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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

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.
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