Genome-wide association analysis reveals the associations of NPHP4, TYW1-AUTS2 and SEMA6D for Behçet's disease and HLA-B*46:01 for its intestinal involvement

Eun Suk Jung; David Ellinghaus; Frauke Degenhardt; Akira Meguro; Seik-Soon Khor; Sören Mucha; Mareike Wendorff; Simonas Juzenas; Nobuhisa Mizuki; Katsushi Tokunaga; Seung Won Kim; Min Goo Lee; Stefan Schreiber; Won Ho Kim; Andre Franke; Jae Hee Cheon

doi:10.1016/j.dld.2023.10.021

Genome-wide association analysis reveals the associations of NPHP4, TYW1-AUTS2 and SEMA6D for Behçet's disease and HLA-B*46:01 for its intestinal involvement

Dig Liver Dis. 2023 Nov 15:S1590-8658(23)01010-1. doi: 10.1016/j.dld.2023.10.021. Online ahead of print.

Authors

Affiliations

¹ 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.
² Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. Electronic address: d.ellinghaus@ikmb.uni-kiel.de.
³ Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany.
⁴ Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁵ Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.
⁶ 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.
⁷ Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea.
⁸ Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
⁹ Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea. Electronic address: geniushee@yuhs.ac.

PMID: 37977914
DOI: 10.1016/j.dld.2023.10.021

Abstract

Background: Intestinal involvement in Behçet'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 × 10^-8), TYW1-AUTS2 (rs60021986; P=1.14 × 10^-9), and SEMA6D (rs4143322; P=5.54 × 10^-9) for overall BD, and a new association with HLA-B*46:01 for intestinal BD (P=1.67 × 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.

Keywords: Behçet's disease; Genome-wide association study; HLA-B*46:01; Intestinal Behçet's disease.