MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions

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.

Human leucocyte antigen-B27 testing in clinical practice: a global perspective

“…A large HLA class I and II alleles study including 4037 individuals from three ethnic groups (White, Asian, and African American) confirmed the association of HLA-B27 with axSpA, which was higher in Han Chinese (93%) and Whites (87.8%) compared to African American (59.7%), and identified other alleles predisposing to axSpA (HLA-A29, B14, B38, B40, B49, B52, DRB1∗11, DPB1∗03:01) [15]. These results were also confirmed by a large study including 1637 East Asian axSpA cases and 1589 ethnically-matched controls, where the associations with HLA-B27, HLA-B40, and HLA-C15, as well as novel association with HLA-DQB1∗04 were identified [16]. While studying SpA in a real-life setting, several cohorts (Table 1) confirmed the previously described associations with HLA-B27, with higher frequencies in axSpA (71.2–89.4%) compared to the whole group of SpA.…”

Genetics of Ankylosing Spondylitis—Focusing on the Ethnic Difference Between East Asia and Europe

“…Except for HLA-B associations, previously reported East Asian-specific association at HLA-C ∗ 15 had been validated. In addition, a novel association at HLA-DQB1 ∗ 04 has been identified ( Wang et al, 2020 ). However, our study needs further validation in larger cohort and conduct with better MHC imputation reference panel of the Pan-Asian population.…”

Global Proteomic Analyses Reveals Abnormal Immune Regulation in Patients With New Onset Ankylosing Spondylitis

“…Antigen processing and presentation play a critical role in the pathophysiology of AS ( 35 – 37 ). Human leukocyte antigens (HLAs) are proteins encoded by genes of the human major histocompatibility complex (MHC).…”