| Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. | |
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MedLine Citation:
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PMID: 22286218 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Soumya Raychaudhuri; Cynthia Sandor; Eli A Stahl; Jan Freudenberg; Hye-Soon Lee; Xiaoming Jia; Lars Alfredsson; Leonid Padyukov; Lars Klareskog; Jane Worthington; Katherine A Siminovitch; Sang-Cheol Bae; Robert M Plenge; Peter K Gregersen; Paul I W de Bakker |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-29 |
Journal Detail:
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Title: Nature genetics Volume: - ISSN: 1546-1718 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9216904 Medline TA: Nat Genet Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [3] Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, USA. [4] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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