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 B44 alleles were identified: B4402-4405, with B4402 and B4403 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 B4402 and B4403 haplotypes, the genotypic profiles were quite different in the two groups. When associated with the A0101, A0201, A2402, A3201, and A6801 alleles, a much more extensive polymorphism of B4402 haplotypes with respect to HLA-C and DRB1 associations was disclosed. On the other hand, B4403 haplotypes were more diverse in the A23-B44 and A29-B44 groups with respect to DRB1 associations. Considering B-C linkage, B4402-Cw0501, B4402-Cw0704, B4402-Cw1604, B4403-Cw0401, B4403-Cw1601, B4404-Cw1601, and B4405-Cw0202 accounted for 98% of all genotypes. Eight A/B/C/DRB1 haplotypes occurred at a relative genotypic frequency of >0.015, with A2902-B4403-Cw1601-DRB10701 (11.2%) and A0201-B4402-Cw0501-DRB10401 (8.4%) as the two most frequent genotypes. Some A and DRB1 alleles were predominantly, if not exclusively, associated with specific B-C pairs: A0301 with B4402-Cw0501 and B4403-Cw0401; A2301 with B4403-Cw0401; A2608 with B4402-Cw0501; A2902 with B4403-Cw1601; DRB10101/0401/0403/0404/1101/1104/0801/1301/1302 with B4402-Cw0501; and DRB10701 with B4403-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.