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Hum Mol Genet DOI:10.1093/hmg/ddu387

Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations.

Publication TypeJournal Article
Year of Publication2014
AuthorsOkada, Y, Kim, K, Han, B, Pillai, NE, Ong, RT-H, Saw, W-Y, Luo, M, Jiang, L, Yin, J, Bang, S-Y, Lee, H-S, Brown, MA, Bae, S-C, Xu, H, Teo, Y-Y, de Bakker, PIW, Raychaudhuri, S
JournalHum Mol Genet
Date Published2014 Dec 20
KeywordsAlleles, Amino Acids, Arthritis, Rheumatoid, Asian Continental Ancestry Group, Autoantibodies, Chromosome Mapping, Citrulline, Epitopes, European Continental Ancestry Group, Gene Expression, Gene Frequency, HLA-B Antigens, HLA-DP beta-Chains, HLA-DRB1 Chains, Humans, Polymorphism, Genetic, Risk

Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles 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-DRβ1 at amino acid position 13, located outside the classical shared epitope (Pomnibus = 6.9 × 10(-135)). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr ≅ Gly > Ser)--but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional Pomnibus = 2.2 × 10(-33)) and 74 (conditional Pomnibus = 1.1 × 10(-8)). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 × 10(-6)) and HLA-DPβ1 (Phe9, conditional P = 3.0 × 10(-5)) 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.


Alternate JournalHum. Mol. Genet.
PubMed ID25070946
PubMed Central IDPMC4245039
Grant List1R01AR062886-01 / AR / NIAMS NIH HHS / United States
1R01AR063759-01A1 / AR / NIAMS NIH HHS / United States
5U01GM092691-04 / GM / NIGMS NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
MANMKBRU-2012-1 / / Department of Health / United Kingdom