Volunteer Bone Marrow Research Articles

Multiple measures for self-identification improve matching donors with patients in unrelated hematopoietic stem cell transplant

BackgroundQuestions persist around whether and how to use race or geographic ancestry in biomedical research and medicine, but these forms of self-identification serve as a critical tool to inform matching algorithms for human leukocyte antigen (HLA) of varying levels of resolution for unrelated hematopoietic stem cell transplant in large donor registries.MethodsHere, we examined multiple self-reported measures of race and ancestry from a survey of a cohort of over 100,000 U.S. volunteer bone marrow donors alongside their high-resolution HLA genotype data.ResultsWe find that these self-report measures are often non-overlapping, and that no single self-reported measure alone provides a better fit to HLA genetic ancestry than a combination including both race and geographic ancestry. We also found that patterns of reporting for race and ancestry appear to be influenced by participation in direct-to-consumer genetic ancestry testing.ConclusionsWhile these data are not used directly in matching for transplant, our results demonstrate that there is a place for the language of both race and geographic ancestry in the critical process of facilitating accurate prediction of HLA in the donor registry context.

Two novel HLA-DQB1 alleles identified by next generation sequencing.

Two novel HLA-DQB1 alleles, HLA-DQB1*05:01:50 and HLA-DQB1*06:486, characterised in bone marrow volunteers.

The novel HLA-DPB1*04:02:01:44 allele identified in a volunteer bone marrow donor.

Nucleotide substitution in the intron 2 of HLA-DPB1*04:02:01:01 results in a novel allele, HLA-DPB1*04:02:01:44.

The novel HLA-B*35:01:77 allele identified in a Russian volunteer bone marrow donor.

Nucleotide substitutions in the 5'UTR and exon 2 of HLA-B*35:01:01:05 result in a novel allele, HLA-B*35:01:77.

Discovery of the novel HLA-A*01:01:01:112 allele in a Greek volunteer bone marrow donor.

HLA-A*01:01:01:112 differs from the HLA-A*01:01:01:01 allele by one nucleotide substitution in the 5'UTR.

Discovery of the novel HLA-B*47:01:01:07 allele in a Greek volunteer bone marrow donor.

HLA-B*47:01:01:07 differs from the HLA-B*47:01:01:03 allele by one nucleotide deletion in the 3'UTR.

The HLA-B*38:110 allele identified in a volunteer bone marrow donor.

HLA-B*38:110 allele differs from HLA-B*38:01:01:01 in codon 202 in exon 4.

The HLA-B*35:02:21 allele identified in a volunteer bone marrow donor.

The HLA-B*35:02:21 allele differs from HLA-B*35:02:01:01 in codon 183 in exon 4.

HLA-B27 positivity in a large miscegenated population of 5,389,143 healthy blood marrow donors in Brazil

BackgroundThe prevalence of HLA-B27 gene positivity in healthy Caucasian communities varies between 8 and 14%. However, there is a lack of information in countries with a high rate of miscegenation, such as Brazil.AimTo estimate the frequency of HLA-B27 in the Brazilian general population using a large national registry database.MethodsThis is a cross-sectional ecological study using the Brazilian Registry of Volunteer Bone Marrow Donors (REDOME) database on HLA-B27 allelic frequency and proportion of positives of healthy donors (18–60 years old). Data were analyzed according to sex, age, race (by self-reported skin color recommended by the Brazilian Institute of Geography and Statistics - IBGE), and geographic region of residence.ResultsFrom 1994 to 2022, a total of 5,389,143 healthy bone marrow donors were included. The overall positivity for HLA-B27 was 4.35% (CI 95% 4.32–4.37%), regardless of sex and age (57.2% were women, mean age was 41.7yo). However, there was a difference between races: 4.85% in Whites; 2.92% in Blacks; 3.76% in Pardos (Browns i.e. mixed races); 3.95% in Amarelos (Yellows i.e. Asian Brazilians); and 3.18% in Indigenous. There was also a difference regarding geographic region of residence (North: 3.62%; Northeast: 3.63%; Southeast: 4.29%; Midwest: 4.5% and 5.25% in South). The homozygosity rate for the HLA-B27 was 1.32% of all the positives and only 0.06% in the general population.ConclusionsOur findings provide the first Brazilian national prevalence for HLA-B27 in 4.35%. There is a gradient gene positivity from North to South, suggesting that the genetic background related to the miscegenation due to colonization, slavery, and some later waves of immigration together with internal migratory flows, could explain our findings.

HLA haplotypes and differential regional mortality caused by COVID-19 in Brazil: an ecological study based on a large bone marrow donor bank dataset.

The coronavirus disease 2019 (COVID-19) mortality rates varied among the states of Brazil during the course of the pandemics. The human leukocyte antigen (HLA) is a critical component of the antigen presentation pathway. Individuals with different HLA genotypes may trigger different immune responses against pathogens, which could culminate in different COVID-19 responses. HLA genotypes are variable, especially in the highly admixed Brazilian population. In this ecological study, we aimed to investigate the correlation between HLA haplotypes and the different regional distribution of COVID-19 mortality in Brazil. HLA data was obtained from 4,148,713 individuals registered in The Brazilian Voluntary Bone Marrow Donors Registry. COVID-19 data was retrieved from epidemiological bulletins issued by State Health Secretariats via Brazil's Ministry of Health from February/2020 to July/2022. We found a positive significant correlation between the HLA-A*01~B*08~DRB1*03 haplotype and COVID-19 mortality rates when we analyzed data from 26 states and the Federal District. This result indicates that the HLA-A*01~B*08~DRB1*03 haplotype may represent an additional risk factor for dying due to COVID-19. This haplotype should be further studied in other populations for a better understanding of the variation in COVID-19 outcomes across the world.

Identification of the novel HLA-C*07:446 allele in a volunteer bone marrow donor.

HLA-C*07:446 differs from HLA-C*07:02:01:01 by one nucleotide substitution at position 809 (C → T) in exon 4.

The HLA-B*58:01:42 allele identified in a volunteer bone marrow donor.

HLA-B*58:01:42 differs from HLA-B*58:01:01:01 in codon 303 in exon 5.

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

Identification of the novel HLA-C*07:02:01:115 allele in a volunteer bone marrow donor.

HLA‐C*07:02:01:115 differs from C*07:02:01:03 by one nucleotide substitution at position gDNA −243 in 5'UTR.

Identification of the novel HLA-A*68:250 allele in a volunteer bone marrow donor from Sao Paulo, Brazil.

The allele HLA-A*68:250 differs from HLA-A*68:27:01 by three nucleotides.

Immunogenetic characteristics of potential donors of hemapoietic stem cells recruited in the North Caucasus

Aim of the study was to investigate the immunogenetic characteristics of the potential donors of hematopoietic stem cells recruited in the North Caucasus and the distribution features of HLA alleles and multilocus haplotypes. Material and methods . Next Generation Sequencing technology was used to identify HLA-A, -B, -C, -DRB1 and -DQB1 alleles from 2663 unrelated bone marrow volunteers living in the Chechen Republic, Stavropol region, Republic of Dagestan. Mass parallel sequencing was performed using the MiSeq™ System («Illumina Inc.», USA). HLA allele and haplotype frequencies were estimated via maximum-likelihood analysis from genotypic data through an expectationmaximization (EM) algorithm for unknown gametic phase using Arlequin v. 3.5.2.2. Results and discussion . In studied population, 47 HLA-A, 77 HLA-B, 39 HLA-C, 54 HLA-DRB1, 22 HLA-DQB1 alleles were selected. Thirteenth alleles, HLA-A*02:01, HLA-A*01:01, HLA-B*13:02, HLA-B*51:01, HLA-C*06:02, HLA-C*04:01, HLA-C*07:02, HLADRB1*07:01, HLA-DRB1*13:01, HLA-DQB1*03:01, HLA-DQB1*02:02, HLA-DQB1*06:03, DQB1*03:02 exhibit frequencies over 10 %. The highest frequency extended haplotype HLA-A*02:01-B*13:02-C*06:02-DRB1*07:01DQB1*02:02, was observed frequencies of 4,5 %. Routine HLA typing allowed us to define 13 new HLA alleles.

A new set of reagents and related software used for NGS based classical and non-classical HLA typing showing evidence for a greater HLA haplotype diversity

To evaluate the HLA typing performance of a new Long-Range PCR NGS set of reagents and its dedicated software, a panel of 41 reference homozygous cell lines from the International Histocompatibility Working Group (IHWG) and a panel of 376 volunteer bone marrow donors were analyzed for classical and non-classical HLA class I and class II genes. All results, except HLA-DPB1, were obtained without any ambiguities at the 3rd field level. Based on the high resolution performance of the reagents, a number of new alleles have been described not only for classical but also for non-classical HLA class I genes, leading to a more accurate haplotype definition. Linkage disequilibrium between HLA-A and HLA-G genes has been defined at 4th field level of resolution. Moreover, for the first time, HLA-DQA2 and DQB2 polymorphisms and their linkage disequilibrium with DQB1 were described.

Immunogenetic characteristics of unrelated hematopoietic stem cell donors recruited in the Sverdlovsk, Saratov, Yaroslavl and Vladimir regions

Aim of the study was to investigate the distribution features of HLA alleles and multilocus haplotypes in potential donors of hematopoietic stem cells recruting in the Sverdlovsk, Saratov, Yaroslavl and Vladimir regions. Material and methods. Sequence Based Typing technology was used to identify human leukocyte antigen (HLA)-A, -B, -C, -DRB1 alleles from 2683 Russian unrelated bone marrow volunteers living in the Sverdlovsk (n = 1018), Saratov (n = 825), Yaroslavl (n = 604) and Vladimir (n = 236) regions. HLA allele and haplotype frequencies were estimated via maximum-likelihood analysis from genotypic data through an expectation-maximization (EM) algorithm for unknown gametic phase. Results and discussion. In all studied populations, 16 HLA-A, 13 HLA-C, 13 HLA-DRB1 alleles were selected. In the locus HLA-B, 28 alleles were detected in the populations of the Sverdlovsk and Yaroslavl regions, 27alleles – in the Saratov region, 25 alleles – in the Vladimir. Seventeen alleles, HLA-A*02, HLA-A*03, HLA-A*01, HLA-A*24, HLA-B*07, HLA-B*35, HLA-С*07, HLA-С*06, HLA-С*04, HLA-С*03, HLA-С*12, HLA-DRB1*15, HLA-DRB1*07, HLA-DRB1*01, HLA-DRB1*13, HLA-DRB1*04, HLA-DRB1*11 exhibit frequencies over 10 %. The highest frequency extended haplotype in the all studied populations HLA-A*01-B*08-C*07-DRB1*03, was observed frequencies of 4,4 % – in the Sverdlovsk region, 3,2 % – in the Saratov region, 4,9 % – in the Yaroslavl region and 4,2 % – in the Vladimir region. Routine HLA typing allowed us to define four new HLA alleles in the populations of the Sverdlovsk and Saratov region.

HLA diversity in Brazil.

Brazil is the fifth largest country in the world in area and the fifth most populous. The Brazilian voluntary Bone Marrow Donor Registry is the third largest in terms of number of donors in the world, being a valuable source of HLA genetics to characterize the donor population of Brazil as well. The genetic background of the Brazilian population is quite heterogeneous, resulting from 5 centuries of admixture among Native Americans, Europeans and Africans, making the Brazilian population unique in terms of genetic ancestry. The unique characteristics of populations in different Brazilian regions make them an exciting focus for genetic diversity studies. Studies on HLA genetic diversity of Brazilian populations have been conducted since the late 1980s and, in this review, we highlight the main findings from studies carried out in Brazil based on classical HLA. In addition, we calculated the genetic distance from the molecular data of the studies included in this review in order to have a broader view of the HLA diversity in Brazilian populations. We emphasize that characterization of HLA diversity is not only important for transplantation programs, but can shed a light on ancestry, history and other demographic patterns with or without association with autoimmune disease.

Description of a novel HLA null allele, DRB1*15:176N.

A new HLA null allele, DRB1*15:176N, was characterized in a Spanish volunteer bone marrow donor.