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

• DOI: 10.1038/ng.3786
• Publication Date: 2017-02-06T17:55:47Z
• Authors: Masaki Takeuchi; Nobuhisa Mizuki; Akira Meguro; Michael J Ombrello; Yohei Kirino; Colleen Satorius; Julie Le; Mary Blake; Burak Erer; Tatsukata Kawagoe; Duran Ustek; Ilknur Tugal-Tutkun; Emire Seyahi; Yilmaz Ozyazgan; Inês Sousa; Fereydoun Davatchi; Vânia Francisco; Farhad Shahram; Bahar Sadeghi Abd...; Abdolhadi Nadji; Niloofar Mojarad ...; Fahmida Ghaderibarmi; Shigeaki Ohno; Atsuhisa Ueda; Yoshiaki Ishigatsubo; Massimo Gadina; Sofia A Oliveira; Ahmet Gül; Daniel L Kastner; Elaine F Remmers
• Keywords: Adult; Male; 0303 health sciences; Genotype; Turkey; Behcet Syndrome; Iran; Polymorphism, Single Nucleotide; Article; 3. Good health; 03 medical and health sciences; Genetic Loci; Case-Control Studies; Humans; Female; Genetic Predisposition to Disease; Alleles; Genome-Wide Association Study

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