Trans-ethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals 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, Andre Franke
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Human molecular genetics
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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.