In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cohort and Blood Sampling
2.2. Proteomics Data Acquisition and Handling
2.3. Data Analysis
3. Results
3.1. Population Statistics
3.2. Nine Proteins Are Significantly Higher in ME/CFS Patients
3.3. Additional Proteins Emerging from a Relaxed q-Value Threshold
3.4. Protein–Protein Association Analysis Points Both to the Ephrin Family and Immune Metabolism
3.5. High Levels of Prediction Are Achieved Using Univariate ROC Curve Analysis
3.6. Highly Enriched Clusters Include Ephrin-Related Pathways and Glucose
3.7. Protein–Protein Correlations Are Highly Disrupted in the Patient Cohort
4. Discussion
4.1. Most Significantly Different Proteins Are More Abundant in the Plasma of ME/CFS Patients
4.2. Much Evidence Implicates Disrupted Ephrin-Eph Signaling in Our Dataset
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gender (n) | Female | Controls | ME/CFS |
---|---|---|---|
20 | 20 | ||
Age | Mean +/− SD | 46 +/− 13.3 | 49.2 +/− 11.8 |
Median (min-max) | 50.5 (27–66) | 52 (27–68) | |
BMI | Mean +/− SD | 23.2 +/− 3.4 | 24 +/− 5.1 |
Median (min-max) | 21.8 (18.1–29.3) | 22.6 (16.8–37.4) | |
Type of onset | Gradual | NA | 35% |
Sudden | NA | 65% | |
Gut symptoms * | 5% | 55% | |
Positive tilt table test ** (n = 12) | ND | 67% | |
Bell’s disability scale *** | 10–20 | 0 | 7 |
30–40 | 0 | 7 | |
50–60 | 1 | 6 | |
90–100 | 19 | 0 | |
SF-36 *** | Physical component summary (PCS) | 55.4 +/− 5.9 | 27 +/− 8.6 |
Mental component summary (MCS) | 53.6 +/− 9.6 | 37.6 +/− 11.8 |
Protein | Full Name | UniProt | EntrezGene | Fold Change | p-Value | q-Value |
---|---|---|---|---|---|---|
RNase1 | Ribonuclease pancreatic | P07998 | RNASE1 (6035) | 1.47 | 0.00002 | 0.035 |
RABP2 | Cellular retinoic acid-binding protein 2 | P29373 | CRABP2 (1382) | 1.47 | 0.00002 | 0.035 |
AIF1L | Allograft inflammatory factor 1-like | Q9BQI0 | AIFL1 (83543) | 1.25 | 0.00002 | 0.035 |
PXDN | Peroxidasin homolog | Q92626 | PXDN (7837) | 1.39 | 0.00005 | 0.038 |
Ephrin-A4 | Ephrin-A4 | P52798 | EFNA4 (1945) | 1.16 | 0.00005 | 0.038 |
TIMD3 | Hepatitis A virus cellular receptor 2 | Q8TDQ0 | HAVCR2 (84868) | 1.1 | 0.00006 | 0.038 |
MXRA7 | Matrix-remodeling-associated protein 7 | P84157 | MXRA7 (439921) | 1.14 | 0.00006 | 0.038 |
TNF sR-I | Tumor necrosis factor receptor superfamily member 1A | P19438 | TNFRSF1A (7132) | 1.28 | 0.00007 | 0.038 |
IL-18 BPa | Interleukin-18-binding protein | O95998 | IL18BP (10068) | 1.24 | 0.00007 | 0.038 |
Term ID * | Term Description | Enrichment Score | Genes Mapped | Pathway Size | False Discovery (afc) |
---|---|---|---|---|---|
HSA-3928663 | EPHA-mediated growth cone collapse | 2.26367 | 17 | 28 | 0.00051 |
CL:416 | Ephrin receptor activity, and Ephrin | 2.07704 | 20 | 23 | 0.00038 |
CL:420 | Ephrin receptor activity, and Ephrin | 2.72701 | 13 | 16 | 0.00038 |
IPR031328 | Ephrin | 3.36604 | 7 | 9 | 0.0049 |
IPR019765 | Ephrin, conserved site | 3.36604 | 7 | 9 | 0.0049 |
IPR001799 | Ephrin receptor-binding domain | 3.36604 | 7 | 9 | 0.0049 |
IPR034252 | Ephrin-A ectodomain | 5.24701 | 4 | 6 | 0.0049 |
Protein | AUC | Protein Ratio | EntrezGene | UniProt | AUC |
---|---|---|---|---|---|
RNase1 | 0.87 | FRDA/TIMD3 * | FXN/HAVCR2 * | Q16595/Q8TDQ0 | 0.95 |
RABP2 | 0.87 | Layilin/CLC4D * | LAYN/CLEC4D * | Q6UX15/Q8WXI8 | 0.94 |
AIF1L | 0.87 | RNase1/EKI1 | RNASE1/ETNK1 | P07998/Q9HBU6 | 0.94 |
PXDN | 0.86 | BMPER/TNF sR-I | BMPER/TNFRSF1A | Q8N8U9/P19438 | 0.93 |
Ephrin-A4 | 0.86 | EphA5/CFTR * | EPHA5/CFTR * | P54756/P13569 | 0.93 |
TIMD3 | 0.85 | TIMD3/CFTR | HAVCR2/CFTR | Q8TDQ0/P13569 | 0.93 |
MXRA7 | 0.85 | VIGLN/EphA5 | HDLBP/EPHA5 | Q00341/P54756 | 0.93 |
TNF sR-I | 0.85 | Keratin-16/CFTR * | KRT16/CFTR * | P08779/P13569 | 0.93 |
IL-18 BPa | 0.85 | P5CR2/Layilin | PYCR2/LAYN | Q96C36/Q6UX15 | 0.92 |
Annotation Cluster | Enrichment Score | GO Term | Protein Count | p-Value | q-Value | |
---|---|---|---|---|---|---|
1 | 14.3 | CC_GO:0005913 | Cell–cell adherens junction | 113 | 4.46 × 10−18 | 6.72 × 10−16 |
MF_GO:0098641 | Cadherin binding involved in cell-cell adhesion | 98 | 1.59 × 10−14 | 3.49 × 10−12 | ||
BP_GO:0098609 | Cell–cell adhesion | 90 | 2.46 × 10−12 | 9.64 × 10−10 | ||
2 | 6.5 | BP_GO:0038083 | Peptidyl-tyrosine autophosphorylation | 24 | 2.06 × 10−9 | 3.93 × 10−7 |
MF_GO:0004715 | Nonmembrane spanning protein tyrosine kinase activity | 22 | 1.21 × 10−6 | 0.00009 | ||
CC_GO:0031234 | Extrinsic component of cytoplasmic side of plasma membrane | 26 | 0.00001 | 0.0004 | ||
3 | 5.5 | BP_GO:0061621 | Canonical glycolysis | 17 | 1.65 × 10−7 | 0.00002 |
BP_GO:0006096 | Glycolytic process | 18 | 3.70 × 10−6 | 0.0003 | ||
BP_GO:0006094 | Gluconeogenesis | 19 | 0.00006 | 0.003 | ||
4 | 5.1 | BP_GO:0050919 | Negative chemotaxis | 21 | 1.37 × 10−8 | 2.17 × 10−6 |
MF_GO:0045499 | Chemorepellent activity | 18 | 2.85 × 10−8 | 2.81 × 10−6 | ||
BP_GO:0048843 | Negative regulation of axon extension involved in axon guidance | 15 | 8.89 × 10−6 | 0.0007 | ||
MF_GO:0030215 | Semaphorin receptor binding | 13 | 0.00005 | 0.002 | ||
BP_GO:0071526 | Semaphorin-plexin signaling pathway | 16 | 0.00006 | 0.003 | ||
MF_GO:0038191 | Neuropilin binding | 10 | 0.0001 | 0.004 | ||
BP_GO:0001755 | Neural crest cell migration | 16 | 0.003 | 0.07 | ||
BP_GO:0008543 | Fibroblast growth factor receptor signaling pathway | 34 | 9.67 × 10−8 | 0.00001 | ||
5 | 5 | BP_GO:0048015 | Phosphatidylinositol-mediated signaling | 40 | 1.22 × 10−7 | 0.00002 |
MF_GO:0046934 | Phosphatidylinositol-4,5-bisphosphate 3-kinase activity | 28 | 1.26 × 10−7 | 0.00001 | ||
MF_GO:0005088 | Ras guanyl-nucleotide exchange factor activity | 41 | 2.52 × 10−7 | 0.00002 | ||
BP_GO:0014066 | Regulation of phosphatidylinositol 3-kinase signaling | 32 | 3.27 × 10−7 | 0.00004 | ||
BP_GO:0046854 | Phosphatidylinositol phosphorylation | 32 | 0.00003 | 0.002 | ||
MF_GO:0005104 | Fibroblast growth factor receptor binding | 12 | 0.0002 | 0.006 | ||
MF_GO:0016303 | 1-phosphatidylinositol-3-kinase activity | 13 | 0.03 | 0.35 | ||
BP_GO:0036092 | Phosphatidylinositol-3-phosphate biosynthetic process | 14 | 0.04 | 0.46 |
Protein | Negative Correlations in Controls Positive Correlations in ME/CFS | Protein | Positive Correlations in Controls Negative Correlations in ME/CFS |
---|---|---|---|
CGA FSHB | 347 (349) | CILP2 | 381 (386) |
FIS1 | 281 (340) | CASC4 | 301 (308) |
TNXB | 251 (331) | TMEM9 | 285 (287) |
CGA LHB | 226 (230) | ENO3 | 280 (296) |
RNF215 | 211 (242) | VWA2 | 267 (291) |
RCN3 | 209 (306) | AMN | 222 (240) |
RNF215.1 | 202 (242) | CLIC5 | 200 (205) |
C3 | 195 (359) | CACNA2D3 | 193 (200) |
GRB14 | 194 (218) | OBP2B | 183 (190) |
FIGF | 144 (271) | THSD7A | 174 (231) |
BRD2 | 129 (132) | C3 | 164 (359) |
ANTXR1 | 124 (166) | TTC9B | 157 (257) |
C1orf210 | 105 (182) | LAMC2 | 143 (151) |
IGFBP1 | 101 (134) | PIANP | 129 (133) |
TTC9B | 100 (257) | TRAPPC3 | 129 (181) |
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Germain, A.; Levine, S.M.; Hanson, M.R. In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling. Proteomes 2021, 9, 6. https://doi.org/10.3390/proteomes9010006
Germain A, Levine SM, Hanson MR. In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling. Proteomes. 2021; 9(1):6. https://doi.org/10.3390/proteomes9010006
Chicago/Turabian StyleGermain, Arnaud, Susan M. Levine, and Maureen R. Hanson. 2021. "In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling" Proteomes 9, no. 1: 6. https://doi.org/10.3390/proteomes9010006
APA StyleGermain, A., Levine, S. M., & Hanson, M. R. (2021). In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling. Proteomes, 9(1), 6. https://doi.org/10.3390/proteomes9010006