Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis.
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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. |
Year of Publication | 2012
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Journal | Nat Genet
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Volume | 44
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Issue | 3
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Pages | 291-6
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Date Published | 2012 Jan 29
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ISSN | 1546-1718
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URL | |
DOI | 10.1038/ng.1076
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PubMed ID | 22286218
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PubMed Central ID | PMC3288335
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Grant list | R01-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
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