Eli Stahl1, Giulia Roda2, Amanda Dobbyn1, Jianzhong Hu1, Zhongyang Zhang1, Helga Westerlind3, Ferdinando Bonfiglio3, Towfique Raj4, Joana Torres5, Anli Chen6, Robert Petras7, Darrell S Pardi8, Alina C Iuga9, Gabriel S Levi6, Wenqing Cao10, Prantesh Jain11, Florian Rieder12, Ilyssa O Gordon12, Judy H Cho1, Mauro D'Amato13, Noam Harpaz6, Ke Hao1, Jean Frederic Colombel14, Inga Peter1. 1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. 2. Inflammatory Bowel Diseases Center, Humanitas Research Hospital, Milan, Italy. 3. Department of Medicine, Karolinska Institutet, Stockholm, Sweden. 4. Ronald M. Loeb Center for Alzheimer's Disease, Departments of Neuroscience, and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. 5. Department of Gastroenterology, Hospital Beatriz Angelo, Loures, Portugal. 6. Department of Pathology, Icahn School of Medicine, New York, New York. 7. AmeriPath Institute of Gastrointestinal Pathology and Digestive Disease, Cleveland, Ohio. 8. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. 9. Department of Biology and Cell Pathology, Columbia University, New York, New York. 10. Division of Anatomic Pathology, New York University Langone Medical Center, New York, New York. 11. Department of Hematology and Oncology, University Hospitals, Case Comprehensive Cancer Center, Cleveland, Ohio. 12. Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio. 13. Department of Medicine, Karolinska Institutet, Stockholm, Sweden; School of Biological Sciences, Monash University, Clayton, Victoria, Australia. 14. The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: jean-frederic.colombel@mssm.edu.
Abstract
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.
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.
Authors: B P M Verhaegh; F de Vries; A A M Masclee; A Keshavarzian; A de Boer; P C Souverein; M J Pierik; D M A E Jonkers Journal: Aliment Pharmacol Ther Date: 2016-03-09 Impact factor: 8.171
Authors: Hamed Khalili; Kristin E Burke; Bjorn Roelstraete; Michael C Sachs; Ola Olén; Jonas F Ludvigsson Journal: Gastroenterology Date: 2020-01-08 Impact factor: 22.682
Authors: Sang-Hoon Kim; Carlos Henrique Serezani; Katsuhide Okunishi; Zbigniew Zaslona; David M Aronoff; Marc Peters-Golden Journal: J Biol Chem Date: 2011-01-19 Impact factor: 5.157
Authors: Kristin E Burke; Ashwin N Ananthakrishnan; Paul Lochhead; Po-Hong Liu; Ola Olen; Jonas F Ludvigsson; James M Richter; Shelley S Tworoger; Andrew T Chan; Hamed Khalili Journal: Gastroenterology Date: 2018-08-23 Impact factor: 22.682
Authors: Hamed Khalili; Jordan E Axelrad; Bjorn Roelstraete; Ola Olén; Mauro D'Amato; Jonas F Ludvigsson Journal: Gastroenterology Date: 2021-01-06 Impact factor: 22.682