title: Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis.
abstract: The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to alleles in HLA-DRB1. However, debate persists about the identity of the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide SNP data in 5,018 individuals with seropositive rheumatoid arthritis (cases) and 14,974 unaffected controls, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1, as well as 3,117 SNPs across the MHC. Conditional and haplotype analyses identified that three amino acid positions (11, 71 and 74) in HLA-DRβ1 and single-amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPβ1 (at position 9), which are all located in peptide-binding grooves, almost completely explain the MHC association to rheumatoid arthritis risk. This study shows how imputation of functional variation from large reference panels can help fine map association signals in the MHC.
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. soumya@broadinstitute.org
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sandor
authors.forename: Eli A
authors.initials: EA
authors.lastname: Stahl
authors.forename: Jan
authors.initials: J
authors.lastname: Freudenberg
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Lee
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Jia
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D055106:Genome-Wide Association Study; D015235:HLA-B Antigens / Q000235:genetics*; D059868:HLA-DP beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D015235:HLA-B Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D059811:HLA-DRB1 Chains