Analysis of 250 HLA-B44 genotypes in European Caucasoids: high diversity and preferential ABCDRB1 associations in B*4402, B*4403, and B*4405 haplotypes

Based on high-resolution DNA typing within 235 pedigrees, a total of 250 HLA-A/B/C/DRB1/DRB3 genotypes have been characterized. These comprise 129 different B44 haplotypes, of which 73.6% occurred only once. Only four different B*44 alleles were identified: B*4402-4405, with B*4402 and B*4403 haplotypes accounting for 57.6 and 36.8%, respectively, of all haplotypes. Although the relative numbers of different A/B/C/DRB1/B3 haplotypic associations were similar in both B*4402 and B*4403 haplotypes, the genotypic profiles were quite different in the two groups. When associated with the A*0101, A*0201, A*2402, A*3201, and A*6801 alleles, a much more extensive polymorphism of B*4402 haplotypes with respect to HLA-C and DRB1 associations was disclosed. On the other hand, B*4403 haplotypes were more diverse in the A23-B44 and A29-B44 groups with respect to DRB1 associations. Considering B-C linkage, B*4402-Cw*0501, B*4402-Cw*0704, B*4402-Cw*1604, B*4403-Cw*0401, B*4403-Cw*1601, B*4404-Cw*1601, and B*4405-Cw*0202 accounted for 98% of all genotypes. Eight A/B/C/DRB1 haplotypes occurred at a relative genotypic frequency of >0.015, with A*2902-B*4403-Cw*1601-DRB1*0701 (11.2%) and A*0201-B*4402-Cw*0501-DRB1*0401 (8.4%) as the two most frequent genotypes. Some A and DRB1 alleles were predominantly, if not exclusively, associated with specific B-C pairs: A*0301 with B*4402-Cw*0501 and B*4403-Cw*0401; A*2301 with B*4403-Cw*0401; A*2608 with B*4402-Cw*0501; A*2902 with B*4403-Cw*1601; DRB1*0101/0401/0403/0404/1101/1104/0801/1301/1302 with B*4402-Cw*0501; and DRB1*0701 with B*4403-Cw*1601. On the basis of this dataset and our experience with searches for phenotypically matched unrelated stem cell donors, several ABDR haplotypes were identified that would confer a higher probability of B44- and C-incompatibility. The analysis of 112 consecutive unrelated stem cell donor searches revealed that 24% of the 400 tested donors were B44-mismatched, and that no single B44 allele- matched donor could be identified for only 7% of the patients. HLA-C incompatibility rate was 22.2% for the patients with > or =1 B44 allele-matched donor(s). This dataset can therefore be used as a predictive tool for B44- and C-disparities in unrelated stem cell transplantation.