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

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

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.

Journal of Crohn's & Colitis, 2022, Vol 16, Issue 3, p414

1873-9946

Academic Journal

10.1093/ecco-jcc/jjab157