched controls. More recently we have taken a similar metabolomics approach for the discovery of prognostic early pregnancy biomarkers for pre-eclampsia. We identified 45 metabolites in plasma at 15 weeks’ gestation as being statistically significant (p<0.05) indicators of the subsequent development of pre-eclampsia in 60 women (and 60 closely matched controls). The majority of these metabolites were chemically identified as simple peptides, fatty acids, keto or hydroxy acids, lipids or phospholipids. Most significantly, a multivariate predictive model combining 14 metabolites gave an Odds Ratio for developing pre-eclampsia of 36 (95% confidence interval 12-108), with an area under the Receiver Operator Characteristic curve of 0.94. These findings have been validated in an entirely different cohort and the model performed robustly [3]. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of pre-eclampsia offers insight into disease pathogenesis, and offers the tantalizing promise of a robust presymptomatic screening test.