title: A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet's disease in HLA-B*51 carriers.
abstract: BACKGROUND
  Endoplasmic reticulum aminopeptidase-1 (ERAP1) protein is highly polymorphic with numerous missense amino acid variants. We sought to determine the naturally occurring ERAP1 protein allotypes and their contribution to Behçet's disease.
  
  
  METHODS
  Genotypes of all reported missense ERAP1 gene variants with 1000 Genomes Project EUR superpopulation frequency >1% were determined in 1900 Behçet's disease cases and 1779 controls from Turkey. ERAP1 protein allotypes and their contributions to Behçet's disease risk were determined by haplotype identification and disease association analyses.
  
  
  RESULTS
  One ERAP1 protein allotype with five non-ancestral amino acids was recessively associated with disease (p=3.13×10-6, OR 2.55, 95% CI 1.70 to 3.82). The ERAP1 association was absent in individuals who lacked HLA-B*51. Individuals who carry HLA-B*51 and who are also homozygous for the haplotype had an increased disease odds compared with those with neither risk factor (p=4.80×10-20, OR 10.96, 95% CI 5.91 to 20.32).
  
  
  CONCLUSIONS
  The Behçet's disease-associated ERAP1 protein allotype was previously shown to have poor peptide trimming activity. Combined with its requirement for HLA-B*51, these data suggest that a hypoactive ERAP1 allotype contributes to Behçet's disease risk by altering the peptides available for binding to HLA-B*51.
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.|Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ombrello
authors.affiliation: Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kirino
authors.affiliation: Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Burak
authors.initials: B
authors.lastname: Erer
authors.affiliation: Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Ilknur
authors.initials: I
authors.lastname: Tugal-Tutkun
authors.affiliation: Cerrahpaşa Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Emire
authors.initials: E
authors.lastname: Seyahi
authors.affiliation: Cerrahpaşa Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Yilmaz
authors.initials: Y
authors.lastname: Özyazgan
authors.affiliation: Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Norman R
authors.initials: NR
authors.lastname: Watts
authors.affiliation: Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Gül
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000626:Aminopeptidases / Q000235:genetics*; D001528:Behcet Syndrome / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D059949:HLA-B51 Antigen / Q000235:genetics*; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D020125:Mutation, Missense; D012307:Risk Factors; D014421:Turkey; D055815:Young Adult
chemical_list: D059949:HLA-B51 Antigen; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human
keywords: Behcet's disease; Gene Polymorphism; Inflammation