Genome-wide association analysis reveals the associations of NPHP4, TYW1-AUTS2 and SEMA6D for Behçet's disease and HLA-B46:01 for its intestinal involvement

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. 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. 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. HLA-B*46:01 is associated with the development of intestinal BD; NPHP4, TYW1–AUTS2, and SEMA6D are susceptibility loci for overall BD.