Cell and Tissue Banking

, Volume 9, Issue 4, pp 347–351

Bulgarian Bone Marrow Donors Registry—past and future directions

Authors

  • Asen Zlatev
    • University Hospital “Alexandrovska”
  • Milena Ivanova
    • Central Laboratory of Clinical ImmunologyUniversity Hospital “Alexandrovska”
  • Snejina Michailova
    • Central Laboratory of Clinical ImmunologyUniversity Hospital “Alexandrovska”
  • Anastasia Mihaylova
    • Central Laboratory of Clinical ImmunologyUniversity Hospital “Alexandrovska”
    • Central Laboratory of Clinical ImmunologyUniversity Hospital “Alexandrovska”
Article

DOI: 10.1007/s10561-007-9046-z

Cite this article as:
Zlatev, A., Ivanova, M., Michailova, S. et al. Cell Tissue Bank (2008) 9: 347. doi:10.1007/s10561-007-9046-z
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Abstract

Recently Bulgarian Bone Marrow Donors Registry (BBMDR) has been established and since August 2005 it has been a member of Bone Marrow Donors Worldwide. Currently the number of healthy donors included in the BBMDR is relatively low. All donors included in the BBMDR are typed for HLA-A, -B, -DRB loci. Phylogenetic analysis based on HLA allele frequencies shows that Bulgarians were characterized with closest genetic similarity to Macedonians, Greeks, Romanians, Cretans and Sardinians in comparison to the other European and Mediterranean populations. On the contrary the second largest ethnic minority–the Roma were the closest to the other Roma populations and North Indians. These differences were due to the predominance of alleles and haplotypes that are specific for the Asian and the other Roma populations. These specific genetic profiles in the Bulgarian ethnic minorities justify the need of an adequate representation of minorities in BBMDR. Future directions for BBMDR development are discussed, including an increase of the total number of donors and these for ethnic minorities, as well the enhancement of the level of resolution of the HLA typing for the donors in the registry.

Keywords

Bulgarian Bone Marrow Donor RegistryBulgariansHLA allelesHLA haplotypesRoma

Haemopoietic stem cells transplantation is modern and highly efficacious method of treatment of hematological malignancies, primary immune deficiencies and recently other diseases. The accomplishment of allogeneic hemopoietic stem cells transplantation is restricted due to need for finding an HLA identical donor. Identification of completely HLA matched donors in the family is possible for only a small proportion of patients. That necessitated the establishment registries of healthy subjects, in order to provide HLA matched haemopoietic stem cells for the patients requiring bone marrow transplantation. Currently about 63 different registries, including more than 10 million voluntary donors are established worldwide and are included in World Marrow Donor Association. The majority of these registries are located in Europe (particularly in West and North Europe) and North America. The number of registries in Eastern Europe is still limited and generally these registries are relatively small. The Bulgarian Bone Marrow Donors Registry (BBMDR) was established within Central Laboratory of Clinical Immunology in 2002 and since August 2005 it has been a member of Bone Marrow Donors Worldwide (BMDW).

The main tasks of the registry include:
  • Donor management activities: recruitment of volunteer stem cell donors, storage and maintenance of donor data and exchange of data with BMDW, handling of national and international requests for unrelated stem cell donors from BBMDR file and distribution of blood and DNA samples for confirmatory typing.

  • Patients search activities: identification of unrelated stem cell donors in the national and international registries for Bulgarian patients in need of transplantation for whom no suitable donor could be identified in the family

  • Coordinating activities: processing requests for donors originating from the country or emanating from abroad and coordinating activities of donor and transplant centers

  • Consultancy activities: providing immunogenetic advise about the feasibility of finding a suitable donor and coordination of the search process

Characteristics of unrelated stem cell donors in BBMDR

The number of healthy unrelated voluntary haemopoietic stem cell donors included in the BBMDR is currently 144 (September 2006), with slight prevalence of female (56%) over male (44%) donors. In both groups the average age is similar—36.9 ± 7.6 for female and 37.3 ± 8.5 for male. All donors included in the registry were typed for HLA-A, -B, -DRB loci. HLA typing for class II alleles was performed by DNA. Additionally, more than 50% of donors were typed also by DNA-based methods for HLA class I alleles (Fig. 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs10561-007-9046-z/MediaObjects/10561_2007_9046_Fig1_HTML.gif
Fig. 1

Number of donors in BBMDR typed for HLA class I (-A, -B) and class II (-DRB) by serology and DNA-based methods

Analysis of HLA allele distribution in BBMDR showed that 4 alleles for HLA-A (A*02, *24, *01, *03) and 5 alleles for HLA-B (B*35, 51, *18, *44, *08) and DRB1 (DRB1*11, *04, *16, *01, *15) loci were prevalent (Fig. 2). Their frequencies represented more than 60% of those observed for the given locus and correspond to the most frequent alleles found in the Bulgarian population (Ivanova et al. 2001; Ivanova et al. 2002). Such allele distribution is characteristic for South European populations (Bodmer et al. 1997; Terasaki et al. 1997; Geer et al. 1998). The analysis of haplotype frequency distribution showed prevalence of rare haplotypes. Haplotypes with frequency lower than 0.005 represented more that 66% of all HLA-A-B-DRB1 haplotypes observed. The proportion of the frequent haplotypes (HF > 0.01) was 34% (Fig. 3). With highest frequency in the BBMDR were found South European A*02-B*18-DRB1*11 and A*24-B*35-DRB1*11 and pan European A*01-B*08-DRB1*03 haplotypes (Arnais-Villena 2001; Papassavas 2000; Clayton 1997). Given the unique ethnic background of the Bulgarian population, some West and Central European haplotypes such as A*01-B*57-DRB1*07 and A*11-B*07-DRB1*15 were detected in our population with lower frequencies (Table 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs10561-007-9046-z/MediaObjects/10561_2007_9046_Fig2_HTML.gif
Fig. 2

HLA-A, -B, -DRB1 allele distribution in the BBMDR

https://static-content.springer.com/image/art%3A10.1007%2Fs10561-007-9046-z/MediaObjects/10561_2007_9046_Fig3_HTML.gif
Fig. 3

HLA-A-B-DRB1 haplotype distribution in the BBMDR

Table 1

The most frequent HLA-A-B-DRB1 haoplotypes in the BBMDR

Haplotype

Haplotype frequency

Other populations where the haplotype has been found

A*02 B*18 DRB1*11

0.03535

Greeks, Sardinians, Italians, French, Portuguese, Romanians, Czech, Slovenians, Croatians, Macedonians

A*01 B*08 DRB1*03

0.03030

 European

A*24 B*35 DRB1*11

0.02448

Greeks, Cypriot, Sardinians, Italians, Spanish, Romanians

A*02 B*51 DRB1*11

0.01515

Greeks, Cypriot, Sardinians, Italians, French, Danish, Portuguese, Slovenians, Croatians, Hungarians

A*02 B*51 DRB1*16

0.01515

Macedonians

A*02 B*27 DRB1*16

0.01515

Caucasians

A*01 B*57 DRB1*07

0.01515

Western European populations

A*03 B*18 DRB1*16

0.01515

Macedonians

A*11 B*07 DRB1*15

0.01515

West Europeans

A*23 B*44 DRB1*07

0.01515

Mediterranean-Europeans

A*24 B*35 DRB1*04

0.01515

Caucasians, Asians

A*26 B*38 DRB1*04

0.01515

Turkish, Macedonians, Jewish

A*24 B*51 DRB1*11

0.01515

Cypriot, Italians, French, Spanish, Slovenians, Croatians

A*03 B*18 DRB1*16

0.01515

Macedonians

Based on HLA allele frequencies in Bulgarians and the second largest minority in Bulgaria–Roma, phylogenetic analysis was performed. Neighbor-joining phylogenetic three with standard genetic distances showed that that Bulgarians were more closely related to Macedonians, Greeks, Romanians, Cretans and Sardinians than to other European populations and Middle East Mediterraneans. It is interesting to note that the Roma were more distant from Bulgarians and clustered with other Roma populations and North Indians (Fig. 4). These differences were due to the fact that common alleles in Bulgarian Roma such as A*0101, *1101, *0211; B*4006, *5201; DRB1*0301, *1502; *1404 were characterized with much higher frequency compared to the Bulgarians. Similar frequencies of these alleles were observed in Asian populations. Similarly to other Romani, it was interesting to note prevalence of HLA-B*4006 and DRB1*1404 alleles in Bulgarian Roma (Fig. 4). In addition, relatively frequently (allele frequencies raging from 0.01 to 0.03) were observed rare for Caucasians alleles, that were not found in Bulgarians: A*0206, *0212, *3303; B*2701, *2704, *3901, *3906; DRB1*1103, *1118, *1202 (Fig. 5). The majority of these alleles were characteristic for Asians (North Indiansa) and are reported in other Roma groups (de Pablo 1992). These differences between Bulgarians and Roma were further supported by analysis of haplotypes. Although some Mediterranean haplotypes were found in Bulgarian Roma, the most frequent haplotypes were not detected in Bulgarians. Similarly to other Romani (Andalusian, Czech) and North Indians the most common haplotype in Bulgarian Roma was A*0101-B*4006-DRB1*1404. The most of other frequent haplotypes were also observed in different Asian ethnic groups.
https://static-content.springer.com/image/art%3A10.1007%2Fs10561-007-9046-z/MediaObjects/10561_2007_9046_Fig4_HTML.gif
Fig. 4

Neighbor-joining dendrogram based on HLA allele frequency data showing relatedness between Bulgarians and other populations. Bootstrap values from 1,000 replicates are given

https://static-content.springer.com/image/art%3A10.1007%2Fs10561-007-9046-z/MediaObjects/10561_2007_9046_Fig5_HTML.gif
Fig. 5

The most frequent HLA alleles in the Bulgarian Roma

This distinct genetic profile emphasized the need to represent correspondingly minorities in the bone marrow donor registries. Ethnic composition of population in Bulgaria is as follow: Bulgarians—87%; Turkish—8%; Roma—4% and others—1%. In BBMDR so far are represented mainly Bulgarians (94%), while the proportion of Roma and Turkish is relatively smaller (2% and 4% respectively) and therefore the number of donors from these ethnic groups should be increased.

Search activities of BBMDR

Despite of the small number of donors, three preliminary search requests for international patients with ALL and Thalassemia from England, France and Macedonia were received by our registry. HLA matched donor was found in BBMDR for one of these patients. BBMDR also provides services for Bulgarian transplant centers with regard to unrelated donor searches. In the period 2005–2006 15 patients, in need of HSCT lacking matched family donor were activated (Fig. 6). Except for one patient, for all other HLA matched donor was found in BMDW. One of the patients was transplanted from unrelated HLA matched donor from ZKRD, and one is in the process of final test for transplantation.
https://static-content.springer.com/image/art%3A10.1007%2Fs10561-007-9046-z/MediaObjects/10561_2007_9046_Fig6_HTML.gif
Fig. 6

Search activities for Bulgarian patients needing unrelated stem cell transplantation. Number of searches per diagnosis

Future directions

Considering the small number of donors recruited so far, one of the main goals of the BBMDR would be to increase the number of voluntary donors by establishment of national network for donor recruitment. Preliminary statistical analysis showed that considering the size of our population and specific genetic background the optimal number of donors in the registry would be 5000. Due to specific genetic characteristics of the Bulgarians, for some patients lacking HLA matched donor in the family it is difficult to find donor in the international registries. Therefore it is necessary to recruit donors with rare alleles and haplotypes in order to increase the probability patients from ethnic minorities to be transplanted. Other important tasks of BBMDR is the improvement of BBMDR database and information system and integration in the European Marrow Donor Information System (EMDIS), accreditation according to WMDA standards, and the improvement of stem cells exchange between BBMDR and other registries within BMDW according to national and international regulations.

Copyright information

© Springer Science+Business Media B.V. 2007