Collagenous Colitis Is Associated With HLA Signature and Shares Genetic Risks With Other Immune-Mediated Diseases.
Alleles
Case-Control Studies
Celiac Disease
/ genetics
Cohort Studies
Colitis, Collagenous
/ genetics
Colitis, Ulcerative
/ genetics
Colon
/ pathology
Crohn Disease
/ genetics
Datasets as Topic
Genetic Association Studies
Genetic Predisposition to Disease
HLA Antigens
/ genetics
Humans
Multifactorial Inheritance
/ immunology
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Risk Factors
Tissue Array Analysis
Collagenous Colitis
Crohn’s Disease
HLA
Immunochip
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
20
06
2019
revised:
17
04
2020
accepted:
27
04
2020
pubmed:
7
5
2020
medline:
7
4
2021
entrez:
7
5
2020
Statut:
ppublish
Résumé
Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease. DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells. Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.
Sections du résumé
BACKGROUND & AIMS
Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease.
METHODS
DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells.
RESULTS
Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases.
CONCLUSIONS
In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.
Identifiants
pubmed: 32371109
pii: S0016-5085(20)30584-9
doi: 10.1053/j.gastro.2020.04.063
pmc: PMC7483815
mid: NIHMS1589987
pii:
doi:
Substances chimiques
HLA Antigens
0
Types de publication
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
549-561.e8Subventions
Organisme : NIDDK NIH HHS
ID : U24 DK062429
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062429
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062422
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK110415
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK123233
Pays : United States
Informations de copyright
Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
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