Introduction
A key feature of IBD pathogenesis is response dysregulation of both the innate and adaptive immune system1,2. Hence specific inflammatory protein profiles may be a promising biomarker approach for diagnosis and personalized therapy in IBD. Serum proteome of IBD, particularly in multi-ethnic Asian patients, remains less defined.
Aims & Methods
We aim to investigate the systemic inflammatory protein profiles in multi-ethnic Asian patients with IBD and compare them to healthy controls.
The study cohort was made up of 92 patients with IBD (50.0% Ulcerative colitis (UC), 43.5% Crohn's disease (CD), 6.5% Unclassified IBD)), and 42 control subjects, who are asymptomatic patients undergoing screening colonoscopy with no endoscopic pathology. Serum protein profiling was performed using the Olink Target 96 Inflammation assay. A partial-least square discriminant analysis was undertaken to identify additional discriminative inflammatory proteins. Univariate t-test analyses, with false discovery rate correction, were also performed to identify proteins unique to either UC or CD.
Results
Participants with IBD were younger (42.0 (±14.7) in UC, 43.2 (±15.1) in CD, p<0.01), with greater representation of South Asian ethnicity (32.5% amongst UC, 19.6% amongst CD, p<0.01) and males (75.0% amongst UC, 69.6% amongst CD, p=0.03), as compared to controls.
We found 18 proteins were differentially abundant amongst IBD patients (p<0.05). Half (n=9) of these inflammatory proteins (AXIN-1, CD8A, CXCL1, EN-RAGE, FGF-23, HGF, IL17A, OSM, TGF-alpha) were elevated in both UC and CD. The other six proteins were elevated only in patients with UC (4E-BP1, CCL11, IL-18R1, IL-20, MMP-10, TRANCE). Of the remaining three, two were less abundant in patients with CD (DNER, SCF) and TNF was elevated only in patients with CD. Of interest, three immunoproteins were differentially abundant in participants with either UC or CD (i.e. CCL11, MMP10, TRANCE).
Molecular functions | Both UC and CD | UC only | CD only | UC vs CD |
Cytokine mediated signaling (GO:0019221) | IL17A CXCL1 OSM HGF | CCL11 TRANCE IL20 | TNF | CCL11 TRANCE
|
Positive regulation of protein kinase B signaling (GO:0051897) | FGF23 HGF OSM TGF-alpha | TRANCE | SCF* TNF | TRANCE |
Immune response (GO:0006955) | CD8A CXCL1 IL17A OSM | IL-18R1 TRANCE |
| TRANCE |
Inflammatory response (GO:0006954) | CXCL1 EN-RAGE IL17A | CCL11 IL-18R1 | TNF | CCL11 |
MAPK cascade (GO:0000165) | FGF-23 HGF TGF-alpha |
| SCF* TNF |
|
Others | AXIN1^ | MMP-10# 4E-BP1$ | DNER*@ | MMP-10# |
Table1: List of immunoproteins differentially abundant (p<0.05) in varying IBD subtypes, grouped by their key common molecular functions. *indicates that the immunoprotein of interest to be less abundant compared to controls. ^AXIN1 functions - Activation of protein kinase (GO:0032147), WNT signaling process (GO:0016055). #MMP-10 function - extracellular matrix organization (GO:0030198). $4E-BP1 function - TOR signaling (GO:0031929). @DNER function - Notch receptor processing (GO:0007220).
Conclusion
Our pilot study in a multi-ethnic Asian population found distinctive serum protein profile in IBD patients. While some protein changes were shared in both UC and CD, other changes were specific for either UC or CD, suggesting different disease pathways in these two IBD subtypes. We reaffirmed that inflammatory proteins, such as EN-RAGE3, MMP-104 and OSM5, were differentially abundant in IBD, consistent with previous reports in predominantly Caucasian cohorts. Further studies with large sample sizes would be required to validate these biomarkers for IBD activity, and prognosis for biologic therapy response.
References
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- Mahida YR. The key role of macrophages in the immunopathogenesis of inflammatory bowel disease. Inflamm Bowel Dis. 2000;6:21–33.
- Foell D, Kucharzik T, Kraft M, et al. Neutrophil derived human S100A12 (EN-RAGE) is strongly expressed during chronic active inflammatory bowel disease. Gut 2003;52:847-853.
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