Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1

Nat Genet. 2013 Feb;45(2):202-7. doi: 10.1038/ng.2520. Epub 2013 Jan 6.


Individuals with Behçet's disease suffer from episodic inflammation often affecting the orogenital mucosa, skin and eyes. To discover new susceptibility loci for Behçet's disease, we performed a genome-wide association study (GWAS) of 779,465 SNPs with imputed genotypes in 1,209 Turkish individuals with Behçet's disease and 1,278 controls. We identified new associations at CCR1, STAT4 and KLRC4. Additionally, two SNPs in ERAP1, encoding ERAP1 p.Asp575Asn and p.Arg725Gln alterations, recessively conferred disease risk. These findings were replicated in 1,468 independent Turkish and/or 1,352 Japanese samples (combined meta-analysis P < 2 × 10(-9)). We also found evidence for interaction between HLA-B*51 and ERAP1 (P = 9 × 10(-4)). The CCR1 and STAT4 variants were associated with gene expression differences. Three risk loci shared with ankylosing spondylitis and psoriasis (the MHC class I region, ERAP1 and IL23R and the MHC class I-ERAP1 interaction), as well as two loci shared with inflammatory bowel disease (IL23R and IL10) implicate shared pathogenic pathways in the spondyloarthritides and Behçet's disease.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / genetics*
  • Analysis of Variance
  • Behcet Syndrome / genetics*
  • Epistasis, Genetic / genetics*
  • Gene Expression Regulation / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Genotype
  • HLA-B51 Antigen / genetics*
  • Humans
  • Japan
  • Minor Histocompatibility Antigens
  • NK Cell Lectin-Like Receptor Subfamily C / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, CCR1 / genetics
  • STAT4 Transcription Factor / genetics
  • Statistics, Nonparametric
  • Turkey


  • CCR1 protein, human
  • HLA-B51 Antigen
  • KLRC4 protein, human
  • Minor Histocompatibility Antigens
  • NK Cell Lectin-Like Receptor Subfamily C
  • Receptors, CCR1
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • Aminopeptidases
  • ERAP1 protein, human