ABSTRACT
The allele HLA-C*07:02:60 differs from HLA-C*07:02:01:01 by a silent nucleotide substitution in exon 4.
Subject(s)
Alleles , HLA-C Antigens/genetics , Polymorphism, Single Nucleotide , Base Sequence , Codon , Exons , HLA-C Antigens/classification , HLA-C Antigens/immunology , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Molecular Sequence Data , Protein Isoforms/classification , Protein Isoforms/genetics , Protein Isoforms/immunology , Sequence Alignment , Unrelated DonorsABSTRACT
The novel DRB1*01:16 allele differs for G to T substitution at position 595 from DRB3*01:01P.
Subject(s)
Alleles , HLA-DRB3 Chains/genetics , Hematopoietic Stem Cell Transplantation , Point Mutation , Amino Acid Substitution , Base Sequence , Child , Cloning, Molecular , Codon , Exons , Family , Genotype , HLA-DRB3 Chains/immunology , Histocompatibility Testing , Humans , Italy , Male , Molecular Sequence Data , Sequence Alignment , Sequence Analysis, DNA , Transplant RecipientsABSTRACT
The simultaneous typing of five-HLA loci at high resolution and the availability of pedigree data allowed us to characterize extended five-locus phased haplotypes in 124 Nigerian families and to compare the observed frequencies with those expected by an expectation-maximization algorithm for unphased data. Despite the occurrence of some frequent alleles at each locus (e.g. B*53:01, which is assumed to protect against Plasmodium falciparum), as many as 82% of the sampled individuals carry two unique five-locus haplotypes and only three extended haplotypes with frequency above 1% exhibit significant linkage disequilibrium. Although preliminary, these results reveal an extreme level of HLA diversity in the Nigerian population, which reflects both its multi-ethnic composition and the very ancient demographic history of African populations.
Subject(s)
HLA-A Antigens/genetics , HLA-B Antigens/genetics , HLA-C Antigens/genetics , HLA-DQ beta-Chains/genetics , HLA-DRB1 Chains/genetics , Haplotypes , Linkage Disequilibrium , Alleles , Family , Gene Expression , Gene Frequency , Genetic Variation , Genetics, Population , HLA-A Antigens/immunology , HLA-B Antigens/immunology , HLA-C Antigens/immunology , HLA-DQ beta-Chains/immunology , HLA-DRB1 Chains/immunology , Histocompatibility Testing , Humans , Nigeria , PedigreeABSTRACT
Mixed chimerism (MC), the simultaneous presence of both host- and donor-derived cells in the recipient, is observed in a large proportion of patients after haematopoietic stem cell transplant (HSCT) to treat haemoglobinopathies. Detected early after transplantation, MC often moves towards complete chimerism, although sometimes it may evolve into graft rejection, especially if the proportion of donor cells is very low. However, some patients develop stable MC, defined as persistent when donor- and host-derived cells coexist for periods longer than 2 years after HSCT. Patients with persistent mixed chimerism (PMC) do not require additional red blood cell support and, regardless of the presence in some cases of an extremely low percentage of donor-derived nucleated cells in the bone marrow, their condition is clinically controlled by an incomplete but functional graft, as they express a two- to fivefold enrichment of donor-derived mature erythrocytes in the peripheral blood. These findings have tremendous implications not only in the context of allogeneic HSCT but also in the design of gene therapy trials based on the autologous transplantation of genetically modified CD34+ cells. Recent studies have shown that durable allograft tolerance has been achieved by induction of haematopoietic chimerism in clinical kidney transplantation, showing the involvement of regulatory T cells. Similarly, it has been shown that the regulatory T cells play a pivotal role in promoting and maintaining immune tolerance in patients that develop a status of PMC after HSCT for Thalassemia.
Subject(s)
Chimerism , Graft Rejection/immunology , Hematopoietic Stem Cell Transplantation , Hemoglobinopathies/immunology , Immune Tolerance/immunology , Humans , Risk FactorsABSTRACT
The information regarding the probability of finding a matched unrelated donor (MUD) within a relatively short time is crucial for the success of hematopoietic stem cell transplantation (HSCT), particularly in patients with malignancies. In this study, we retrospectively analyzed 315 Italian patients who started a search for a MUD, in order to assess the distribution of human leukocyte antigen (HLA) alleles and haplotypes in this population of patients and to evaluate the probability of finding a donor. Comparing two groups of patients based on whether or not a 10/10 HLA-matched donor was available, we found that patients who had a fully-matched MUD possessed at least one frequent haplotype more often than the others (45.6% vs 14.3%; P = 0.000003). In addition, analysis of data pertaining to the HLA class I alleles distribution showed that, in the first group of patients, less common alleles were under-represented (20.2% vs 40.0%; P = 0.006). Therefore, the presence of less frequent alleles represents a negative factor for the search for a potential compatible donor being successful, whereas the presence of one frequent haplotype represents a positive predictive factor. Antigenic differences between patient and donor observed at C and DQB1 loci, were mostly represented by particular B/C or DRB1/DQB1 allelic associations. Thus, having a particular B or DRB1 allele, linked to multiple C or DQB1 alleles, respectively, might be considered to be associated with a lower probability of a successful search. Taken together, these data may help determine in advance the probability of finding a suitable unrelated donor for an Italian patient.
Subject(s)
Donor Selection , HLA Antigens/genetics , Hematopoietic Stem Cell Transplantation , Tissue Donors , Alleles , Gene Frequency/genetics , Genetic Loci/genetics , Haplotypes/genetics , Humans , Italy , Unrelated DonorsABSTRACT
The novel HLA-DPA1*01:130 allele differs from HLA-DPA1*01:03:01:03 by one nucleotide substitution in Exon 3.
Subject(s)
HLA-DP alpha-Chains , High-Throughput Nucleotide Sequencing , Humans , Alleles , Histocompatibility Testing , HLA-DP alpha-Chains/geneticsABSTRACT
The new allele, officially named HLA DRB1*14:129, differs from HLA DRB1*14:54 in exon 2.
Subject(s)
Alleles , HLA-DRB1 Chains/genetics , Point Mutation , Base Sequence , Exons , HLA-DRB1 Chains/immunology , Histocompatibility Testing , Humans , Molecular Sequence Data , Stem Cell Transplantation , Tissue DonorsABSTRACT
The novel allele human leukocyte antigen(HLA)-DQB1*06:04:04 differs from HLA-DQB1*06:04:01 by a silent nucleotide substitution at codon 75 (TTG â CTG).
Subject(s)
Alleles , HLA-DQ beta-Chains/genetics , Base Sequence , Exons/genetics , Humans , Molecular Sequence Data , Sequence AlignmentABSTRACT
The novel allele HLA-DQB1*04:09 differs from DQB1*04:02:01 by three nonsynonymous nucleotide substitutions in exon 2.
Subject(s)
Alleles , HLA-DQ beta-Chains/genetics , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Base Sequence , Exons , Histocompatibility Testing , Humans , Italy , Molecular Sequence Data , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Sequence Alignment , Sequence Analysis, DNAABSTRACT
We present here the results of the Analysis of HLA Population Data (AHPD) project of the 16th International HLA and Immunogenetics Workshop (16IHIW) held in Liverpool in May-June 2012. Thanks to the collaboration of 25 laboratories from 18 different countries, HLA genotypic data for 59 new population samples (either well-defined populations or donor registry samples) were gathered and 55 were analysed statistically following HLA-NET recommendations. The new data included, among others, large sets of well-defined populations from north-east Europe and West Asia, as well as many donor registry data from European countries. The Gene[rate] computer tools were combined to create a Gene[rate] computer pipeline to automatically (i) estimate allele frequencies by an expectation-maximization algorithm accommodating ambiguities, (ii) estimate heterozygosity, (iii) test for Hardy-Weinberg equilibrium (HWE), (iv) test for selective neutrality, (v) generate frequency graphs and summary statistics for each sample at each locus and (vi) plot multidimensional scaling (MDS) analyses comparing the new samples with previous IHIW data. Intrapopulation analyses show that HWE is rarely rejected, while neutrality tests often indicate a significant excess of heterozygotes compared with neutral expectations. The comparison of the 16IHIW AHPD data with data collected during previous workshops (12th-15th) shows that geography is an excellent predictor of HLA genetic differentiations for HLA-A, -B and -DRB1 loci but not for HLA-DQ, whose patterns are probably more influenced by natural selection. In Europe, HLA genetic variation clearly follows a north to south-east axis despite a low level of differentiation between European, North African and West Asian populations. Pacific populations are genetically close to Austronesian-speaking South-East Asian and Taiwanese populations, in agreement with current theories on the peopling of Oceania. Thanks to this project, HLA genetic variation is more clearly defined worldwide and better interpreted in relation to human peopling history and HLA molecular evolution.
Subject(s)
HLA-DP Antigens/genetics , HLA-DQ Antigens/genetics , HLA-DRB1 Chains/genetics , Asia , Ethnicity , Europe , Gene Frequency , Genetic Variation , Genetics, Population , Genotype , Haplotypes , Humans , Oceania , Population GroupsABSTRACT
DQB1*05:304 allele was identical to DQB1*05:02:01 except for a single nucleotide substitution.
Subject(s)
High-Throughput Nucleotide Sequencing , Nucleotides , Humans , Base Sequence , Alleles , HLA-DQ beta-Chains/geneticsABSTRACT
The new allele shows one nucleotide change from C*07:02:01:01 at 351 nt from C to A, resulting in an amino acid change at codon 93 of exon 3 from H to Q.
Subject(s)
Alleles , Exons/genetics , HLA-C Antigens/genetics , Mutation/genetics , Amino Acid Sequence , DNA Probes, HLA/genetics , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Italy , Molecular Sequence Data , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , Tissue DonorsABSTRACT
HLA-A*03:143 has one nucleotide change from A*03:01: 01:01 at nt 406 from G to C, resulting in an amino acid change at codon 112 of exon 3 from Gly to Arg.
Subject(s)
HLA-A3 Antigen/genetics , Alleles , Amino Acid Substitution , Base Sequence , DNA/genetics , Exons , Female , Genotyping Techniques , Haplotypes , Histocompatibility Testing , Humans , Italy , Male , Molecular Sequence Data , Pedigree , Polymorphism, Single Nucleotide , Sequence Homology, Nucleic AcidABSTRACT
The novel HLA-C allele C*06:58 shows one nucleotide change from C*06:02:01:01 at nt 366 from G to A, resulting in an amino acid change at codon 98 of exon 3 from Met to Ile.
Subject(s)
Alleles , Amino Acid Substitution , Exons/genetics , HLA-C Antigens/genetics , Family , Female , Humans , Italy , Male , Sequence Analysis, DNAABSTRACT
The novel allele HLA-C*16:07:02 differs from HLA-C* 16:07:01 by a silent nucleotide substitution at codon 220 (TAC â TAT).
Subject(s)
HLA-C Antigens/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Alleles , Base Sequence , Benin/ethnology , DNA Primers , Exons , Female , HLA-C Antigens/immunology , Haplotypes , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Male , Middle Aged , Molecular Sequence Data , Nucleotides/genetics , Point Mutation , Polymerase Chain Reaction , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Sequence Analysis, DNA , SiblingsABSTRACT
The new allele differs from HLA-DPB1*23:01 in exon 3.
Subject(s)
HLA-DP beta-Chains/genetics , Polymorphism, Single Nucleotide , Alleles , Base Sequence , Chromosomes, Human, Pair 6 , Exons , HLA-DP beta-Chains/immunology , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Molecular Sequence Data , Sequence Alignment , Sequence Analysis, DNA , Tissue DonorsABSTRACT
Polymorphisms in the 3' untranslated region (3'UTR) of HLA-G, an important player in immunological tolerance, could be involved in post-transcriptional expression control, and their association with different clinical immune-related conditions including autoimmunity and transplantation is of mounting interest. Most studies have focused on a 14 base pair (bp) insertion/deletion (ins/del), while additional single-nucleotide polymorphisms (SNPs) in the HLA-G 3'UTR have been described but not extensively investigated for their clinical relevance. Here we have comparatively studied the association between 3'UTR haplotypes of HLA-G, or the 14 bp ins/del, with clinical outcome of HLA-identical sibling hematopoietic stem cell transplantation (HSCT) in 147 Middle Eastern beta-thalassemia patients. Sequence based typing of 3'UTR HLA-G polymorphisms in the patients and in 102 healthy Italian blood donors showed strong linkage disequilibrium between the 14 bp ins/del and five 3'UTR SNPs, which together could be arranged into eight distinct haplotypes based on expectation-maximization studies, with four predominant haplotypes (UTRs1-4). After HSCT, we found a moderate though not significant association between the presence of UTR-2 in double dose and protection from acute graft versus host disease (hazard ratio (HR) 0.45, 95% confidence intervals (CI): 0.14-1.45; P = 0.18), an effect that was also seen when the corresponding 14 bp ins/ins genotype was considered alone (HR 0.42, 95% CI: 0.16-1.06; P = 0.07). No association was found with rejection or survival. Taken together, our data show that there is no apparent added value of considering entire 3'UTR HLA-G haplotypes for risk prediction after allogeneic HSCT for beta-thalassemia.
Subject(s)
3' Untranslated Regions/genetics , Graft vs Host Disease/genetics , HLA-G Antigens/genetics , Hematopoietic Stem Cell Transplantation , beta-Thalassemia/genetics , 3' Untranslated Regions/immunology , Adolescent , Adult , Case-Control Studies , Child , Child, Preschool , Female , Genotype , Graft vs Host Disease/diagnosis , Graft vs Host Disease/immunology , Haplotypes/genetics , Haplotypes/immunology , Humans , Immune Tolerance , Italy , Linkage Disequilibrium , Male , Mutagenesis, Insertional , Polymorphism, Genetic , Sequence Deletion , Siblings , Transplantation, Homologous , Treatment Outcome , beta-Thalassemia/immunology , beta-Thalassemia/therapyABSTRACT
Human leukocyte antigen (HLA) class I sequence-based typing (SBT) for hematopoietic unrelated donor searching in an Italian Caucasian patient showed the presence of a novel HLA-A allele defined as A*31:48. HLA-A*31:48 has one nucleotide change from A*31:01:02 at nt 727 from C to T, resulting in an amino acid change at codon 219 of exon 4 from Arg to Trp.