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.

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.

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