A European HLA Isolate and Its Implications for Hematopoietic Stem Cell Transplant Donor Procurement

Abstract

Europeans have often been considered a homogenous group in registry donor match predictions, but it is now evident that HLA haplotype frequencies vary across the European continent. Earlier studies have indicated that Finns in northeastern Europe have unique HLA characteristics, and the increasing availability of high-resolution registry donor data is now making more detailed comparisons possible. In the first phase of the present study, estimated HLA haplotype frequencies in stem cell donor registries of Finland and its neighbors Sweden and Russia were calculated using the algorithm of the German National Bone Marrow Donor Registry (ZKRD) and their frequencies were compared with one another and also with that of Germany. Virtual donor searches for 1492 high-resolution typed Finnish patients in the Finnish, Swedish and German registries were then performed, using individual match predictions for each registry. In the last phase, the impact of specifically Finnish-enriched HLA haplotypes on Finnish patients and the use of Finnish registry donors was assessed by analyzing 647 consecutive hematopoietic stem cell transplantation (HSCT) donor searches and 40 exported Finnish HSCTs. The Finnish HLA landscape was more homogenous than the 3 other studied populations, but also genetically distinct from them. The match predictions found a probable 10/10 match for 71%, 41%, and 31% of the Finnish patients in the German, Finnish, and Swedish registries, respectively. Thirty-four of Finland's 100 most frequent HLA haplotypes were represented with a frequency of <.0003 in Germany, and with an 8- to 3262-fold greater frequency in Finland than in Germany. Patients carrying these Finnish-enriched haplotypes were less likely to receive a matched HSCT but more likely to receive it from a domestic donor. Registry donors carrying them were more likely to donate stem cells, both nationally and internationally. The Finnish HLA isolate has a significant impact on both Finnish patients and registry donors, explaining the high use of national registry donors for Finnish patients. Haplotype frequency estimations are an important tool for small registries as well, to help optimize donor match predictions and the size of individual registries.

A study of selected hematopoietic stem cell donors provided by an intermediate size registry

“…Poor (GF ≤ 5. 22 However, with few exceptions 9,23,24 no detailed analysis has been performed on the selected donors with respect to HLA and non-HLA characteristics.…”

The complexity and diversity of major histocompatibility complex challenge disease association studies

“…In the Finnish population, the common European HLA alleles and haplotypes as well as unique enrichments of haplotypes are presented. 42,43 .This was evident in a study where HLA-DRB1 imputation showed very low accuracy rate (<30%) for some alleles such as HLA-DRB1*01:01, HLA-DRB1*13:01, and HLA-DRB1*15:01 belonging to the five most frequent HLA-DRB1 alleles in the Finnish population when the reference material was from a large heterogeneous European population and not from the Finnish population. 44 Low imputation accuracy for HLA-DRB1 has also been described by other studies covering heterogeneous study cohorts or diverse ancestry groups.…”

“…Western and Eastern Finnish populations exhibit peculiar genetic features reflecting the settlement and population history of Finland. In the Finnish population, the common European HLA alleles and haplotypes as well as unique enrichments of haplotypes are presented …”

“…The strongest protective haplotype for T1D is DRB1*15:01‐DQA1*01:02‐DQB1*06:02 with the frequency of 1% vs 20% in diabetics and general population, respectively, but varying between populations. HLA‐DRB1*15:01 and HLA‐DQB1*06:02 have also been found to be resistance genes for HIV‐1 infection in Chinese and in European‐descent populations, respectively, corresponding to the protective genes in T1D . HLA‐DRB1*15:01 seems to be protective in Grave's disease and the haplotype DRB1*15:01‐DQA1*01:02‐DQB1*06:02 in European‐descent patients with autoimmune polyglandular syndrome and in Moroccan patients with pemphigus .…”

“…HLA-DRB1*15:01 and HLA-DQB1*06:02 have also been found to be resistance genes for HIV-1 infection in Chinese and in European-descent populations, respectively, corresponding to the protective genes in T1D. 42,43,82,83 HLA-DRB1*15:01 seems to be protective in Grave's disease and the haplotype DRB1*15:01-DQA1*01:02-DQB1*06:02 in European-descent patients with autoimmune polyglandular syndrome and in Moroccan patients with pemphigus. [44][45][46][47] In the Finnish population, we found the haplotype HLA-B*07-DRB1*15:01 to be protective for coronary artery disease 84 .…”