The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease
Selected publication · Journal of Crohn's and Colitis, 2021
Bourgonje A., Hu S., Spekhorst L., Zhernakova D., Vich Vila A., Li Y., Voskuil M., van Berkel L., Bley Folly B., Charrout M., Mahfouz A., Reinders M., van Heck J., Joosten L., Visschedijk M., van Dullemen H., Faber K., Samsom J., Festen E., Dijkstra G., Weersma R.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Pathophysiology | Plasma |  Olink Target 96 |
Editor's note
This was the largest proteogenomic study on Inflammatory Bowel Disease (IBD) ever undertaken at the time of its publication, with 92 inflammatory proteins measured in almost 1,200 IBD patients and healthy controls using the Olink Target 96 Inflammation panel. Multiple IBD-associated biomarkers were identified and several key proteins remained elevated in patients in clinical remission. Other proteins were differentially expressed in IBD patients who underwent surgery, mirroring changes in the gut microbiome.
Combining the protein data with GWAS identified multiple gene variants associated with differential expression of IBD-associated proteins, confirming some previous findings and identifying several entirely novel protein quantitative trait loci (pQTLs). The authors concluded, “This study highlights many associations between genotype, phenotype, and circulating proteins that are known to modulate a variety of inflammatory pathways in the context of IBD. These, in turn, may provide a foundation for future mechanistic research that is required to disentangle the relevant pathophysiological pathway”.
Abstract
Background and Aims
Protein profiling in patients with inflammatory bowel diseases [IBD] for diagnostic and therapeutic purposes is underexplored. This study analysed the association between phenotype, genotype, and the plasma proteome in IBD.
Methods
A total of 92 inflammation-related proteins were quantified in plasma of 1028 patients with IBD (567 Crohn’s disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations. Corresponding whole-exome sequencing and global screening array data of 919 patients with IBD were included to analyse the effect of genetics on protein levels (protein quantitative trait loci [pQTL] analysis). Intestinal mucosal RNA sequencing and faecal metagenomic data were used for complementary analyses.
Results
Thirty-two proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins were independent of active inflammation; 69 proteins were associated with 15 demographic and clinical factors. Fibroblast growth factor-19 levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen novel cis-pQTLs were identified and 10 replicated from previous studies. One trans-pQTL of the fucosyltransferase 2 [FUT2] gene [rs602662] and two independent cis-pQTLs of C-C motif chemokine 25 [CCL25] affected plasma CCL25 levels. Intestinal gene expression data revealed an overlapping cis-expression [e]QTL-variant [rs3745387] of the CCL25 gene. The FUT2 rs602662 trans-pQTL was associated with reduced abundances of faecal butyrate-producing bacteria.
Conclusions
This study shows that genotype and multiple disease phenotypes strongly associate with the plasma inflammatory proteome in IBD, and identifies disease-associated pathways that may help to improve disease management in the future.