Estimation of high-resolution HLA-A, -B, -C, -DRB1 allele and haplotype frequencies based on 8862 German stem cell donors and implications for strategic donor registry planning
Introduction
High-resolution donor-recipient matching for the human leukocyte antigen (HLA)–A, HLA-B, HLA-C, and HLA-DRB1 genes improves patient survival after unrelated hematopoietic stem cell transplantation [1], [2]. As a consequence, unrelated donor search is aimed at finding donors who match with the corresponding patients at least for these four genes at high resolution [3]. In this context, the availability of high-resolution HLA haplotype frequency distributions is helpful for two reasons. First, it increases the efficiency of individual donor searches, as many registered donors are listed only with incomplete HLA information; one or more relevant HLA genes may be typed only at low/intermediate resolution or not at all. Search coordinators can use high-resolution haplotype frequency distributions of the donor population to identify donors who have, despite their incomplete HLA typing information, high probabilities to be optimal matches for specific patients. Advanced search algorithms as HapLogic [4] or OptiMatch [5] use haplotype frequency distributions to automatically sort potential donors with incomplete HLA information by matching probabilities. Second, population-specific HLA haplotype frequency distributions determine how many patients find matching donors in a registry with n donors from the analyzed population [6], [7], [8]. This quantity has implications for strategic donor registry planning, as donor centers and registries have to deal with limited resources and must decide to which extent these resources should be allocated for ongoing donor recruitment efforts.
Available population-specific estimations of haplotype frequency distributions that are based on large data set sizes are often, at least partly, restricted to low-resolution HLA results [7], [8], [9], [10]. This is caused by the fact that large data sets of several thousand HLA-typed individuals mainly exist in unrelated stem cell donor registries. Donor registry HLA data, however, are generally heterogeneous with respect to typed HLA genes (only HLA-A and HLA-B or HLA-A, HLA-B, and HLA-DRB1 or more complete typing), typing resolution (high or low/intermediate resolution), and typing method (molecular methods or serology). Also, the discovery of new allelic variants compromises high-resolution typing data over time [11]. Furthermore, HLA data of registered stem cell donors often accumulate over several years. Additional HLA typing after registration may be carried out within the scope of specific donor searches (patient-directed typing) or initiated by the donor center or registry (prospective typing). In both cases, the selection for additional typing is based on the donor's HLA phenotype as it is known until then. Recently it was shown that such data characteristics do not generally prevent the estimation of haplotype frequencies through the expectation-maximization (EM) algorithm [12]. However, application of the EM algorithm remains computationally challenging in this setting.
The German Bone Marrow Donor Center (DKMS) has started to carry out “full” HLA typing, i.e., high-resolution typing of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 genes, at donor recruitment for young male donors in 2005. By now, all new DKMS donors are typed this way. It has been shown that this approach can be advantageous for donor center operations [13]. Furthermore, these data can serve as a bias-free data set for haplotype frequency estimations without the above-mentioned difficulties.
We estimated gene and haplotype frequencies of the German stem cell donor pool based on 8862 donors who were typed at high resolution for HLA-A, HLA-B, HLA-C, and HLA-DRB1 at recruitment. Our results are used to estimate the probability of finding fully matched donors by donor registry size. In particular, we analyze how matching probabilities depend on various matching requirements.
Section snippets
Donors
Analyses are based on donors who were recruited between March 2005 and December 2005. All donors who were recruited at donor drives within this period and fulfilled the project eligibility criteria (male gender, age <26 years) were typed for HLA-A, HLA-B, HLA-C, and HLA-DRB1 at high resolution. At recruitment, donors were asked to indicate their ethnic descent based on country of origin. A total of 8904 donors who declared themselves to be of German descent were included in the analysis. Donor
Allele and antigen frequencies
The numbers of observed alleles for the different HLA genes were 61 for HLA-A, 101 for HLA-B, 47 for HLA-C, and 68 for HLA-DRB1. Allele frequencies are given in Table 1. Cumulative allele frequencies for the four analyzed HLA genes are displayed in Fig. 1. The highest allelic diversity exists for HLA-B within our data set, the lowest diversity occurs for HLA-A.
In some cases HLA typing did not lead to unambiguous results, most probably through the existence of new alleles. This observation was
Discussion
In this work we present high-resolution allele and haplotype frequencies of the German population based on an unbiased data set of 8862 individuals. No such data have been published for the German population so far. As donor-recipient matching in hematopoietic stem cell transplantation should consider the HLA-A, HLA-B, HLA-C, and HLA-DRB1 genes at high resolution [3], these data are of high relevance for both individual donor searches and strategic donor registry planning.
We have transformed
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