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


TAKEUCHI M., MIZUKI N., MEGURO A., OMBRELLO M. J. , KIRINO Y., SATORIUS C., ...More

NATURE GENETICS, vol.49, no.3, pp.438-443, 2017 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 49 Issue: 3
  • Publication Date: 2017
  • Doi Number: 10.1038/ng.3786
  • Title of Journal : NATURE GENETICS
  • Page Numbers: pp.438-443

Abstract

We analyzed 1,900 Turkish Behcet'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-IL18, IRF8, and CEBPB-PTPN1, with genomewide significance (P < 5 x 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 R1PK2 and LACC1. The disease associated allele of rs4402765, the lead marker at 11.1A-ILIB, was associated with both decreased IL-1 alpha and increased IL-1 beta production. ABO non-secretor genotypes for two ancestry specific FUT2 SNPs showed strong disease association (P = 5.89 x 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 Behcet's disease susceptibility.