Comprehensive association analyses of extraintestinal manifestations in inflammatory bowel disease.
Inflammatory bowel disease
extraintestinal manifestations
genetics
serology
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
27 Feb 2024
27 Feb 2024
Historique:
received:
16
07
2022
revised:
11
02
2024
accepted:
13
02
2024
medline:
16
3
2024
pubmed:
16
3
2024
entrez:
15
3
2024
Statut:
aheadofprint
Résumé
Patients with IBD frequently develop extraintestinal manifestations (EIM) that significantly contribute to morbidity. We assembled the largest multi-cohort dataset to-date to investigate the clinical, serological, and genetic factors associated with EIM complications in IBD. Data were available in 12,083 unrelated European ancestry IBD cases with presence/absence of EIMs (ankylosing spondylitis (AS-SI), primary sclerosing cholangitis (PSC), peripheral arthritis, and skin and ocular manifestations) across four cohorts (Cedars-Sinai Medical Center, NIDDK IBD Genetics Consortium, SHARE Consortium, and RISK cohort). Clinical and serological parameters were analyzed by univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. Most EIMs occurred more commonly in patients with female sex (overall EIM: P=9.0E-05, OR=1.2 [1.1-1.4]), CD (especially colonic disease location; P=9.8E-09, OR=1.7 [1.4-2.0]), and in subjects who required surgery (both CD and UC; P=3.6E-19, OR=1.7 [1.5-1.9]). Smoking increased risk of EIMs except for PSC where there was a 'protective' effect. Multiple serological associations were observed including with PSC (ANCA, ASCA, anti-CBir1) and any EIM (ANCA, ASCA, anti-I2). We identified genome-wide significant associations within MHC (AS-SI P=1.4E-15, OR=2.5 [2.0-3.1]; PSC P=2.7E-10, OR=2.8 [2.0-3.8]; ocular P=2E-08, OR=3.6 [2.3-5.6]; and overall EIM P=8.4E-09, OR=2.2 [1.7-2.9]) and CPEB4 (SKIN P=2.7E-08, OR=1.5 [1.3-1.8]). Genetic associations implicated TNF, JAK-STAT and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. We have identified demographic, clinical and genetic associations with EIMs that reveal underlying mechanisms and implicate novel and existing drug targets: important steps towards more personalized approach to IBD management.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
Patients with IBD frequently develop extraintestinal manifestations (EIM) that significantly contribute to morbidity. We assembled the largest multi-cohort dataset to-date to investigate the clinical, serological, and genetic factors associated with EIM complications in IBD.
METHODS
METHODS
Data were available in 12,083 unrelated European ancestry IBD cases with presence/absence of EIMs (ankylosing spondylitis (AS-SI), primary sclerosing cholangitis (PSC), peripheral arthritis, and skin and ocular manifestations) across four cohorts (Cedars-Sinai Medical Center, NIDDK IBD Genetics Consortium, SHARE Consortium, and RISK cohort). Clinical and serological parameters were analyzed by univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations.
RESULTS
RESULTS
Most EIMs occurred more commonly in patients with female sex (overall EIM: P=9.0E-05, OR=1.2 [1.1-1.4]), CD (especially colonic disease location; P=9.8E-09, OR=1.7 [1.4-2.0]), and in subjects who required surgery (both CD and UC; P=3.6E-19, OR=1.7 [1.5-1.9]). Smoking increased risk of EIMs except for PSC where there was a 'protective' effect. Multiple serological associations were observed including with PSC (ANCA, ASCA, anti-CBir1) and any EIM (ANCA, ASCA, anti-I2). We identified genome-wide significant associations within MHC (AS-SI P=1.4E-15, OR=2.5 [2.0-3.1]; PSC P=2.7E-10, OR=2.8 [2.0-3.8]; ocular P=2E-08, OR=3.6 [2.3-5.6]; and overall EIM P=8.4E-09, OR=2.2 [1.7-2.9]) and CPEB4 (SKIN P=2.7E-08, OR=1.5 [1.3-1.8]). Genetic associations implicated TNF, JAK-STAT and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated.
CONCLUSION
CONCLUSIONS
We have identified demographic, clinical and genetic associations with EIMs that reveal underlying mechanisms and implicate novel and existing drug targets: important steps towards more personalized approach to IBD management.
Identifiants
pubmed: 38490347
pii: S0016-5085(24)00232-4
doi: 10.1053/j.gastro.2024.02.026
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.