Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet’s disease susceptibility

Abstract

We analyzed 1,900 Turkish Behçet’s disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated single nucleotide polymorphism (SNP) was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three novel loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P<5×10(−8)) by direct genotyping, and ADO-EGR2 by imputation. ADO-EGR2, IRF8, and CEBPB-PTPN1 replicated by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls replicated ADO-EGR2 and IRF8 and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker of the IL1A-IL1B locus, was associated with both decreased interleukin-1α and increased interleukin-1β production. ABO non-secretor genotypes of two ancestry-specific FUT2 SNPs showed strong disease association (P=5.89×10(−15)). Our findings extend shared susceptibility genes with Crohn’s disease and leprosy, and implicate mucosal factors and the innate immune response to microbial exposure in Behçet’s disease susceptibility.