Identification of previously unrecognized predisposing factors for ankylosing spondylitis from analysis of HLA-B27 extended haplotypes in Sardinia

Arthritis Rheum. 2007 Aug;56(8):2640-51. doi: 10.1002/art.22820.


Objective: To define the contribution of HLA genes other than HLA-B27 in conferring susceptibility to ankylosing spondylitis (AS), through analysis of HLA-B27 haplotypes in Sardinian subjects.

Methods: Ninety-eight patients with AS, 133 HLA-B27-positive controls (of whom 33 were positive for HLA-B*2709), and 190 randomly selected controls were genotyped for microsatellites and single-nucleotide polymorphisms (SNPs) spanning the HLA region.

Results: Haplotypes carrying either the B*2705 or the B*2709 allele were found to share a conserved region downstream of the HLA-B gene and a functional polymorphism in the HLA-E gene (R128G), while differing in all other markers. Notably, the presence of an A at SNP rs1264457, encoding for Arg-128, was significantly increased in the cohort of patients (P = 6 x 10(-6), corrected P = 3 x 10(-5)) but not in B*2705- or B*2709-positive controls. Comparing the alleles co-occurring at each HLA marker, we identified a region differentiating patients with AS and B*2705-matched controls. In particular, there was a markedly increased prevalence of heterozygosity at rs1264457 among B27-positive controls (74%, versus 47% in patients and 54% in random controls), suggesting a protective role of G128 in AS. Moreover, other markers around the HLA-B gene were also differentially represented.

Conclusion: These results demonstrate a significant difference in the frequency of some HLA markers between AS patients and B*2705-positive controls, which could be attributed to the opposite chromosome. In particular, the differential distribution of a functional polymorphism in the HLA-E gene suggests a possible role of natural killer function in AS pathogenesis.

Publication types

  • Multicenter Study

MeSH terms

  • DNA / blood
  • Gene Frequency
  • Genetic Markers
  • Genetic Predisposition to Disease*
  • HLA Antigens / genetics
  • HLA-B27 Antigen / genetics*
  • HLA-B27 Antigen / immunology
  • Haplotypes
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Italy / epidemiology
  • Linkage Disequilibrium / genetics
  • Microsatellite Repeats / genetics
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide / genetics
  • Spondylitis, Ankylosing / epidemiology
  • Spondylitis, Ankylosing / genetics*
  • Spondylitis, Ankylosing / immunology


  • Genetic Markers
  • HLA Antigens
  • HLA-B27 Antigen
  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • DNA