title: HLA-E gene polymorphism associates with ankylosing spondylitis in Sardinia.
abstract: BACKGROUND
  Ankylosing spondylitis (AS) is a severe, chronic inflammatory disease strongly associated with HLA-B27. The presence of additional HLA risk factors has been suggested by several studies. The aim of the current study is to assess the occurrence of an additional HLA susceptibility locus in the region between HLA-E and HLA-C in the Sardinian population.
  
  
  METHODS
  200 random controls, 120 patients with AS and 175 HLA-B27 positive controls were genotyped for six single nucleotide polymorphisms (SNPs) spanning the HLA region between HLA-E and HLA-C loci previously shown to harbour an additional susceptibility locus for AS. Allele, genotype and haplotype frequencies were compared.
  
  
  RESULTS
  The data confirm our previous finding of a significant increase in patients with AS of allele A at SNP rs1264457 encoding for an Arg at the functional HLA-E polymorphism (Arg128/Gly128). This was due to a remarkable increase in the frequency of genotype A/A in patients vs HLA-B27-matched controls (51% vs 29%; P for trend: 5 x 10-5). Genotype distribution of three other SNPs mapping in genes (GNL1, PRR3 and ABCF-1) close to HLA-E and showing high LD with it, was also significantly skewed. Accordingly, haplotype distribution was also remarkably different. The frequency of the haplotype AAGA, is 42% in random controls, increases to 53% in the HLA-B27-positive controls, and reaches 68% in patients with AS (P values: 2 x 10-11 vs random and 3 x 10-4 vs HLA-B27 controls).
  
  
  CONCLUSIONS
  There is a strong association between the presence of a haplotype in genes mapping between HLA-E and HLA-C and AS due to an increase of homozygous markers in patients. The strongest association however, is with the HLA-E functional polymorphism rs1264457. Since HLA-E is the ligand for the NKG2A receptor, these data point to the natural killer (NK) activity as possible player in the pathogenesis of AS.
authors.affiliation: Department of Cell Biology and Development, University "La Sapienza", via dei Sardi, 70, 00185 Roma, Italy. fabiana.paladini@uniroma1.it
authors.forename: Fabiana
authors.initials: F
authors.lastname: Paladini
authors.forename: Francesca
authors.initials: F
authors.lastname: Belfiore
authors.forename: Elisa
authors.initials: E
authors.lastname: Cocco
authors.forename: Carlo
authors.initials: C
authors.lastname: Carcassi
authors.forename: Alberto
authors.initials: A
authors.lastname: Cauli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vacca
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Fiorillo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mathieu
authors.forename: Isabella
authors.initials: I
authors.lastname: Cascino
authors.forename: Rosa
authors.initials: R
authors.lastname: Sorrentino
mesh_terms: D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics*; D015796:HLA-B27 Antigen / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007558:Italy; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000235:genetics*; D000097625:HLA-E Antigens
chemical_list: D006680:HLA Antigens; D015796:HLA-B27 Antigen; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D000097625:HLA-E Antigens