HLA‐B44 subtypes and the chance of finding HLA compatible donor/recipient pairs for bone marrow transplantation: a haplotype study of 303 Italian families

Abstract

A total of 1176 HLA-A,B,DR haplotypes were reconstructed by typing 303 unrelated families referred to our laboratory during the last seven years for the search of HLA identical sibs in view of bone marrow transplantation. A total of 614 different three-locus haplotypes were found. Most of them (83.6%) were present only once or twice, whereas 24/614 (3.9%) were found 6-28 times each. HLA-B44 was present in 4 of these most frequent haplotypes. HLA-B44 has been implicated as the molecular target for bone marrow allograft rejection. Therefore, a better knowledge of the HLA-B44 haplotype relationships might prove useful for the programming of registries of unrelated bone marrow donors. Eighty five serologically defined HLA-B44 unrelated subjects, either one or both parents from the above families, were subtyped by a high-resolution sequence-specific oligonucleotide probing approach. Moreover, 34 unrelated potential donors recruited for those patients that did not find a suitable donor among their siblings were subtyped also for HLA-B44. B*4403, which accounted for 47/85 (55.3%) serologically defined B44 alleles, appeared in strong, statistically significant, linkage disequilibrium with HLA-A29, -A23 and -DR7. On the other hand, B*4402, which covered virtually all other B44 alleles, showed prevalent gametic associations with HLA-A2 and HLA-A24. The linkage disequilibrium between HLA alleles is the key for the low frequency of HLA-B44 mismatches in donors selected as HLA-A,B,DRB1 identical to patients waiting for unrelated bone marrow transplantation. If a given patient presents unusual haplotypes, the chance of finding HLA-B44 mismatches may be higher because of the presence of different haplotype relationships in the donors.

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

“…As expected from previous studies (2–4, 6, 9, 12–14), the association of the B44 allotypes with HLA‐A,‐C, and ‐DRB1 alleles was not random. Among the 14 different B44‐C haplotypes detected in this study, five B–C haplotypes accounted for 92.4% (231/250) of all genotypes: B*4402‐Cw*0501, B*4402‐Cw*0704, B*4402‐Cw*1604, B*4403‐Cw*0401, and B*4403‐Cw*1601.…”

“…It comprises as much as 44 alleles defined by DNA sequencing (B*4402‐4439), including three alleles with silent substitutions in the coding sequence, two null alleles, and one allele with only soluble antigen produced (1). HLA‐B44 allele distribution varies widely in worldwide populations, with B*4402 and B*4403 being the predominant alleles in most populations analyzed so far (2–7), followed by B*4405, B*4404, and B*4406 (8, 9). B*4402 appears more prevalent than B*4403 in North European and North American Caucasoid populations (4, 5, 9), whereas B*4403 is by far the most frequent allele in South European (2–4, 7), Middle‐Eastern, African, Asian, or Hispanic populations (5, 9).…”

“…Analysis of B*4402‐ and B*4403‐bearing ABDR haplotypes revealed a larger diversity in European (3, 4) or North‐American Caucasoids (9, 12) compared to Asians (6). Preferential associations of the two most common B44 alleles, B*4402 and B*4403, with HLA‐A, ‐C, and ‐DR antigens or alleles have been reported (2–4, 9, 10, 13, 14), usually characterized by the maximum likelihood method. Exhaustive high‐resolution analyses of A/B/C/DRB1/B3/B5 haplotypic associations within the B44 group confirmed by family studies are rare (3, 6).…”

HLA-A29-Positive Uveitis: Birdshot Chorioretinopathy, What Else

“…BSCR is strongly associated with HLA-A29, and at least 96% of BSCR patients are HLA-A29 carriers [14]. The prevalence of HLA-A29 is about 7% in the general population [1, 8, 9, 10], while in the normal Italian population a frequency of 4.76% has been reported [15]. Although HLA-A29 seems to play a major role, the prevalence of the disease in the HLA-A29-positive population remains low, indicating that there are additional susceptibility factors for disease development.…”

Strong association between HLA‐Cw*0706 and HLA‐B*44032 in the Bubi population from Equatorial Guinea

“…HLA‐B44 subtyping in different European populations has revealed an inverse north‐south gradient in the frequencies of B*4402 and B*4403. While B*4402 is prevalent in northern Europe, the opposite is true for B*4403 which is more frequent in the populations of the Mediterranean countries ( 4, 6). In this study, 15 out of 19 B44pos Cw7pos Dutch Caucasians were typed B*4402.…”