期刊
GASTROENTEROLOGY
卷 159, 期 2, 页码 549-+出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2020.04.063
关键词
Collagenous Colitis; Immunochip; HLA; Crohn's Disease
资金
- Common Fund of the Office of the Director of the National Institutes of Health (NIH)
- National Cancer Institute
- National Human Genome Research Institute
- National Heart, Lung, and Blood Institute
- National Institute of Drug Abuse
- Natioal Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- NIH [DK062429, DK062422]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK110415] Funding Source: NIH RePORTER
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.
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