Fine-Mapping Major Histocompatibility Complex Associations in ACPA-Positive Rheumatoid Arthritis Identified Shared HLA Amino Acid Polymorphisms in Asian and European Populations.

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 ( P omnibus = 6.9 & 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 P omnibus = 2.2 & 2.2 × 10 ?33 ) and 74 (conditional P omnibus = 1.1 & 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.This work was supported by the National Institutes of Health (1R01AR062886-01, 5U01GM092691-04 and 1R01AR063759-01A1), the Arthritis Foundation, a Clinical Scientist Development Award to S.R. from the Doris Duke Foundation, the Japan Society of the Promotion of Science (JSPS), Japan Science and Technology Agency (JST), and by the Korean Health Technology R&D Project, Ministry of Health & Welfare, Korea (A121983). M.A.B. was funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship and Queensland Premier′s Fellowship for Science. P.I.W.D.B. is the recipient of a Vernieuwingsimpuls VIDI Award (project 016.126.354) from the Netherlands Organization for Scientific Research (NWO)