Precision Medicine in Preeclampsia: Metabolomic and Lipidomic Investigation of Disease Mechanisms

Preeclampsia (PreE) is a complex and heterogenous disorder. We combined metabolomics and lipidomics analyses to investigate PreE pathogenesis and thus identify potential therapeutic targets. This is a prospective study in which serum was collected in 76 cases of PreE diagnosed based on ACOG criteria and 39 controls. Direct Injection Liquid Chromatography-Mass Spectrometry and Nuclear Magnetic Resonance spectroscopy were used to perform metabolomic and lipidomic analysis. Metabolite set enrichment analysis was used to identify which pathways were directly related to the pathogenesis of PreE. Variable Importance in Projection (VIP) analysis was used to determine which metabolites were most significantly dysregulated in PreE as compared to controls, with the metabolite VIP rank directly correlated with PreE. The mean (SD) gestational age (weeks) in PreE vs. controls at birth was 33.257 (4.255) vs. 36.025 (3.296), gestational age (weeks) at sample collection was 33.25 (4.22) vs. 36.20 (3.27), and birthweight (grams) was 2378.2 (975.432) vs. 3364.9 (320.845). All comparisons were significant with p< 0.0001 for all. A total of 521 lipids and 93 endogenous metabolites were evaluated. The most significantly altered metabolites include: Isobutyric acid (a short chain fatty acid associated with gut microbiome dysbiosis and linked to hypertension), Probetaine (which reduces homocysteine levels and endothelial dysfunction), and Taurochenodeoxycholic acid (a bile acid involved in lipid metabolism). The significant metabolites and VIP scores are shown (Figure 1). Metabolite set enrichment analysis (Figure 2) revealed significant perturbation in lipid metabolism. Catecholamine metabolism, critical to neurohormonal regulation of blood pressure was also dysregulated. The major dysregulated metabolic pathway in PreE appears to be that of lipid metabolism. This is consistent with increased risk of PreE in obese and diabetic populations. Further, more detailed, and global analysis of lipid dysfunction in PreE is clearly warranted.View Large Image Figure ViewerDownload Hi-res image Download (PPT)