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

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.

• Authors: Yukinori Okada, Kwangwoo Kim, Buhm Han, Nisha E Pillai, Rick T-H Ong, Woei-Yuh Saw, Ma Luo, Lei Jiang, Jian Yin, So-Young Bang, Hye-Soon Lee, Matthew A Brown, Sang-Cheol Bae, Huji Xu, Yik-Ying Teo, Paul I W de Bakker, Soumya Raychaudhuri
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 25 Pg. 6916-26 (Dec 20 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 25070946 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Amino Acids
• Autoantibodies
• Epitopes
• HLA-B Antigens
• HLA-DP beta-Chains
• HLA-DPB1 antigen
• HLA-DRB1 Chains
• Citrulline

Topics

• Alleles
• Amino Acids (genetics, immunology)
• Arthritis, Rheumatoid (ethnology, genetics, immunology, pathology)
• Asian People
• Autoantibodies (biosynthesis)
• Chromosome Mapping
• Citrulline (immunology)
• Epitopes (chemistry, immunology)
• Gene Expression
• Gene Frequency
• HLA-B Antigens (genetics, immunology)
• HLA-DP beta-Chains (genetics, immunology)
• HLA-DRB1 Chains (genetics, immunology)
• Humans
• Polymorphism, Genetic
• Risk
• White People