title: Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity.
abstract: The HLA protein, HLA-B*51, encoded by HLA-B in MHC, is the strongest known genetic risk factor for Behçet disease (BD). Associations between BD and other factors within the MHC have been reported also, although strong regional linkage disequilibrium complicates their confident disentanglement from HLA-B*51. In the current study, we examined a combination of directly obtained and imputed MHC-region SNPs, directly obtained HLA-B locus types, and imputed classical HLA types with their corresponding polymorphic amino acid residues for association with BD in 1,190 cases and 1,257 controls. SNP mapping with logistic regression of the MHC identified the HLA-B/MICA region and the region between HLA-F and HLA-A as independently associated with BD (P < 1.7 × 10(-8)). HLA-B*51, -A*03, -B*15, -B*27, -B*49, -B*57, and -A*26 each contributed independently to BD risk. We directly examined rs116799036, a noncoding SNP upstream of HLA-B that was recently suggested to underlie the association of HLA-B*51 with BD, but we were unable to replicate that finding in our collection. Instead, we mapped the BD association to seven MHC class I (MHC-I) amino acid residues, including anchor residues that critically define the selection and binding of peptides to MHC-I molecules, residues known to influence MHC-I-killer immunoglobulin-like receptor interactions, and a residue located in the signal peptide of HLA-B. The locations of these variants collectively implicate MHC-I peptide binding in the pathophysiology of BD. Furthermore, several lines of evidence suggest a role for altered regulation of cellular cytotoxicity in BD pathogenesis.
authors.affiliation: Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; ombrellomj@mail.nih.gov kastnerd@mail.nih.gov.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ombrello
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine and Faculty of Medicine, Yokohama City 236-0004, Japan;
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kirino
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141;Departments of Medical Genetics andEpidemiology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands; and.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Gül
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; ombrellomj@mail.nih.gov kastnerd@mail.nih.gov.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
mesh_terms: D000483:Alleles; D001528:Behcet Syndrome / Q000235:genetics* / Q000276:immunology*; D005805:Genes, MHC Class I; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059949:HLA-B51 Antigen / Q000235:genetics*; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology; D015810:Linkage Disequilibrium; D016015:Logistic Models; D015999:Multivariate Analysis; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D021382:Protein Sorting Signals; D012307:Risk Factors
chemical_list: D059949:HLA-B51 Antigen; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; D021382:Protein Sorting Signals
keywords: HLA imputation; antigen presentation; autoinflammation; killer immunoglobulin-like receptors; natural killer cells