Author:
Degenhardt Frauke,Mayr Gabriele,Wendorff Mareike,Boucher Gabrielle,Ellinghaus Eva,Ellinghaus David,ElAbd Hesham,Rosati Elisa,Hübenthal Matthias,Juzenas Simonas,Abedian Shifteh,Vahedi Homayon,BK Thelma,Yang Suk-Kyun,Ye Byong Duk,Cheon Jae Hee,Datta Lisa Wu,Daryani Naser Ebrahim,Ellul Pierre,Esaki Motohiro,Fuyuno Yuta,McGovern Dermot PB,Haritunians Talin,Hong Myhunghee,Juyal Garima,Jung Eun Suk,Kubo Michiaki,Kugathasan Subra,Lenz Tobias L.,Leslie Stephen,Malekzadeh Reza,Midha Vandana,Motyer Allan,Ng Siew C,Okou David T,Raychaudhuri Soumya,Schembri John,Schreiber Stefan,Song Kyuyoung,Sood Ajit,Takahashi Atsushi,Torres Esther A,Umeno Junji,Alizadeh Behrooz Z.,Weersma Rinse K,Wong Sunny H,Yamazaki Keiko,Karlsen Tom H,Rioux John D,Brant Steven R,Franke Andre, ,
Abstract
ABSTRACTInflammatory 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 9,272 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 across different ethnicities but also identified population-specific signals. 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.
Publisher
Cold Spring Harbor Laboratory