ABSTRACT: BACKGROUND:The association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort. METHODS:A total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n?=?9689), and association tested using logistic regression controlling for population stratification effects. RESULTS:A strong association was seen with HLA-B*27 (odds ratio (OR)?=?205.3, P?=?5.76?×?10-244). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR?=?7.62, P?=?9.30?×?10-19), and confirmed association is also seen with HLA-B*40 at suggestive level (OR?=?1.65, P?=?2.54?×?10-4). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P?=?7.24?×?10-241), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians. CONCLUSIONS:This study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B.