Abstract

Objective. To investigate the potential association of major histocompatibility complex (MHC) markers other than HLA-B27 with ankylosing spondylitis (AS). Methods. A total of 603 patients with AS and 542 healthy control subjects, all of whom were HLA-B27 positive, were selected for this study based on clinical criteria. First, high-density genotyping across the MHC region (2,360 single-nucleotide polymorphisms [SNPs]) was performed in a cohort of 191 patients and 241 control subjects. After a fine-mapping study, 5 SNPs from the HLA-DPA1/DPB1 region were validated in a second cohort of 412 patients with AS and 301 healthy control subjects. Results. Seventeen SNPs located within or near the HLA-DPA1 and HLA-DPB1 loci showed association with AS (P = 1.38 x 10(-5) to 0.05). In addition, multimarker tests, both linkage disequilibrium and sliding windows, showed association of some groups of adjacent SNPs within the HLA-DPA1/DPB1 region with AS (P = 1.0 x 10(-4) to 3.96 x 10(-7)). We validated the association by genotyping 5 SNPs from the DPA1/DPB1 region in an additional cohort and obtained P values from 6.42 x 10(-5) to 0.01 in the analysis of the combined cohorts. Subtyping analysis of HLA-DPA1 and HLA-DPB1 showed that HLA-DPA1*01:03, A1*02:01, and B1*13:01 were the subtypes most susceptible to AS. Conclusion. HLA markers and linkage disequilibrium blocks near HLA-DPA1 and HLA-DPB1 are statistically associated with AS. We identified a region located around the HLA-DPA1 and HLA-DPB1 loci associated with AS, another region within the MHC that is different from HLA-B27.