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Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations
Cited 116 time in
Web of Science
Cited 122 time in Scopus
- Authors
- Issue Date
- 2014-12
- Publisher
- Oxford University Press
- Citation
- Human Molecular Genetics, Vol.23 No.25, pp.6916-6926
- Abstract
- Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. Wefine-mapped RA riskalleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DR beta 1 at amino acid position 13, located outside the classical shared epitope (P-omnibus = 6.9 x 10(-135)). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr congruent to Gly > Ser)-but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional P-omnibus = 2.2 x 10(-33)) and 74 (conditional P-omnibus = 1.1 x 10(-8)). Outside of HLA-DR beta 1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 x 10(-6)) and HLA-DP beta 1 (Phe9, conditional P = 3.0 x 10(-6)) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. HLA-DRB1*09:01) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC.
- ISSN
- 0964-6906
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