Abstract

Trans-ethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals shared but also ethnicity-specific disease associations

Hum Mol Genet. 2021 Feb 8;ddab017. doi: 10.1093/hmg/ddab017. Online ahead of print.

Frauke Degenhardt 1, Gabriele Mayr 1, Mareike Wendorff 1, Gabrielle Boucher 2, Eva Ellinghaus 3, David Ellinghaus 1 4, Hesham ElAbd 1, Elisa Rosati 1, Matthias Hübenthal 1 5, Simonas Juzenas 1, Shifteh Abedian 6 7, Homayon Vahedi 7, B K Thelma 8, Suk-Kyun Yang 9, Byong Duk Ye 9, Jae Hee Cheon 10, Lisa Wu Datta 11, Naser Ebrahim Daryani 12, Pierre Ellul 13, Motohiro Esaki 14, Yuta Fuyuno 14 15, Dermot P B McGovern 16, Talin Haritunians 16, Myhunghee Hong 17, Garima Juyal 18, Eun Suk Jung 1 10, Michiaki Kubo 19, Subra Kugathasan 20 21, Tobias L Lenz 22, Stephen Leslie 23, Reza Malekzadeh 7, Vandana Midha 24, Allan Motyer 23, Siew C Ng 25, David T Okou 26, Soumya Raychaudhuri 27 28 29 30 31, John Schembri 13, Stefan Schreiber 1 32, Kyuyoung Song 17, Ajit Sood 24, Atsushi Takahashi 33, Esther A Torres 34, Junji Umeno 14, Behrooz Z Alizadeh 6, Rinse K Weersma 35, Sunny H Wong 25, Keiko Yamazaki 15, Tom H Karlsen 4 36, John D Rioux 2, Steven R Brant 11 37, MAAIS Recruitment Center; Andre Franke 1, International IBD Genetics Consortium

 
     

Author information

  • 1Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
  • 2Université de Montréal and the Montréal Heart Institute, Research Center, Montréal Heart Institute, Montréal, Québec, Canada.
  • 3K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • 4Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
  • 5Department of Dermatology, Venerology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 6Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands.
  • 7Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
  • 8Department of Genetics, University of Delhi South Campus, New Delhi, India.
  • 9Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 10Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
  • 11Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, John Hopkins University School of Medicine, Baltimore, USA.
  • 12Department of Gastroenterology, Emam Hospital, Tehran University of Medical Sciences, Tehran, Iran.
  • 13Department of Gastroenterology, Mater Dei Hospital, Msida, Malta.
  • 14Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 15Laboratory for Genotyping Development, Center for Integrative Medical Sciences, Riken, Yokohama, Japan.
  • 16F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • 17Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
  • 18School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
  • 19RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 20Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 21Pediatric Institute, Children's Healthcare of Atlanta, Atlanta, USA.
  • 22Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön, Germany.
  • 23Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, Australia.
  • 24Dayanand Medical College and Hospital, Ludhiana, India.
  • 25Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong.
  • 26Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, USA.
  • 27Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 28Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 29Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
  • 30Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
  • 31Centre for Genetics and Genomics Versus Arthritis, Division of Muscolosceletal and Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
  • 32Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • 33Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, Riken, Yokohama, Japan.
  • 34Department of Medicine, University of Puerto Rico Center for IBD, University of Puerto Rico School of Medicine, Rio Piedras, Puerto Rico.
  • 35Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • 36Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway.
  • 37Department of Medicine, Rutgers Robert Wood Johnson School of Medicine and Department of Genetics, Rutgers University Brunswick and Piscataway, New Jersey, USA.

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD, and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such a delineation could not be made due to tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a trans-ethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analysed the physico-chemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids such. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

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