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Kallberg H., Padyukov L., Plenge R.M., Ronnelid J., Gregersen P.K., van der Helm-van Mil A.H., Toes R.E., Huizinga T.W., Klareskog L., Alfredsson L. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Genome-wide association study of rheumatoid arthritis in Koreans: population-specific loci as well as overlap with European susceptibility loci. Gregersen P.K., Silver J., Winchester R.J. For trans-ethnic comparisons of HLA variant risks, we obtained distributions of the amino acid polymorphism frequencies and their risks on ACPA-positive RA from the previous study in the European populations (12). Ding B., Padyukov L., Lundstrom E., Seielstad M., Plenge R.M., Oksenberg J.R., Gregersen P.K., Alfredsson L., Klareskog L. Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region. We had access to four-digit classical typing data for HLA-DPA1 and HLA-DPB1 for datasets (i) and (ii), but not for (iii). Haplotypes with frequency ≥0.005 in controls are indicated. These findings illustrate the value of trans-ethnic association analysis that can exploit differences in LD structure and allele frequency among populations for the fine-mapping of causal variants. We compared ACPA-positive and negative patients with pSS and assessed the risk of evolution to RA. 2020 May;32(3):279-288. doi: 10.1097/BOR.0000000000000705. PCs estimated for QC-filtered GWAS subjects using whole-genome SNP data was used to correct potential population structures in the following analysis focusing on the MHC region. Anti–citrullinated protein antibody (ACPA)–positive rheumatoid arthritis (RA) is known for its more severe disease course, compared to ACPA‐negative RA. We applied postimputation QC criteria of MAF > 0.5% for the association analysis. Is ACPA positivity the main driver for rheumatoid arthritis treatment? Amino acid positions and the HLA genes to be included as covariates were consecutively selected in a forward stepwise fashion (33). yk,l is the lth PC for kth cohort, and z is the indicator dummy variable for the three cohorts. doi: 10.1136/ard.2010.138032. UK guidelines recommend that all early active rheumatoid arthritis (RA) patients are offered combination DMARDs and short-term corticosteroids. The most significantly associated amino acid polymorphisms are labeled with their positions, while the positions of the amino acid polymorphisms in LD with them are labeled with parenthesis. The segment connecting amino acid residues represents pairwise LD between them, and the thickness of the segment corresponds to the value of r2 as indicated in the legend. The points on the axis represent respective amino acid residues (or haplotypes), of which vertical positions represent their binominal OR of respective amino acid residues. The Asian reference panel showed modest imputation performance for four-digit alleles of HLA-A and HLA-B (<75.1%), whereas the combined Asian and European panel yielded improved concordance rates (>84.1%). This site needs JavaScript to work properly. The dotted horizontal line represents the significance threshold of P = 5.0 × 10−8. both HLA-DRB1*15:01 and HLA-DRB1*15:02 for candidate alleles) (13). S2 and Table S4, http://www.broadinstitute.org/mpg/snp2hla/. For construction of the imputation reference panel of HLA variants for Asian ancestry, we enrolled 530 unrelated Asian subjects consisting of (i) HapMap Phase II Japanese and Han Chinese (JPT + CHB) populations (n = 89) (14); (ii) the Singapore Chinese population (n = 91) (13); and (iii) pan-Asian datasets including 111 Chinese, 119 Indian and 120 Malaysian subjects (n = 350). All variants were encoded as biallelic markers representing the presence and absence of the variants, and singletons were removed from the combined reference panel. For conditional analysis on the HLA gene, we included all the amino acid positions and classical HLA alleles as covariates. When we considered the HLA-DRβ1 amino acid model based on the current Asian study (positions 11, 13, 57 and 74), we confirmed that effect sizes were significantly correlated between Asians and Europeans (r = 0.94, P = 5.0 × 10−7; Supplementary Material, Fig. Association plots of the tested variants in the MHC region to ACPA-positive RA in Asians. Keywords: Through the stepwise regression analysis for HLA-DRβ1, we found independent RA risks of positions 11, 13, 57 and 74 (top four panels), while amino acid polymorphisms reported in Europeans also showed better fitness of the model (positions 11, 13, 71 and 74; bottom panel). eCollection 2019. Positions 11 and 13 were considered as a single position due to their strong LD and local vicinity. We note that improvement in imputation accuracy was not consistent for all HLA genes; the combined Asian and European panel showed slightly lower accuracy for HLA-DRB1 alleles (76.2% genotype concordance for four-digit alleles for the Asian-only panel and 74.4% for the combined panel). Odds ratios of the haplotypes consisting of the risk HLA amino acid polymorphisms and their 95% confidence intervals are plotted based on those in Asians, Trans-ethnic comparisons of allele frequencies and LD structure of RA risk HLA amino acid polymorphisms. The combined reference panel of Asians and Europeans (n = 5666) demonstrated comparable or better imputation accuracy than the Asian or European panel alone (87.2% genotype concordance for four-digit alleles and average correlation coefficient = 0.91 for high-frequency alleles; Table 1; Supplementary Material, Fig. HLA gene names and HLA alleles are conventionally written in italic. was funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship and Queensland Premier′s Fellowship for Science. HLA-DRB1*09:01 risk in the Asian populations) (10,11) has made it challenging to draw definitive conclusions about the role of HLA-DRB1 in RA susceptibility. 2017 Nov;16(11):1096-1102. doi: 10.1016/j.autrev.2017.09.002. Association plots of the tested variants in the MHC region to ACPA-positive RA in Asians. Concordance rates for each HLA gene, we empirically compared imputed and genotyped dosages! 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