PMID- 33555323
OWN - NLM
STAT- MEDLINE
DCOM- 20211125
LR  - 20211204
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 30
IP  - 5
DP  - 2021 Apr 27
TI  - Transethnic analysis of the human leukocyte antigen region for ulcerative colitis 
      reveals not only shared but also ethnicity-specific disease associations.
PG  - 356-369
LID - 10.1093/hmg/ddab017 [doi]
AB  - 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 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-DRB1*15 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 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. 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.
CI  - (c) The Author(s) 2021. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Degenhardt, Frauke
AU  - Degenhardt F
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
FAU - Mayr, Gabriele
AU  - Mayr G
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
FAU - Wendorff, Mareike
AU  - Wendorff M
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
FAU - Boucher, Gabrielle
AU  - Boucher G
AD  - Research Center, Montreal Heart Institute, Universite de Montreal and the 
      Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada.
FAU - Ellinghaus, Eva
AU  - Ellinghaus E
AD  - K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, 
      University of Oslo, 0372 Oslo, Norway.
FAU - Ellinghaus, David
AU  - Ellinghaus D
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
AD  - Norwegian PSC Research Center, Department of Transplantation Medicine, Division 
      of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital 
      Rikshospitalet, 0372 Oslo, Norway.
FAU - ElAbd, Hesham
AU  - ElAbd H
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
FAU - Rosati, Elisa
AU  - Rosati E
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
FAU - Hubenthal, Matthias
AU  - Hubenthal M
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
AD  - Department of Dermatology, Venerology and Allergy, University Hospital 
      Schleswig-Holstein, 24105 Kiel, Germany.
FAU - Juzenas, Simonas
AU  - Juzenas S
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
FAU - Abedian, Shifteh
AU  - Abedian S
AD  - Department of Epidemiology, University Medical Center Groningen, 9713 Groningen, 
      The Netherlands.
AD  - Digestive Disease Research Center, Digestive Disease Research Institute, Tehran 
      University of Medical Sciences, Tehran 1411713135, Iran.
FAU - Vahedi, Homayon
AU  - Vahedi H
AD  - Digestive Disease Research Center, Digestive Disease Research Institute, Tehran 
      University of Medical Sciences, Tehran 1411713135, Iran.
FAU - Thelma, B K
AU  - Thelma BK
AD  - Department of Genetics, University of Delhi South Campus, New Delhi, Delhi 
      110021, India.
FAU - Yang, Suk-Kyun
AU  - Yang SK
AD  - Department of Gastroenterology, Asan Medical Center, University of Ulsan College 
      of Medicine, Seoul 05505, Republic of Korea.
FAU - Ye, Byong Duk
AU  - Ye BD
AD  - Department of Gastroenterology, Asan Medical Center, University of Ulsan College 
      of Medicine, Seoul 05505, Republic of Korea.
FAU - Cheon, Jae Hee
AU  - Cheon JH
AD  - Department of Internal Medicine and Institute of Gastroenterology, Yonsei 
      University College of Medicine, Seoul 03722, Republic of Korea.
FAU - Datta, Lisa Wu
AU  - Datta LW
AD  - Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of 
      Medicine, John Hopkins University School of Medicine, Baltimore, MD 21205, USA.
FAU - Daryani, Naser Ebrahim
AU  - Daryani NE
AD  - Department of Gastroenterology, Emam Hospital, Tehran University of Medical 
      Sciences, Tehran 1419733141, Iran.
FAU - Ellul, Pierre
AU  - Ellul P
AD  - Department of Gastroenterology, Mater Dei Hospital, Msida, Malta.
FAU - Esaki, Motohiro
AU  - Esaki M
AD  - Department of Medicine and Clinical Science, Graduate School of Medical Sciences, 
      Kyushu University, Fukuoka 812-8582, Japan.
FAU - Fuyuno, Yuta
AU  - Fuyuno Y
AD  - Department of Medicine and Clinical Science, Graduate School of Medical Sciences, 
      Kyushu University, Fukuoka 812-8582, Japan.
AD  - Laboratory for Genotyping Development, Center for Integrative Medical Sciences, 
      Riken, Yokohama 351-0198, Japan.
FAU - McGovern, Dermot P B
AU  - McGovern DPB
AD  - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, 
      Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
FAU - Haritunians, Talin
AU  - Haritunians T
AD  - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, 
      Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
FAU - Hong, Myhunghee
AU  - Hong M
AD  - Department of Biochemistry and Molecular Biology, University of Ulsan College of 
      Medicine, Seoul, 136-701 Korea.
FAU - Juyal, Garima
AU  - Juyal G
AD  - School of Biotechnology, Jawaharlal Nehru University, New Delhi, Delhi 110067, 
      India.
FAU - Jung, Eun Suk
AU  - Jung ES
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
AD  - Department of Internal Medicine and Institute of Gastroenterology, Yonsei 
      University College of Medicine, Seoul 03722, Republic of Korea.
FAU - Kubo, Michiaki
AU  - Kubo M
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, 351-0198, Japan.
FAU - Kugathasan, Subra
AU  - Kugathasan S
AD  - Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, 
      USA.
AD  - Pediatric Institute, Children's Healthcare of Atlanta, Atlanta, GA, USA.
FAU - Lenz, Tobias L
AU  - Lenz TL
AD  - Research Group for Evolutionary Immunogenomics, Max Planck Institute for 
      Evolutionary Biology, 24306 Plon, Germany.
FAU - Leslie, Stephen
AU  - Leslie S
AD  - Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative 
      Genomics, University of Melbourne, Victoria 3010, Australia.
FAU - Malekzadeh, Reza
AU  - Malekzadeh R
AD  - Digestive Disease Research Center, Digestive Disease Research Institute, Tehran 
      University of Medical Sciences, Tehran 1411713135, Iran.
FAU - Midha, Vandana
AU  - Midha V
AD  - Dayanand Medical College and Hospital, Ludhiana, Punjab 141001, India.
FAU - Motyer, Allan
AU  - Motyer A
AD  - Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative 
      Genomics, University of Melbourne, Victoria 3010, Australia.
FAU - Ng, Siew C
AU  - Ng SC
AD  - Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese 
      University of Hong Kong, Hong Kong.
FAU - Okou, David T
AU  - Okou DT
AD  - Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, 
      Emory University School of Medicine, Atlanta, GA 30322, USA.
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
AD  - Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA 02114, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA 02114, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, 
      USA.
AD  - Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 
      USA.
AD  - Centre for Genetics and Genomics Versus Arthritis, Division of Musculosceletal 
      and Dermatological Sciences, School of Biological Sciences, University of 
      Manchester, Manchester, UK.
FAU - Schembri, John
AU  - Schembri J
AD  - Department of Gastroenterology, Mater Dei Hospital, Msida, Malta.
FAU - Schreiber, Stefan
AU  - Schreiber S
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
AD  - Department of Medicine, Christian-Albrechts-University, 24105 Kiel, Germany.
FAU - Song, Kyuyoung
AU  - Song K
AD  - Department of Biochemistry and Molecular Biology, University of Ulsan College of 
      Medicine, Seoul, 136-701 Korea.
FAU - Sood, Ajit
AU  - Sood A
AD  - Dayanand Medical College and Hospital, Ludhiana, Punjab 141001, India.
FAU - Takahashi, Atsushi
AU  - Takahashi A
AD  - Laboratory for Statistical and Translational Genetics, Center for Integrative 
      Medical Sciences, Riken, Yokohama, 230-0045, Japan.
FAU - Torres, Esther A
AU  - Torres EA
AD  - Department of Medicine, University of Puerto Rico Center for IBD, University of 
      Puerto Rico School of Medicine, Rio Piedras, San Juan, PR 00936-5067, USA.
FAU - Umeno, Junji
AU  - Umeno J
AD  - Department of Medicine and Clinical Science, Graduate School of Medical Sciences, 
      Kyushu University, Fukuoka 812-8582, Japan.
FAU - Alizadeh, Behrooz Z
AU  - Alizadeh BZ
AD  - Department of Epidemiology, University Medical Center Groningen, 9713 Groningen, 
      The Netherlands.
FAU - Weersma, Rinse K
AU  - Weersma RK
AD  - Department of Gastroenterology and Hepatology, University of Groningen and 
      University Medical Center Groningen, 9700 AB Groningen, The Netherlands.
FAU - Wong, Sunny H
AU  - Wong SH
AD  - Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese 
      University of Hong Kong, Hong Kong.
FAU - Yamazaki, Keiko
AU  - Yamazaki K
AD  - Laboratory for Genotyping Development, Center for Integrative Medical Sciences, 
      Riken, Yokohama 351-0198, Japan.
FAU - Karlsen, Tom H
AU  - Karlsen TH
AD  - Norwegian PSC Research Center, Department of Transplantation Medicine, Division 
      of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital 
      Rikshospitalet, 0372 Oslo, Norway.
AD  - Research Institute for Internal Medicine, Division of Surgery, Inflammatory 
      Diseases and Transplantation, Oslo University Hospital Rikshospitalet and 
      University of Oslo, 0372 Oslo, Norway.
FAU - Rioux, John D
AU  - Rioux JD
AD  - Research Center, Montreal Heart Institute, Universite de Montreal and the 
      Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada.
FAU - Brant, Steven R
AU  - Brant SR
AD  - Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of 
      Medicine, John Hopkins University School of Medicine, Baltimore, MD 21205, USA.
AD  - Department of Medicine, Rutgers Robert Wood Johnson School of Medicine and 
      Department of Genetics, Rutgers University Brunswick and Piscataway, NJ 
      08903-0019, USA.
CN  - MAAIS Recruitment Center
FAU - Franke, Andre
AU  - Franke A
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
CN  - International IBD Genetics Consortium
LA  - eng
GR  - U01 DK062413/DK/NIDDK NIH HHS/United States
GR  - U01 DK062431/DK/NIDDK NIH HHS/United States
GR  - U01 DK062432/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (HLA Antigens)
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (Peptides)
SB  - IM
MH  - Alleles
MH  - Cohort Studies
MH  - Colitis, Ulcerative/*genetics
MH  - Ethnicity/*genetics
MH  - Gene Frequency
MH  - Genetic Association Studies
MH  - *Genetic Predisposition to Disease
MH  - Genotype
MH  - HLA Antigens/*genetics
MH  - HLA-DQ Antigens/*genetics
MH  - HLA-DRB1 Chains/*genetics
MH  - Haplotypes
MH  - Humans
MH  - Linkage Disequilibrium
MH  - Peptides/*genetics
MH  - Polymorphism, Single Nucleotide
MH  - Protein Binding
PMC - PMC8098114
EDAT- 2021/02/09 06:00
MHDA- 2021/11/26 06:00
PMCR- 2021/02/08
CRDT- 2021/02/08 12:11
PHST- 2020/07/31 00:00 [received]
PHST- 2020/10/27 00:00 [revised]
PHST- 2020/12/23 00:00 [accepted]
PHST- 2021/02/09 06:00 [pubmed]
PHST- 2021/11/26 06:00 [medline]
PHST- 2021/02/08 12:11 [entrez]
PHST- 2021/02/08 00:00 [pmc-release]
AID - 6101453 [pii]
AID - ddab017 [pii]
AID - 10.1093/hmg/ddab017 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2021 Apr 27;30(5):356-369. doi: 10.1093/hmg/ddab017.