Polymerase chain reaction (PCR)-based genotyping was used to characterize the features of HLA class II molecular polymorphisms in a Slavic population of North-Western Russia. Two hundred individuals were analyzed for the DRB1 gene, and 100 persons randomly selected from this cohort were additionally typed for DQA1, DQB1 and DPB1 genes. Allele and haplotype frequencies were found to be similar to those observed in other Caucasian populations, with the exception of considerably high prevalence of the DPB1*0301 allele (16.0%) in the group studied. The high rate of diversity was observed within DRB1*04 and DRB1*14 specificities, as well as for extended DR-DQ haplotypes. In addition, significant number of "unusual" DR-DQ linkage patterns have been detected. The data seem to reflect the complexity of ethnic background of "European" Russians and may be helpful for the development of international network between donor registries.
Severe aplastic anemia (SAA) is a heterogeneous hematological disorder with a high mortality. Genetic predisposition has been shown to play a role in a considerable proportion of SAA cases. For instance, the human lymphocyte antigen HLA-DR2 has been repeatedly demonstrated to be over-represented in SAA patients. In this paper, we expand on the evidence for the contribution of HLA polymorphism in the susceptibility to SAA, which was obtained using the "high-resolution" technique of HLA-DRB1 subtyping. The DRB1*1501 allele appeared to be responsible for the predominance of DR2 specificity in SAA patients and was the most significant risk factor for this disease. It was observed in 23/44 (52.3%) patients versus 22/100 (22.0%) donors [odds ratio (OR) = 3.9; 95% confidence interval (CI): 1.8-8.3; P = 0.0005, corrected P (Pc) < 0.05]. In addition, DRB1*04 alleles also displayed non-random distribution in the SAA group. In particular, DRB1*04 variants coding for alanine at position 74 of the DR beta 1 chain (HLA-DR4-Ala74 beta subtype) were detected in all 13 DR4-positive SAA patients but only in 15/24 (62.5%) controls (OR = 16.6; 95% CI: 0.9-312.0; P = 0.015). Multiple comparison analysis confirmed that the HLA-DR4-Ala74 beta subtype confers susceptibility to SAA independently from the DRB1*1501 allele. Finally, examination of the clinical records has shown that the HLA-DR4-Ala74 beta subtype is associated with poor outcome of SAA.
The association between severe aplastic anemia (AA) and DR2 antigen seems to be well established. However, since discrimination between two DR2-associated splits, namely DR15 and DR16, rarely was performed, it remains unclear whether one or both of these subvariants are responsible for AA susceptibility. In this study, we have analyzed the HLA-DR allelic distribution in a group of 37 AA patients of slavic origin from North-Western Russia. The experimental design included PCR-based amplification of DRB-specific sequences, followed by reverse dot-blot hybridization of the biotinylated PCR-product with the set of sequence-specific oligonucleotide probes. HLA-DRB alleles were identified by non-radioactive enzymatic reaction, then standard serological specificities of HLA-DR antigen were estimated according to the WHO nomenclature. Whereas DR15 subtype occurred more often in the patients (23.0% vs. 13.3%, p< 0.05), DR16 split did not show the same tendency. The results, show the overall predominance of HLA-DR2 specificity (DR15+DR16) did not reach statistical significance (24.4% vs.17.5%, p<0.2). Thus, we conclude that repeatedly reported DR2 frequency increase in AA patients is mainly attributed to the prevalence of DR15 subtype.
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