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

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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.

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APA

Okada, Y., Kim, K., Han, B., Pillai, N. E., Ong, R. T. H., Saw, W. Y., … Raychaudhuri, S. (2014). Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Human Molecular Genetics, 23(25), 6916–6926. https://doi.org/10.1093/hmg/ddu387

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