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Nat Genet DOI:10.1038/ng.1076

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

Publication TypeJournal Article
Year of Publication2012
AuthorsRaychaudhuri, S, Sandor, C, Stahl, EA, Freudenberg, J, Lee, H-S, Jia, X, Alfredsson, L, Padyukov, L, Klareskog, L, Worthington, J, Siminovitch, KA, Bae, S-C, Plenge, RM, Gregersen, PK, de Bakker, PIW
JournalNat Genet
Volume44
Issue3
Pages291-6
Date Published2012 Jan 29
ISSN1546-1718
KeywordsAmino Acid Substitution, Arthritis, Rheumatoid, Case-Control Studies, Genome-Wide Association Study, Haplotypes, HLA-B Antigens, HLA-DP beta-Chains, HLA-DRB1 Chains, Humans, Major Histocompatibility Complex, Models, Molecular, Polymorphism, Single Nucleotide
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.

URLhttp://dx.doi.org/10.1038/ng.1076
DOI10.1038/ng.1076
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22286218?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID22286218
PubMed Central IDPMC3288335
Grant ListR01-AR057108 / AR / NIAMS NIH HHS / United States
G1001799 / / Medical Research Council / United Kingdom
R01-AR44422 / AR / NIAMS NIH HHS / United States
K08AR055688 / AR / NIAMS NIH HHS / United States
R01 AR044422 / AR / NIAMS NIH HHS / United States
U01 GM092691 / GM / NIGMS NIH HHS / United States
K08 AR055688-01A1S1 / AR / NIAMS NIH HHS / United States
R01 AR057108 / AR / NIAMS NIH HHS / United States
K08 AR055688-04 / AR / NIAMS NIH HHS / United States
K08 AR055688 / AR / NIAMS NIH HHS / United States
K08 AR055688-05 / AR / NIAMS NIH HHS / United States
R01 AR056768 / AR / NIAMS NIH HHS / United States
/ / Wellcome Trust / United Kingdom
U01-GM092691 / GM / NIGMS NIH HHS / United States