title: Fine mapping of a major histocompatibility complex in ankylosing spondylitis: association of the HLA-DPA1 and HLA-DPB1 regions.
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 × 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Díaz-Peña
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aransay
authors.forename: Jacome
authors.initials: J
authors.lastname: Bruges-Armas
authors.forename: Antonio
authors.initials: A
authors.lastname: López-Vázquez
authors.forename: Naiara
authors.initials: N
authors.lastname: Rodríguez-Ezpeleta
authors.forename: Iñaki
authors.initials: I
authors.lastname: Mendibil
authors.forename: Alejandra
authors.initials: A
authors.lastname: Sánchez
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Torre-Alonso
authors.forename: Bruno F
authors.initials: BF
authors.lastname: Bettencourt
authors.forename: Juan
authors.initials: J
authors.lastname: Mulero
authors.forename: Eduardo
authors.initials: E
authors.lastname: Collantes
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Larrea
mesh_terms: D000328:Adult; D000483:Alleles; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059867:HLA-DP alpha-Chains / Q000235:genetics*; D059868:HLA-DP beta-Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000235:genetics*
chemical_list: D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; C071172:HLA-DPA1 antigen; C071170:HLA-DPB1 antigen