PMID- 37977914 OWN - NLM STAT- Publisher LR - 20231117 IS - 1878-3562 (Electronic) IS - 1590-8658 (Linking) DP - 2023 Nov 15 TI - Genome-wide association analysis reveals the associations of NPHP4, TYW1-AUTS2 and SEMA6D for Behcet's disease and HLA-B*46:01 for its intestinal involvement. LID - S1590-8658(23)01010-1 [pii] LID - 10.1016/j.dld.2023.10.021 [doi] AB - BACKGROUND: Intestinal involvement in Behcet's disease (BD) is associated with poor prognosis and is more prevalent in East Asian than in Mediterranean populations. Identifying the genetic causes of intestinal BD is important for understanding the pathogenesis and for appropriate treatment of BD patients. METHODS: We performed genome-wide association studies (GWAS) and imputation/replication genotyping of human leukocyte antigen (HLA) alleles for 1,689 Korean and Turkish patients with BD (including 379 patients with intestinal BD) and 2,327 healthy controls, followed by replication using 593 Japanese patients with BD (101 patients with intestinal BD) and 737 healthy controls. Stratified cross-phenotype analyses were performed for 1) overall BD, 2) intestinal BD, and 3) intestinal BD without association of overall BD. RESULTS: We identified three novel genome-wide significant susceptibility loci including NPHP4 (rs74566205; P=1.36 x 10(-8)), TYW1-AUTS2 (rs60021986; P=1.14 x 10(-9)), and SEMA6D (rs4143322; P=5.54 x 10(-9)) for overall BD, and a new association with HLA-B*46:01 for intestinal BD (P=1.67 x 10(-8)) but not for BD without intestinal involvement. HLA peptide binding analysis revealed that Mycobacterial peptides, have a stronger binding affinity to HLA-B*46:01 compared to the known risk allele HLA-B*51:01. CONCLUSIONS: HLA-B*46:01 is associated with the development of intestinal BD; NPHP4, TYW1-AUTS2, and SEMA6D are susceptibility loci for overall BD. CI - Copyright (c) 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. FAU - Jung, Eun Suk AU - Jung ES AD - Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea; Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. FAU - Ellinghaus, David AU - Ellinghaus D AD - Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. Electronic address: d.ellinghaus@ikmb.uni-kiel.de. FAU - Degenhardt, Frauke AU - Degenhardt F AD - Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. FAU - Meguro, Akira AU - Meguro A AD - Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan. FAU - Khor, Seik-Soon AU - Khor SS AD - Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan. FAU - Mucha, Soren AU - Mucha S AD - Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. FAU - Wendorff, Mareike AU - Wendorff M AD - Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. FAU - Juzenas, Simonas AU - Juzenas S AD - Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany; Institute of Biotechnology, Life Science Centre, Vilnius University, Vilnius, Lithuania. FAU - Mizuki, Nobuhisa AU - Mizuki N AD - Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan. FAU - Tokunaga, Katsushi AU - Tokunaga K AD - Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan. FAU - Kim, Seung Won AU - Kim SW AD - Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea. FAU - Lee, Min Goo AU - Lee MG AD - Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea. FAU - Schreiber, Stefan AU - Schreiber S AD - Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. FAU - Kim, Won Ho AU - Kim WH AD - Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea. FAU - Franke, Andre AU - Franke A AD - Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. FAU - Cheon, Jae Hee AU - Cheon JH AD - Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea. Electronic address: geniushee@yuhs.ac. LA - eng PT - Journal Article DEP - 20231115 PL - Netherlands TA - Dig Liver Dis JT - Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver JID - 100958385 SB - IM OTO - NOTNLM OT - Behcet's disease OT - Genome-wide association study OT - HLA-B*46:01 OT - Intestinal Behcet's disease COIS- Conflicts of interest No potential conflict of interest relevant to this article was reported. EDAT- 2023/11/18 11:42 MHDA- 2023/11/18 11:42 CRDT- 2023/11/17 22:01 PHST- 2023/10/02 00:00 [received] PHST- 2023/10/29 00:00 [revised] PHST- 2023/10/30 00:00 [accepted] PHST- 2023/11/18 11:42 [medline] PHST- 2023/11/18 11:42 [pubmed] PHST- 2023/11/17 22:01 [entrez] AID - S1590-8658(23)01010-1 [pii] AID - 10.1016/j.dld.2023.10.021 [doi] PST - aheadofprint SO - Dig Liver Dis. 2023 Nov 15:S1590-8658(23)01010-1. doi: 10.1016/j.dld.2023.10.021.