Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations

Frauke Degenhardt; Gabriele Mayr; Mareike Wendorff; Gabrielle Boucher; Eva Ellinghaus; David Ellinghaus; Hesham ElAbd; Elisa Rosati; Matthias Hübenthal; Simonas Juzenas; Shifteh Abedian; Homayon Vahedi; B K Thelma; Suk-Kyun Yang; Byong Duk Ye; Jae Hee Cheon; Lisa Wu Datta; Naser Ebrahim Daryani; Pierre Ellul; Motohiro Esaki; Yuta Fuyuno; Dermot P B McGovern; Talin Haritunians; Myhunghee Hong; Garima Juyal; Eun Suk Jung; Michiaki Kubo; Subra Kugathasan; Tobias L Lenz; Stephen Leslie; Reza Malekzadeh; Vandana Midha; Allan Motyer; Siew C Ng; David T Okou; Soumya Raychaudhuri; John Schembri; Stefan Schreiber; Kyuyoung Song; Ajit Sood; Atsushi Takahashi; Esther A Torres; Junji Umeno; Behrooz Z Alizadeh; Rinse K Weersma; Sunny H Wong; Keiko Yamazaki; Tom H Karlsen; John D Rioux; Steven R Brant; MAAIS Recruitment Center; Andre Franke; International IBD Genetics Consortium

doi:10.1093/hmg/ddab017

Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations

Hum Mol Genet. 2021 Apr 27;30(5):356-369. doi: 10.1093/hmg/ddab017.

Authors

Frauke Degenhardt¹, Gabriele Mayr¹, Mareike Wendorff¹, Gabrielle Boucher², Eva Ellinghaus³, David Ellinghaus^{1

4}, Hesham ElAbd¹, Elisa Rosati¹, Matthias Hübenthal^{1

5}, Simonas Juzenas¹, Shifteh Abedian^{6

7}, Homayon Vahedi⁷, B K Thelma⁸, Suk-Kyun Yang⁹, Byong Duk Ye⁹, Jae Hee Cheon¹⁰, Lisa Wu Datta¹¹, Naser Ebrahim Daryani¹², Pierre Ellul¹³, Motohiro Esaki¹⁴, Yuta Fuyuno^{14

15}, Dermot P B McGovern¹⁶, Talin Haritunians¹⁶, Myhunghee Hong¹⁷, Garima Juyal¹⁸, Eun Suk Jung^{1

10}, Michiaki Kubo¹⁹, Subra Kugathasan^{20

21}, Tobias L Lenz²², Stephen Leslie²³, Reza Malekzadeh⁷, Vandana Midha²⁴, Allan Motyer²³, Siew C Ng²⁵, David T Okou²⁶, Soumya Raychaudhuri^{27

28

29

30

31}, John Schembri¹³, Stefan Schreiber^{1

32}, Kyuyoung Song¹⁷, Ajit Sood²⁴, Atsushi Takahashi³³, Esther A Torres³⁴, Junji Umeno¹⁴, Behrooz Z Alizadeh⁶, Rinse K Weersma³⁵, Sunny H Wong²⁵, Keiko Yamazaki¹⁵, Tom H Karlsen^{4

36}, John D Rioux², Steven R Brant^{11

37}; MAAIS Recruitment Center; Andre Franke¹; International IBD Genetics Consortium

Affiliations

¹ Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.
² Research Center, Montréal Heart Institute, Université de Montréal and the Montréal Heart Institute, Montréal, Québec H1T 1C8, Canada.
³ K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway.
⁴ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway.
⁵ Department of Dermatology, Venerology and Allergy, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
⁶ Department of Epidemiology, University Medical Center Groningen, 9713 Groningen, The Netherlands.
⁷ Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran.
⁸ Department of Genetics, University of Delhi South Campus, New Delhi, Delhi 110021, India.
⁹ Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
¹⁰ Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
¹¹ Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, John Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹² Department of Gastroenterology, Emam Hospital, Tehran University of Medical Sciences, Tehran 1419733141, Iran.
¹³ Department of Gastroenterology, Mater Dei Hospital, Msida, Malta.
¹⁴ Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
¹⁵ Laboratory for Genotyping Development, Center for Integrative Medical Sciences, Riken, Yokohama 351-0198, Japan.
¹⁶ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁷ Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 136-701 Korea.
¹⁸ School of Biotechnology, Jawaharlal Nehru University, New Delhi, Delhi 110067, India.
¹⁹ RIKEN Center for Integrative Medical Sciences, Yokohama, 351-0198, Japan.
²⁰ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
²¹ Pediatric Institute, Children's Healthcare of Atlanta, Atlanta, GA, USA.
²² Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany.
²³ Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, Victoria 3010, Australia.
²⁴ Dayanand Medical College and Hospital, Ludhiana, Punjab 141001, India.
²⁵ Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong.
²⁶ Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
²⁷ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.
²⁸ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.
²⁹ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
³⁰ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
³¹ Centre for Genetics and Genomics Versus Arthritis, Division of Musculosceletal and Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
³² Department of Medicine, Christian-Albrechts-University, 24105 Kiel, Germany.
³³ Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, Riken, Yokohama, 230-0045, Japan.
³⁴ Department of Medicine, University of Puerto Rico Center for IBD, University of Puerto Rico School of Medicine, Rio Piedras, San Juan, PR 00936-5067, USA.
³⁵ Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9700 AB Groningen, The Netherlands.
³⁶ Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo, 0372 Oslo, Norway.
³⁷ Department of Medicine, Rutgers Robert Wood Johnson School of Medicine and Department of Genetics, Rutgers University Brunswick and Piscataway, NJ 08903-0019, 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 as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic 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 analyzed the physicochemical 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 not only 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. 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Cohort Studies
Colitis, Ulcerative / genetics*
Ethnicity / genetics*
Gene Frequency
Genetic Association Studies
Genetic Predisposition to Disease*
Genotype
HLA Antigens / genetics*
HLA-DQ Antigens / genetics*
HLA-DRB1 Chains / genetics*
Haplotypes
Humans
Linkage Disequilibrium
Peptides / genetics*
Polymorphism, Single Nucleotide
Protein Binding

Substances

HLA Antigens
HLA-DQ Antigens
HLA-DRB1 Chains
Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding