HLA-E gene polymorphism associates with ankylosing spondylitis in Sardinia.
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.
Paladini
Fabiana
F
Department of Cell Biology and Development, University "La Sapienza", via dei Sardi, 70, 00185 Roma, Italy. fabiana.paladini@uniroma1.it
Belfiore
Francesca
F
Cocco
Elisa
E
Carcassi
Carlo
C
Cauli
Alberto
A
Vacca
Alessandra
A
Fiorillo
Maria Teresa
MT
Mathieu
Alessandro
A
Cascino
Isabella
I
Sorrentino
Rosa
R
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
D006680:HLA Antigens; D015796:HLA-B27 Antigen; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D000097625:HLA-E Antigens