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- Title
Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations.
- Authors
Okada, Yukinori; Kim, Kwangwoo; Han, Buhm; Pillai, Nisha E.; Ong, Rick T.-H.; Saw, Woei-Yuh; Luo, Ma; Jiang, Lei; Yin, Jian; Bang, So-Young; Lee, Hye-Soon; Brown, Matthew A.; Bae, Sang-Cheol; Xu, Huji; Teo, Yik-Ying; de Bakker, Paul I.W.; Raychaudhuri, Soumya
- Abstract
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.
- Publication
Human Molecular Genetics, 2014, Vol 23, Issue 25, p6916
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddu387