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THU0223 Genetics of behçet’s disease in sardinia: two distinct extended hla haplotypes harbor the B*51 allele in normal population and in patients
  1. M. Piga1,
  2. F. Paladini2,
  3. S. Lai3,
  4. G. Passiu4,
  5. C. Carcassi3,
  6. R. Sorrentino2,
  7. A. Mathieu1
  1. 1Chair of Rheumatology and Rheumatology Unit, University Clinic of Cagliari, Cagliari
  2. 2Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biologia e Biotecnologie “Charles Darwin”, Sapienza Università di Roma, Roma
  3. 3Chair of Medical Genetics, University of Cagliari, Cagliari
  4. 4Chair of Rheumatology and Rheumatology Unit, University of Sassari, Sassari, Italy


Background Several observations suggest that genes other than HLA-B*51 might be implicated in BD susceptibility and pathogenesis. In particular, as a consequence of the strong linkage disequilibrium characterizing the MHC region, it cannot be ruled out that HLA-B*51 is included in haplotypes with other functional genes partly responsible of genetic susceptibility to BD. The distribution of HLA alleles in Sardinian natives is characterized by highly preserved haplotypes.

Objectives To define the contribution of HLA genes and extended HLA haplotypes conferring susceptibility to Behçet’s Disease (BD), through analysis of Sardinian subjects.

Methods Forty-five unrelated Sardinian patients with BD, diagnosed according to the ISG criteria, 45 HLA-B*51 positive and 185 unselected healthy controls were enrolled in the study. DNA samples were typed for HLA class I and class II alleles and genotyped for microsatellites (MICA-TM) and single-nucleotide polymorphisms (rs1264457 HLA–E; rs2281820 motilin; rs1799724 at -857, rs361525 at -238 TNF-alpha) spanning the HLA region.

Statistical analysis was carried out using Chi-square test with Yates’ correction or Fischer’s exact test. The strength of association was estimated by calculating the Odds Ratio (OR) with 95% Confidence Interval (95% CI). A value of p<0.05 was considered statistically significant where Bonferroni’s correction was applied. The LD between pairs of loci was calculated performing a likelihood-ratio test, whose empirical distribution is obtained by a permutation procedure using the statistical software Arlequin (version 3.11, Bern, Switzerland). The significance (p<0.01) of the observed likelihood ratio is found by computing the null distribution of this ratio under the hypothesis of LD, using a permutation procedure. All markers were in Hardy-Weinberg equilibrium. Maximum-likelihood haplotype frequencies and their distribution were estimated using an Expectation-Maximization algorithm and polymorphic alleles within each investigated HLA locus were constructed into extended haplotypes.

Results The HLA-B*51 allele, in particular the B*51:01, was the only allele conferring susceptibility to BD (pc=0.0042; OR =4.4; 95% CI =2.0 to 9.6), among those investigated.

The B*51 allele was more frequently carried by a haplotype (A2; Cw2; B*51:01; DRB1*11; DQA1*05; DQB1*03) that reached its highest frequency in patients with BD.Linkage disequilibrium analysis showed the existence of a B*51 haplotype (A2; Cw2; B*51:01; DRB1*04; DQA1*03; DQB1*03) not associated with susceptibility to the disease (figure 1). None of the investigated microsatellites and SNPs showed a different distribution in B*51 haplotypes characterizing healthy controls and BD patients.

Conclusions We confirmed that B*51 is the major genetic susceptibility factor to BD and we described a significant low frequency of A2; Cw2; B*51:01; DRB1*04; DQA1*03; DQB1*03 haplotype in our patients. It might be speculated this haplotype lacks a hypothetical co-susceptibility genetic factor to BD in Sardinian natives.

Disclosure of Interest None Declared

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