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Transethnic Analysis of the Human Leukocyte Antigen Region for Ulcerative Colitis Reveals Not Only Shared But Also Ethnicity-Specific Disease Associations Publisher Pubmed



Degenhardt F1 ; Mayr G1 ; Wendorff M1 ; Boucher G2 ; Ellinghaus E3 ; Ellinghaus D1, 4 ; Elabd H1 ; Rosati E1 ; Hubenthal M1, 5 ; Juzenas S1 ; Abedian S6, 7 ; Vahedi H7 ; Thelma BK8 ; Yang SK9 Show All Authors
Authors
  1. Degenhardt F1
  2. Mayr G1
  3. Wendorff M1
  4. Boucher G2
  5. Ellinghaus E3
  6. Ellinghaus D1, 4
  7. Elabd H1
  8. Rosati E1
  9. Hubenthal M1, 5
  10. Juzenas S1
  11. Abedian S6, 7
  12. Vahedi H7
  13. Thelma BK8
  14. Yang SK9
  15. Ye BD9
  16. Cheon JH10
  17. Datta LW11
  18. Daryani NE12
  19. Ellul P13
  20. Esaki M14
  21. Fuyuno Y14, 15
  22. Mcgovern DPB16
  23. Haritunians T16
  24. Hong M17
  25. Juyal G10, 18
  26. Jung ES1, 10
  27. Kubo M19
  28. Kugathasan S20, 21
  29. Lenz TL22
  30. Leslie S23
  31. Malekzadeh R7
  32. Midha V24
  33. Motyer A23
  34. Ng SC25
  35. Okou DT26
  36. Raychaudhuri S27, 28, 29, 30, 31
  37. Schembri J13
  38. Schreiber S1, 32
  39. Song K17
  40. Sood A24
  41. Takahashi A33
  42. Torres EA34
  43. Umeno J14
  44. Alizadeh BZ6
  45. Weersma RK35
  46. Hwong S25
  47. Yamazaki K15
  48. Karlsen TH4, 36
  49. Rioux JD2
  50. Brant SR11, 37
Show Affiliations
Authors Affiliations
  1. 1. Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, 24105, Germany
  2. 2. Research Center, Montreal Heart Institute, Montreal, H1T 1C8, QC, Canada
  3. 3. K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, 0372, Norway
  4. 4. Norwegian Psc Research Center, Division of Surgery, Oslo University Hospital Rikshospitalet, Inflammatory Diseases and Transplantation, Oslo, 0372, Norway
  5. 5. Department of Dermatology, University Hospital Schleswig-Holstein, Venerology and Allergy, Kiel, 24105, Germany
  6. 6. Department of Epidemiology, University Medical Center Groningen, Groningen, 9713, Netherlands
  7. 7. Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, 1411713135, Iran
  8. 8. Department of Genetics, University of Delhi South Campus, New Delhi, Delhi, 110021, India
  9. 9. Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
  10. 10. Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, 03722, South Korea
  11. 11. Department of Medicine, Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, John Hopkins University School of Medicine, Baltimore, 21205, MD, United States
  12. 12. Department of Gastroenterology, Tehran University of Medical Sciences, Emam Hospital, Tehran, 1419733141, Iran
  13. 13. Department of Gastroenterology, Mater Dei Hospital, Msida, Malta
  14. 14. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
  15. 15. Laboratory for Genotyping Development, Center for Integrative Medical Sciences, Riken, Yokohama, 351-0198, Japan
  16. 16. F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA, United States
  17. 17. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 136-701, South Korea
  18. 18. School of Biotechnology, Jawaharlal Nehru University, New Delhi, Delhi, 110067, India
  19. 19. Riken Center for Integrative Medical Sciences, Yokohama, 351-0198, Japan
  20. 20. Department of Pediatrics, Emory University School of Medicine, Atlanta, 30322, GA, United States
  21. 21. Pediatric Institute, Children's Healthcare of Atlanta, Atlanta, GA, United States
  22. 22. Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plon, 24306, Germany
  23. 23. Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, 3010, VIC, Australia
  24. 24. Dayanand Medical College and Hospital, Ludhiana, Punjab, 141001, India
  25. 25. Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong
  26. 26. Department of Pediatrics, Division of Gastroenterology, Emory University School of Medicine, Hepatology and Nutrition, Atlanta, 30322, GA, United States
  27. 27. Center for Data Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, 02114, MA, United States
  28. 28. Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, 02114, MA, United States
  29. 29. Department of Biomedical Informatics, Harvard Medical School, Boston, 02115, MA, United States
  30. 30. Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, United States
  31. 31. Division of Musculosceletal and Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
  32. 32. Department of Medicine, Christian-Albrechts-University, Kiel, 24105, Germany
  33. 33. Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, Riken, Yokohama, 230-0045, Japan
  34. 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, United States
  35. 35. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, 9700 AB, Netherlands
  36. 36. Research Institute for Internal Medicine, Division of Surgery, Oslo University Hospital Rikshospitalet and University of Oslo, Inflammatory Diseases and Transplantation, Oslo, 0372, Norway
  37. 37. Department of Medicine, Rutgers University Brunswick and Piscataway, 08903-0019, NJ, United States

Source: Human Molecular Genetics Published:2021


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 DRB101:03 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-DRB115 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 DRB101:03 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. © 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: Journals.permissions@oup.com.