title: Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1.
abstract: 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.
authors.affiliation: Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kirino
authors.forename: George
authors.initials: G
authors.lastname: Bertsias
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ishigatsubo
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Mizuki
authors.forename: Ilknur
authors.initials: I
authors.lastname: Tugal-Tutkun
authors.forename: Emire
authors.initials: E
authors.lastname: Seyahi
authors.forename: Yilmaz
authors.initials: Y
authors.lastname: Ozyazgan
authors.forename: F Sevgi
authors.initials: FS
authors.lastname: Sacli
authors.forename: Burak
authors.initials: B
authors.lastname: Erer
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.forename: Zeliha
authors.initials: Z
authors.lastname: Emrence
authors.forename: Atilla
authors.initials: A
authors.lastname: Cakar
authors.forename: Neslihan
authors.initials: N
authors.lastname: Abaci
authors.forename: Duran
authors.initials: D
authors.lastname: Ustek
authors.forename: Colleen
authors.initials: C
authors.lastname: Satorius
authors.forename: Atsuhisa
authors.initials: A
authors.lastname: Ueda
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Takeno
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.forename: Geryl M
authors.initials: GM
authors.lastname: Wood
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ombrello
authors.forename: Akira
authors.initials: A
authors.lastname: Meguro
authors.forename: Ahmet
authors.initials: A
authors.lastname: Gül
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
mesh_terms: D000626:Aminopeptidases / Q000235:genetics*; D000704:Analysis of Variance; D001528:Behcet Syndrome / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D059949:HLA-B51 Antigen / Q000235:genetics*; D006801:Humans; D007564:Japan; D015778:Minor Histocompatibility Antigens; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054389:Receptors, CCR1 / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics; D018709:Statistics, Nonparametric; D014421:Turkey
chemical_list: C515300:CCR1 protein, human; D059949:HLA-B51 Antigen; C527066:KLRC4 protein, human; D015778:Minor Histocompatibility Antigens; D055654:NK Cell Lectin-Like Receptor Subfamily C; D054389:Receptors, CCR1; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D000626:Aminopeptidases; C464841:ERAP1 protein, human