Scientific Publications

Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis.

Publication TypeJournal Article
AuthorsRaychaudhuri, S., Sandor C., Stahl EA, Freudenberg J., Lee HS, Jia X., Alfredsson L., Padyukov L., Klareskog L., Worthington J., Siminovitch KA, Bae SC, Plenge RM, Gregersen PK, and de Bakker PI
AbstractThe 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.
Year of Publication2012
JournalNature genetics
Volume44
Issue3
Pages291-6
Date Published (YYYY/MM/DD)2012/01/29
ISSN Number1061-4036
DOI10.1038/ng.1076
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/22286218?dopt=Abstract