MHC Associations of Ankylosing Spondylitis in East Asians Are Driven By HLA-B Amino-Acid Position 97, Confirming Findings in European Descent Subjects

Abstract

Background/Purpose: Whilst HLA-B27 is the MHC allele associated with AS, there is strong evidence indicating that other HLA-B alleles and MHC genes are involved in the disease. Large studies in European case-control cohorts have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, -A and 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 (Cortes et al, Nat Com, 2015). A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02 (Kim et al, Arthritis Res Ther, 2015). In the current study, we examined in an expanded East Asian cohort the MHC associations of AS.

Methods: 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 was imputed using the SNP2HLA program using the Korean HLA reference panel (n=413) and association tested using logistic regression using 10 principal components to control for population stratification effects. Only HLA types with imputation information scores >0.8 were considered.

Results: Strong association was seen with HLA-B*27 (odds ratio (OR) 158, P=10-127). Controlling for this association, risk association is seen with HLA-B*40 (OR=8.22, P=7.66×10-83). Controlling for both HLA-B*27 and –B*40, no other HLA-B associations are seen (P>0.05). At amino-acid level the strongest association seen in uncontrolled analysis was with histidine or tyrosine at position 9 in HLA-B (p=10-155), but association at P<10-100 was seen with multiple HLA-B amino acids at P<10-100 including asparagine (found on HLA-B*27 alleles) at position 97, previously reported to be the main amino-acid determining HLA-B associations with AS. Controlling for HLA-B27 alone, or with –B27 and –B40, the strongest HLA amino-acid association remains with HLA-B position 97 (serine, found on HLA-B*7, *8, *15, *2707, *40, *41, *48; P=10-115 and 10-71 respectively)

Conclusion: This study confirms in East Asians that the primary amino-acid driver of HLA associations in AS is amino-acid position 97, which remains associated with AS independently of both HLA-B*27 and –B*40, the two key driver alleles in this ethnicity.