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, Eleonora A.M. Festen, Gerard DijkstraRinse K. Weersma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)414-429
Number of pages16
JournalJournal of Crohn's and Colitis
Issue number3
Publication statusPublished - 1 Mar 2022

Bibliographical note

Funding Information:
This work was supported by the collaborative T cell-driven Immune Mediated Inflammatory Diseases [TIMID] project [LSHM18057-SGF] financed by the PPP allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen [SGF] to stimulate public-private partnerships and co-financing by health foundations that are part of the SGF. This work was further supported by Takeda [no grant number, to LMS], a VENI grant from Nederlandse Organisatie voor Wetenschappelijk Onderzoek [NWO] [grant no. 194.006, to DVZ], and the Junior Scientific Masterclass [JSM] of the University of Groningen [grant no. 17-57, to ARB].

Publisher Copyright: © 2021 The Author(s).


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