Fine mapping of a major histocompatibility complex in ankylosing spondylitis: association of the HLA-DPA1 and HLA-DPB1 regions

Arthritis Rheum. 2011 Nov;63(11):3305-12. doi: 10.1002/art.30555.


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 × 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 × 10⁻⁴ to 3.96 × 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 × 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • HLA-DP alpha-Chains / genetics*
  • HLA-DP beta-Chains / genetics*
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Major Histocompatibility Complex / genetics*
  • Polymorphism, Single Nucleotide
  • Spondylitis, Ankylosing / genetics*


  • HLA-DP alpha-Chains
  • HLA-DP beta-Chains
  • HLA-DPA1 antigen
  • HLA-DPB1 antigen