Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populationsopen access
- 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
- Issue Date
- Dec-2014
- Publisher
- OXFORD UNIV PRESS
- Citation
- HUMAN MOLECULAR GENETICS, v.23, no.25, pp.6916 - 6926
- Indexed
- SCIE
SCOPUS
- Journal Title
- HUMAN MOLECULAR GENETICS
- Volume
- 23
- Number
- 25
- Start Page
- 6916
- End Page
- 6926
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/25713
- DOI
- 10.1093/hmg/ddu387
- ISSN
- 0964-6906
- 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.
- Files in This Item
-
Go to Link
- Appears in
Collections - 서울 의과대학 > 서울 내과학교실 > 1. Journal Articles
![qrcode](https://api.qrserver.com/v1/create-qr-code/?size=55x55&data=https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/25713)
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.