TY - JOUR
T1 - The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease
AU - Bourgonje, Arno R.
AU - Hu, Shixian
AU - Spekhorst, Lieke M.
AU - Zhernakova, Daria V.
AU - Vila, Arnau Vich
AU - Li, Yanni
AU - Voskuil, Michiel D.
AU - van Berkel, Lisette A.
AU - Folly, Brenda Bley
AU - Charrout, Mohammed
AU - Mahfouz, Ahmed
AU - Reinders, Marcel J. T.
AU - van Heck, Julia I. P.
AU - Joosten, Leo A. B.
AU - Visschedijk, Marijn C.
AU - van Dullemen, Hendrik M.
AU - Faber, Klaas Nico
AU - Samsom, Janneke N.
AU - Festen, Eleonora A. M.
AU - Dijkstra, Gerard
AU - Weersma, Rinse K.
N1 - 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).
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
KW - Inflammatory bowel disease
KW - genetics
KW - proteomics
UR - https://www.scopus.com/pages/publications/85127362764
U2 - 10.1093/ecco-jcc/jjab157
DO - 10.1093/ecco-jcc/jjab157
M3 - Article
C2 - 34491321
SN - 1873-9946
VL - 16
SP - 414
EP - 429
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
IS - 3
ER -