Trans-ethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals shared but also ethnicity-specific disease associations

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 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project received infrastructure support from the DFG Excellence Cluster No. 306 "Inflammation at Interfaces". M.W. and H.E. are supported by the German Research Foundation (DFG) through the Research Training Group 1743, "Genes, Environment and Inflammation". E.E. received funding from the European Union Seventh Framework Program (FP7-PEOPLE-2013-COFUND; grant agreement No. 609020 (Scientia Fellows)). S.A. is supported by joint funding from the University Medical Center Groningen, Groningen, The Netherlands, and Institute for Digestive System Disease, Tehran University of Medical Sciences, Tehran, Iran. Funding for the Multicenter African American IBD Study (MAAIS) samples, for the GENESIS samples, and for the African Americans recruited by Cedars Sinai was provided by the U.S.A. National Institutes of Health (NIH) grants DK062431 (S.R.B.), DK 087694 (S.K.), and DK062413 (D.P.B.M), respectively. This work was supported by a grant from the BioBank Japan Project and, in part, by a Grant-in-Aid for Scientific Research (B) (26293180) funded by the Ministry of Education, Culture, Sports, Science, and Technology, Japan. This research was supported by a Mid-career Researcher Program grant through the National Research Foundation of Korea to K.S. (2017R1A2A1A05001119), funded by the Ministry of Science, Information & Communication Technology and Future Planning, and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (grant number: HI18C0094), Republic of Korea. Funding for the Indian samples was provided by the Centre of Excellence in Genome Sciences and Predictive Medicine (Grant # BT/01/COE/07/UDSC/2008) from the Department of Biotechnology, Government of India). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The recruitment of study subjects was approved by the ethics committees or institutional review boards of all individual participating centers or countries. Written informed consent was obtained from all study participants. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The ImmunoChip data used in this study are proprietary to the IIBGDC genetics consortium and may be requested from the consortium. Any data produced within this study, may be requested from the corresponding authors upon reasonable request including association statistics of imputed and genotyped SNVs. * (A) : Alpha chain of an HLA protein (B) : Beta chain of an HLA protein AA : African American population of this study AFR : African American population of the 1000 Genomes/HapMap population see also ) AMR : Admixed American population of the 1000 Genomes/HapMap population (see also ) AF : Allele Frequency CEU : Utah Residents (CEPH) with Northern and Western European Ancestry of the 1000 Genomes/HapMap population (see also ) CI : Confidence Interval EAS : East Asian population of the 1000 Genomes/HapMap population (see also ) EUR : Caucasian population of this population or (mentioned within the context of the 1000Genomes/HapMap population European data of the latter; see also ) F1, F3 : Atchley Factors 1 and 3, that contain information on 54 amino acid properties HLA : Human Leukocyte Antigen HLA- A : Human Leukocyte Antigen gene locus A HLA- B : Human Leukocyte Antigen gene locus B HLA- C : Human Leukocyte Antigen gene locus C HLA- DRA : Human Leukocyte Antigen gene locus DRA HLA- DRB1 : Human Leukocyte Antigen gene locus DRB1 HLA- DRB3 : Human Leukocyte Antigen gene locus DRB3 HLA- DRB4 : Human Leukocyte Antigen gene locus DRB4 HLA- DRB5 : Human Leukocyte Antigen gene locus DRB5 HLA- DQA1 : Human Leukocyte Antigen gene locus DQA1 HLA- DQB1 : Human Leukocyte Antigen gene locus DQB1 HLA- DPA1 : Human Leukocyte Antigen gene locus DPA1 HLA- DPB1 : Human Leukozyten Antigen gene locus DPB1 IND : Indian population IRN : Iranian population JPN : Japanese population KOR : Korean population MAF : Minor Allele Frequency MLE : Maximum Likelihood Estimator MLT : Maltese population PRI : Puerto Rican population P1-P9 : Pockets 1 to 9 of the HLA protein within the HLA peptide binding site QC : Quality Control SAS : South Asian population of the 1000 Genomes/HapMap population (see also ) SNP : Single Nucleotide Polymorphism (MAF >= 1%) SNV : Single Nucleotide Variation (MAF < 1%) xHLA : extended HLA region YRI : Yoruba in Ibadan, Nigeria population of the 1000 Genomes/HapMap population (see also )