Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.
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.
Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.|Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Masaki
M
Takeuchi
Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Nobuhisa
N
Mizuki
Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Akira
A
Meguro
Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Michael J
MJ
Ombrello
Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Yohei
Y
Kirino
Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Colleen
C
Satorius
Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Julie
J
Le
Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Mary
M
Blake
Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Burak
B
Erer
Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Tatsukata
T
Kawagoe
Department of Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey.
Duran
D
Ustek
Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Ilknur
I
Tugal-Tutkun
Department of Internal Medicine, Division of Rheumatology, Cerrahpasş a Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Emire
E
Seyahi
Department of Ophthalmology, Cerrahpaşa Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Yilmaz
Y
Ozyazgan
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.|Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Inês
I
Sousa
Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Fereydoun
F
Davatchi
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.|Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Vânia
V
Francisco
Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Farhad
F
Shahram
Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Bahar Sadeghi
BS
Abdollahi
Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Abdolhadi
A
Nadji
Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Niloofar Mojarad
NM
Shafiee
Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Fahmida
F
Ghaderibarmi
Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Shigeaki
S
Ohno
Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Atsuhisa
A
Ueda
Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Yoshiaki
Y
Ishigatsubo
Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Massimo
M
Gadina
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.|Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Sofia A
SA
Oliveira
Department of Internal Medicine, Division of Rheumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Ahmet
A
Gül
Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Daniel L
DL
Kastner
Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Elaine F
EF
Remmers
D000328:Adult; D000483:Alleles; D001528:Behcet Syndrome / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D007492:Iran; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014421:Turkey