Table 5.
Enriched metabolic pathways perturbed between different case groups and control group (corresponding to Fig. 1).
| Region codesa | Enriched pathways (cut-off, *p < 0.01) | Outcome | p valueb | Number of identified metabolites perturbed in the pathway | FDRc |
|---|---|---|---|---|---|
| ABCDE (5) | Aminoacyl-tRNA: biosynthesis in cytoplasm | GH | 1.9E−06 | 6/98 | 1.6E−05 |
| HDP | 7.6E−10 | 9/98 | 2.5E−08 | ||
| PE | 2.8E−13 | 12/98 | 1.5E−11 | ||
| PTB | 4.4E−10 | 7/98 | 1.0E−08 | ||
| sPTB | 9.4E−06 | 4/98 | 9.7E−05 | ||
| Aminoacyl-tRNA: biosynthesis in mitochondrion | GH | 6.1E−07 | 6/81 | 6.7E−06 | |
| HDP | 1.3E−10 | 9/81 | 7.4E−09 | ||
| PE | 2.6E−14 | 12/81 | 2.1E−12 | ||
| PTB | 1.1E−10 | 7/81 | 5.1E−09 | ||
| sPTB | 4.4E−06 | 4/81 | 6.8E−05 | ||
| l-Threonine metabolism | GH | 3.9E−05 | 4/50 | 2.6E−04 | |
| HDP | 9.1E−05 | 4/50 | 1.1E−03 | ||
| PE | 1.9E−04 | 4/50 | 2.0E−03 | ||
| PTB | 2.3E−06 | 4/50 | 3.4E−05 | ||
| sPTB | 6.2E−07 | 4/50 | 1.9E−05 | ||
| Renal secretion of organic electrolytes | GH | 2.1E−04 | 4/77 | 1.2E−03 | |
| HDP | 4.9E−04 | 4/77 | 5.1E−03 | ||
| PE | 1.0E−03 | 4/77 | 7.8E−03 | ||
| PTB | 9.5E−03 | 2/77 | 2.9E−02 | ||
| sPTB | 5.2E−03 | 2/77 | 1.8E−02 | ||
| Urea cycle | GH | 8.4E−03 | 2/36 | 2.4E−02 | |
| HDP | 2.5E−05 | 4/36 | 4.1E−04 | ||
| PE | 1.8E−06 | 5/36 | 3.3E−05 | ||
| PTB | 2.1E−03 | 2/36 | 1.6E−02 | ||
| sPTB | 1.2E−03 | 2/36 | 8.6E−03 | ||
| ABCD (1) | Signal transduction: Amino acid-dependent mTORC1 activation | GH | 4.9E−04 | 4/96 | 2.1E−03 |
| HDP | 1.1E−03 | 4/96 | 9.8E−03 | ||
| PE | 3.6E−09 | 9/96 | 9.9E−08 | ||
| PTB | 3.1E−05 | 4/96 | 3.5E−04 | ||
| ACDE (1) | Leucine, isoleucine and valine metabolism | GH | 5.9E−04 | 3/43 | 2.2E−03 |
| PE | 1.9E−03 | 3/43 | 1.2E−02 | ||
| PTB | 7.3E−05 | 3/43 | 6.6E−04 | ||
| sPTB | 1.7E−03 | 2/43 | 8.6E−03 | ||
| ABC (14) | Aberrant lipid trafficking and metabolism in age-related macular degeneration pathogenesis | GH | 1.6E−03 | 3/60 | 5.5E−03 |
| HDP | 2.9E−03 | 3/60 | 2.2E−02 | ||
| PE | 3.9E−04 | 4/60 | 3.5E−03 | ||
| Cholesterol and Sphingolipid transport/distribution to the intracellular membrane compartments (normal and CF) | GH | 9.0E−11 | 7/38 | 2.0E−09 | |
| HDP | 4.3E−10 | 7/38 | 1.8E−08 | ||
| PE | 1.7E−09 | 7/38 | 5.6E−08 | ||
| Cholesterol and sphingolipid transport/generic schema (normal and CF) | GH | 5.6E−13 | 8/35 | 1.8E−11 | |
| HDP | 3.4E−12 | 8/35 | 2.9E−10 | ||
| PE | 1.7E−11 | 8/35 | 6.9E−10 | ||
| Cholesterol and sphingolipid transport/influx to the early endosome in lung (normal and CF) | GH | 5.5E−03 | 2/29 | 1.7E−02 | |
| HDP | 8.4E−03 | 2/29 | 5.0E−02 | ||
| PE | 2.2E−05 | 4/29 | 3.2E−04 | ||
| Cholesterol and sphingolipid transport/recycling to plasma membrane in lung (normal and CF) | GH | 7.5E−08 | 5/29 | 1.2E−06 | |
| HDP | 2.3E−07 | 5/29 | 6.3E−06 | ||
| PE | 5.9E−07 | 5/29 | 1.4E−05 | ||
| Cholesterol and sphingolipid transport/transport from Golgi and ER to the apical membrane (normal and CF) | GH | 2.7E−07 | 5/37 | 3.6E−06 | |
| HDP | 8.0E−07 | 5/37 | 1.9E−05 | ||
| PE | 2.1E−06 | 5/37 | 3.4E−05 | ||
| Chylomicron dyslipidemia in type 2 diabetes and metabolic syndrome X | GH | 5.5E−04 | 3/42 | 2.1E−03 | |
| HDP | 4.6E−05 | 4/42 | 5.9E−04 | ||
| PE | 1.8E−03 | 3/42 | 1.2E−02 | ||
| Cortisol biosynthesis from cholesterol | GH | 4.1E−04 | 3/38 | 1.9E−03 | |
| HDP | 3.1E−05 | 4/38 | 4.6E−04 | ||
| PE | 6.5E−05 | 4/38 | 7.1E−04 | ||
| HDL dyslipidemia in type 2 diabetes and metabolic syndrome X | GH | 4.1E−04 | 3/38 | 1.9E−03 | |
| HDP | 7.7E−04 | 3/38 | 7.6E−03 | ||
| PE | 1.3E−03 | 3/38 | 9.6E−03 | ||
| Lipoprotein metabolism | GH | 2.3E−03 | 3/68 | 7.4E−03 | |
| HDP | 1.7E−05 | 5/68 | 3.2E−04 | ||
| PE | 7.1E−03 | 3/68 | 3.4E−02 | ||
| Metabolic syndrome X (general schema) | GH | 2.4E−05 | 3/15 | 1.7E−04 | |
| HDP | 4.5E−05 | 3/15 | 5.9E−04 | ||
| PE | 1.3E−06 | 4/15 | 2.7E−05 | ||
| Metabolism of l-proline and derivatives | GH | 1.8E−04 | 4/74 | 1.1E−03 | |
| HDP | 4.2E−04 | 4/74 | 4.7E−03 | ||
| PE | 6.6E−05 | 5/74 | 7.1E−04 | ||
| Transport: HDL-mediated reverse cholesterol transport | GH | 5.5E−04 | 3/42 | 2.1E−03 | |
| HDP | 1.0E−03 | 3/42 | 9.6E−03 | ||
| PE | 1.8E−03 | 3/42 | 1.2E−02 | ||
| Transport: intracellular cholesterol transport | GH | 1.8E−16 | 12/83 | 1.2E−14 | |
| HDP | 3.1E−15 | 12/83 | 5.1E−13 | ||
| PE | 2.2E−17 | 14/83 | 3.6E−15 | ||
| BCD (1) | Myeloid-derived suppressor cells and M2 macrophages in cancer | HDP | 1.3E−05 | 5/64 | 2.7E−04 |
| PE | 6.0E−03 | 3/64 | 3.0E−02 | ||
| PTB | 6.7E−03 | 2/64 | 2.9E−02 | ||
| AB (1) | Androgen biosynthetic pathways | GH | 3.8E−03 | 3/82 | 1.2E−02 |
| HDP | 7.0E−03 | 3/82 | 4.3E−02 | ||
| BC (6) | Aspartate and asparagine metabolism | HDP | 5.1E−03 | 3/73 | 3.4E−02 |
| PE | 6.2E−05 | 5/73 | 7.1E−04 | ||
| Glycine and l-serine metabolism | HDP | 3.7E−03 | 4/133 | 2.6E−02 | |
| PE | 1.0E−03 | 5/133 | 7.8E−03 | ||
| l-Arginine metabolism | HDP | 6.3E−03 | 3/79 | 4.1E−02 | |
| PE | 1.1E−03 | 4/79 | 8.2E−03 | ||
| Muscle contraction: regulation of eNOS activity in endothelial cells | HDP | 3.7E−03 | 3/65 | 2.6E−02 | |
| PE | 5.3E−04 | 4/65 | 4.5E−03 | ||
| Niacin-HDL metabolism | HDP | 1.4E−03 | 3/46 | 1.1E−02 | |
| PE | 2.3E−03 | 3/46 | 1.3E−02 | ||
| Regulation of lipid metabolism: G-alpha(q) regulation of lipid metabolism | HDP | 2.8E−03 | 3/59 | 2.2E−02 | |
| PE | 4.8E−03 | 3/59 | 2.5E−02 | ||
| CD (1) | Immune response: distinct metabolic pathways in naive and effector CD8+ T cells | PE | 8.9E−03 | 3/74 | 3.9E−02 |
| PTB | 8.8E−03 | 2/74 | 2.9E−02 | ||
| DE (3) | Activation of cortisol production in major depressive disorder | PTB | 2.6E−03 | 2/40 | 1.7E−02 |
| sPTB | 1.4E−03 | 2/40 | 8.6E−03 | ||
| Renal secretion of drugs | PTB | 3.6E−03 | 2/47 | 2.0E−02 | |
| sPTB | 2.0E−03 | 2/47 | 8.8E−03 | ||
| Transcription role of VDR in regulation of genes involved in osteoporosis | PTB | 5.7E−03 | 2/59 | 2.8E−02 | |
| sPTB | 3.1E−03 | 2/59 | 1.2E−02 | ||
| A(2) | Regulation of lipid metabolism: PPAR regulation of lipid metabolism | GH | 9.2E−07 | 5/47 | 8.7E−06 |
| Transport regulation of ATP-binding transporters by Retinoic acid and orphan nuclear receptor PXR | 9.8E−03 | 2/39 | 2.7E−02 | ||
| B(2) | Immune response: The effect of IDO1 on T cell metabolism | HDP | 8.8E−03 | 3/89 | 5.0E−02 |
| Putative pathways of oleic acid sensing in ventromedial hypothalamus in obesity | 8.9E−03 | 2/30 | 5.0E−02 | ||
| C(8) | Antioxidant effects of statins in COPD | PE | 5.0E−03 | 3/60 | 2.5E−02 |
| Apoptosis and survival: NO signaling in apoptosis | 7.7E−03 | 2/23 | 3.6E−02 | ||
| Apoptosis and survival: NO signaling in survival | 8.4E−03 | 2/24 | 3.8E−02 | ||
| Beta-alanine metabolism | 4.7E−05 | 4/35 | 6.3E−04 | ||
| Environmental factors-induced inflammatory signaling in normal and asthmatic airway epithelium | 1.9E−03 | 3/43 | 1.2E−02 | ||
| mne-glutamate-glutamine metabolism | 2.2E−04 | 5/95 | 2.1E−03 | ||
| l-Lysine metabolism | 2.0E−03 | 4/93 | 1.2E−02 | ||
| Reactive oxygen and nitrogen species production in eosinophils in asthma | 4.8E−03 | 3/59 | 2.5E−02 | ||
| D(3) | Catecholamine metabolism | sPTB | 9.0E−03 | 2/75 | 2.9E−02 |
| Immune response: T regulatory cell-mediated modulation of antigen-presenting cell functions | 7.1E−03 | 2/66 | 2.9E−02 | ||
| Tyrosine metabolism p.1 (dopamine) | 7.9E−03 | 2/70 | 2.9E−02 |
Metabolic pathways between cases (e.g., GH, HDP, PE, PTB, and sPTB) and controls were enriched by GeneGo MetaCore using Enrichment by Pathway Maps.
aCapital letters (A, B, C, D, E, and their combinations) and numbers are corresponding to the Venn diagram in Fig. 1. Pathways in a region with single capital letter are specific to a certain phenotype; while pathways in a region with combination of letters indicate the common pathways being impacted in different phenotypes. A, gestational hypertension (GH); B, hypertensive disorder of pregnancy (HDP); C, pre-eclampsia (PE); D, preterm birth (PTB); E, spontaneous preterm birth (sPTB).
bThe p value that was generated from the hypergeometric test in Metacore indicates the significance of enrichment of metabolites in pathway mapping. A lower p value indicates a higher significance in the pathway enrichment.
cFDR = false discovery rate.