HLA-E typing of more than 2.5 million potential hematopoietic stem cell donors: Methods and population-specific allele frequencies.

We developed a cost-efficient workflow for genotyping HLA-E by NGS and applied it for genotyping more than 2.5 million potential stem cell donors. The data obtained were used to determine HLA-E allele frequency distributions for 104 populations. Our results confirm the known dominance of the alleles E*01:01 and E*01:03, which have a combined frequency of more than 0.99 in 97 of the 104 populations. E*01:01 is more frequent in Africa and the western part of South America, E*01:03 in Southeast and East Asia. E*01:03 shows a pronounced regional substructure at the high-resolution level with E*01:03:01G being particularly common in a large connected region extending from Turkey to China, E*01:03:02G in Northwestern Europe and E*01:03:03 in Central and Eastern Europe as well as Central Asia. The presented results are relevant both as a basis for further population genetics studies and for optimizing stem cell donor searches.

Higher frequencies of HLA DQB1*05:01 and anti-glycosphingolipid antibodies in a cluster of severe Guillain-Barré syndrome.

Few regional and seasonal Guillain-Barré syndrome (GBS) clusters have been reported so far. It is unknown whether patients suffering from sporadic GBS differ from GBS clusters with respect to clinical and paraclinical parameters, HLA association and antibody response to glycosphingolipids and Campylobacter jejuni (Cj). We examined 40 consecutive patients with GBS from the greater Munich area in Germany with 14 of those admitted within a period of 3 months in fall 2010 defining a cluster of GBS. Sequencing-based HLA typing of the HLA genes DRB1, DQB1, and DPB1 was performed, and ELISA for anti-glycosphingolipid antibodies was carried out. Clinical and paraclinical findings (Cj seroreactivity, cerebrospinal fluid parameters, and electrophysiology) were obtained and analyzed. GBS cluster patients were characterized by a more severe clinical phenotype with more patients requiring mechanical ventilation and higher frequencies of autoantibodies against sulfatide, GalC and certain ganglioside epitopes (54 %) as compared to sporadic GBS cases (13 %, p = 0.017). Cj seropositivity tended to be higher within GBS cluster patients (69 %) as compared to sporadic cases (46 %, p = 0.155). We noted higher frequencies of HLA class II allele DQB1*05:01 in the cluster cohort (23 %) as compared to sporadic GBS patients (3 %, p = 0.019). Cluster of severe GBS was defined by higher frequencies of autoantibodies against glycosphingolipids. HLA class II allele DQB1*05:01 might contribute to clinical worsening in the cluster patients.

Regional differences in HLA antigen and haplotype frequency distributions in Germany and their relevance to the optimization of hematopoietic stem cell donor recruitment.

We analyzed regional differences in human leukocyte antigen (HLA)-A, -B, and -DR antigen and haplotype frequencies based on a sample of approximately 320,000 German donors in order to identify regions that are especially suited for ongoing stem cell donor recruitment. Geographic partitioning was carried out by postal code regions. Analysis of genetic distances suggests the existence of three regional clusters in South (regions 6-9), East (0-1), and Northwest (2-5) Germany. The southern cluster shows most favorable characteristics with respect to haplotypic and phenotypic diversity and the occurrence of rare HLA antigens. The opposite behavior is shown by regions 2-4 of the northwestern cluster. As a result of lower HLA diversity, completeness of a regional donor file in region 4 with 100,000 donors would be higher than that of a file in region 7 with 170,000 donors. This fact shows the relevance of regional HLA differences for practical donor registry planning. Results such as those presented in this work can be used to diminish the problem of decreasing marginal benefit of donor recruitment, as more than 13 million donors are registered worldwide today.

Criteria for initiation and evaluation of minority donor programs and application to the example of donors of Turkish descent in Germany.

Minority donor programs aim to improve access to unrelated hematopoietic SCT for specific ethnic groups through directed donor recruitment. We have developed criteria for initiation and evaluation of such programs and applied them to the situation of donors of Turkish descent in Germany, as well as a program by DKMS German Bone Marrow Center that targets this group. Criteria for program initiation include the number of accessible minority donors, potential impact on the chances of finding matching donors, and general access to unrelated transplantation for patients of the targeted group. Success criteria comprise number and availability of recruited donors, the effect of these donors on the HLA phenotype distribution of a donor file, and the number of donations resulting from the program. More than 40 000 donors of Turkish descent have been recruited within the analyzed program to date. Recruited minority donors show more favorable demographic characteristics but lower availability rates than do German donors. Although HLA haplotype distributions of Turkish and German donors differ considerably, patients with common Turkish HLA phenotypes should benefit from the German donor pool even without a specific minority program. The analysis of donations from minority donors, however, shows specific benefits for patients with rare HLA phenotypes.