The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease

Arno R. Bourgonje, Shixian Hu, Lieke M. Spekhorst, Daria V. Zhernakova, Arnau Vich Vila, Yanni Li, Michiel D. Voskuil, Lisette A. van Berkel, Brenda Bley Folly, Mohammed Charrout, Ahmed Mahfouz, Marcel J T Reinders, Julia I. P. van Heck, Leo A. B. Joosten, Marijn C. Visschedijk, Hendrik M. van Dullemen, Klaas Nico Faber, Janneke N. Samsom, Noortje Festen, Gerard DijkstraRinse K. Weersma*

*Corresponding author for this work

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Abstract

Background and Aims
Protein profiling in patients with inflammatory bowel diseases (IBD) for diagnostic and therapeutic purposes is underexplored in IBD. This study analysed the association between phenotype, genotype and the plasma proteome in IBD.
Methods
Ninety-two (92) inflammation-related proteins were quantified in plasma of 1,028 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 fecal metagenomic data were used for complementary analyses.
Results
Thirty-two (32) proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins independent of active inflammation. Sixty-nine (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 fecal 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.
Original languageEnglish
JournalJournal of Crohn's and Colitis
DOIs
Publication statusAccepted/In press - 7-Sep-2021

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