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.