RESUMO
Patients in need of hematopoietic stem cell transplantation often rely on unrelated stem cell donors matched in certain human leukocyte antigen (HLA) genes. Donor search is complicated by the extensive allelic variability of the HLA system. Therefore, large registries of potential donors are maintained in many countries worldwide. Population-specific HLA characteristics determine the registry benefits for patients and also the need for further regional donor recruitment. In this work, we analyzed HLA allele and haplotype frequencies of donors of DKMS Chile, the first Chilean donor registry, with self-assessed "non-Indigenous" (n=92,788) and "Mapuche" (n=1,993) ancestry. We identified HLA alleles that were distinctly more abundant in the Chilean subpopulations than in worldwide reference populations, four of them particularly characteristic for the Mapuche subpopulation, namely B*39:09g, B*35:09, DRB1*04:07g, and DRB1*16:02g. Both population subsamples carried haplotypes of both Native American and European origin at high frequencies, reflecting Chile's complex history of admixture and immigration. Matching probability analysis revealed limited benefits for Chilean patients (both non-Indigenous and Mapuche) from donor registries of non-Chilean donors, thus indicating a need for ongoing significant donor recruitment efforts in Chile.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Humanos , Chile , Alelos , HaplótiposRESUMO
The killer-cell immunoglobulin-like receptors (KIR) recognize human leukocyte antigen (HLA) molecules to regulate the cytotoxic and inflammatory responses of natural killer cells. KIR genes are encoded by a rapidly evolving gene family on chromosome 19 and present an unusual variation of presence and absence of genes and high allelic diversity. Although many studies have associated KIR polymorphism with susceptibility to several diseases over the last decades, the high-resolution allele-level haplotypes have only recently started to be described in populations. Here, we use a highly innovative custom next-generation sequencing method that provides a state-of-art characterization of KIR and HLA diversity in 706 individuals from eight unique South American populations: five Amerindian populations from Brazil (three Guarani and two Kaingang); one Amerindian population from Paraguay (Aché); and two urban populations from Southern Brazil (European and Japanese descendants from Curitiba). For the first time, we describe complete high-resolution KIR haplotypes in South American populations, exploring copy number, linkage disequilibrium, and KIR-HLA interactions. We show that all Amerindians analyzed to date exhibit the lowest numbers of KIR-HLA interactions among all described worldwide populations, and that 83-97% of their KIR-HLA interactions rely on a few HLA-C molecules. Using multiple approaches, we found signatures of strong purifying selection on the KIR centromeric region, which codes for the strongest NK cell educator receptors, possibly driven by the limited HLA diversity in these populations. Our study expands the current knowledge of KIR genetic diversity in populations to understand KIR-HLA coevolution and its impact on human health and survival.
Assuntos
Antígenos HLA , Indígenas Sul-Americanos/genética , Receptores KIR , Alelos , Frequência do Gene , Genética Populacional , Antígenos HLA/genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Receptores KIR/genética , Seleção GenéticaRESUMO
The KIR (killer-cell immunoglobulin-like receptor) region is characterized by structural variation and high sequence similarity among genes, imposing technical difficulties for analysis. We undertook the most comprehensive study to date of KIR genetic diversity in a large population sample, applying next-generation sequencing in 2,130 United States European-descendant individuals. Data were analyzed using our custom bioinformatics pipeline specifically designed to address technical obstacles in determining KIR genotypes. Precise gene copy number determination allowed us to identify a set of uncommon gene-content KIR haplotypes accounting for 5.2% of structural variation. In this cohort, KIR2DL4 is the framework gene that most varies in copy number (6.5% of all individuals). We identified phased high-resolution alleles in large multi-locus insertions and also likely founder haplotypes from which they were deleted. Additionally, we observed 250 alleles at 5-digit resolution, of which 90 have frequencies ≥1%. We found sequence patterns that were consistent with the presence of novel alleles in 398 (18.7%) individuals and contextualized multiple orphan dbSNPs within the KIR complex. We also identified a novel KIR2DL1 variant, Pro151Arg, and demonstrated by molecular dynamics that this substitution is predicted to affect interaction with HLA-C. No previous studies have fully explored the full range of structural and sequence variation of KIR as we present here. We demonstrate that pairing high-throughput sequencing with state-of-art computational tools in a large cohort permits exploration of all aspects of KIR variation including determination of population-level haplotype diversity, improving understanding of the KIR system, and providing an important reference for future studies.
Assuntos
Variação Estrutural do Genoma/genética , Receptores Imunológicos/genética , Receptores KIR/genética , Alelos , Estudos de Coortes , Genótipo , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , América do Norte , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
BACKGROUND: The association of HLA mismatching with kidney allograft survival has been well established. We examined whether amino acid (AA) mismatches (MMs) at the antigen recognition site of HLA molecules represent independent and incremental risk factors for kidney graft failure (GF) beyond those MMs assessed at the antigenic (2-digit) specificity. METHODS: Data on 240 024 kidney transplants performed between 1987 and 2009 were obtained from the Scientific Registry of Transplant Recipients. We imputed HLA-A, -B, and -DRB1 alleles and corresponding AA polymorphisms from antigenic specificity through the application of statistical and population genetics inferences. GF risk was evaluated using Cox proportional-hazards regression models adjusted for covariates including patient and donor risk factors and HLA antigen MMs. RESULTS: We show that estimated AA MMs at particular positions in the peptide-binding pockets of HLA-DRB1 molecule account for a significant incremental risk that was independent of the well-known association of HLA antigen MMs with graft survival. A statistically significant linear relationship between the estimated number of AA MMs and risk of GF was observed for HLA-DRB1 in deceased donor and living donor transplants. This relationship was strongest during the first 12 months after transplantation (hazard ratio, 1.30 per 15 DRB1 AA MM; P < 0.0001). CONCLUSIONS: This study shows that independent of the well-known association of HLA antigen (2-digit specificity) MMs with kidney graft survival, estimated AA MMs at peptide-binding sites of the HLA-DRB1 molecule account for an important incremental risk of GF.
Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/genética , Transplante de Rim , Polimorfismo Genético , Seguimentos , Marcadores Genéticos , Antígenos HLA/imunologia , Humanos , Modelos Lineares , Modelos de Riscos ProporcionaisRESUMO
Veinte pacientes que sufrieron infarto de miocardio anterior extenso con 5 y hasta 72 horas de evolución, se sometieron a angioplastia trasluminal percutánea (PTCA) primaria con stent. La fracción de eyección ventriculográfica osciló entre 21 porciento y 30 porciento y estuvo en correlación con la ecocardiografía bidimensional. Entre los 7 y 12 días se les implantaron, a través de la arteria coronaria descendente anterior y con oclusión de la vena coronaria anterior, células mononucleares CD 34(+) y CD38(-) extraídas de la médula del paciente en una cantidad promedio de 22 x 10 p6. Se efectuaron controles ecocardiográficos cada 7 y hasta 60 días, en los cuales se observó un progresivo aumento de la fracción de eyección (FE) desde 25 porciento hasta 45 porciento en los primeros 60 días, y mejoría a los 90 días de la FE de 80 porciento. Entre los 90 y 120 días se efectuó vertriculografía y coronariografía y se observó permeabilidad de todos los stents implantados y mejoría de la FE de 80 porciento en todos los pacientes con respecto a la FE basal. Los estudios de Spect fueron negativos con ergometrías negativas a los 700 Kg. Este grupo fue comparado con 16 pacientes sometidos sólo a PTCA primaria con stent observándose un incremento de la FE de 45 porciento con respecto a la FE basal en los 90 días; se presentaron 12porciento de reestenosis.Conclusiones: el implante de células madre (stem cells) mejora el desempeño del ventrículo izquierdo luego del infarto de miocardio y al parecer evita la reestenosis coronaria post-implante de stent.