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3.
J Allergy Clin Immunol ; 140(6): 1660-1670.e16, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28400115

RESUMO

BACKGROUND: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). METHODS: Twelve patients with cDGS underwent transplantation with allogeneic cultured thymus. OBJECTIVE: We sought to confirm and extend the results previously obtained in a single center. RESULTS: Two patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1). CONCLUSIONS: This study confirms the previous reports that thymus transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.


Assuntos
Doenças Autoimunes/imunologia , Síndrome de DiGeorge/terapia , Transplante de Órgãos , Complicações Pós-Operatórias/imunologia , Linfócitos T/imunologia , Timo/transplante , Doenças Autoimunes/etiologia , Células Cultivadas , Criança , Pré-Escolar , Síndrome de DiGeorge/imunologia , Europa (Continente) , Feminino , Humanos , Reconstituição Imune , Lactente , Masculino , Técnicas de Cultura de Órgãos , Transplante Homólogo , Resultado do Tratamento
4.
J Allergy Clin Immunol ; 139(1): 232-245, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27577878

RESUMO

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.


Assuntos
Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Genome Med ; 7: 130, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26684649

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. Here, we validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics. METHODS: A high-throughput sequencing strategy of 12 genes linked to HLH was validated in 13 patients with previously identified HLH-associated mutations and prospectively evaluated in 58 HLH patients. Moreover, 2504 healthy individuals from the 1000 Genomes project were analyzed in silico for variants in the same genes. RESULTS: Analyses revealed a mutation detection sensitivity of 97.3%, an average coverage per gene of 98.0%, and adequate coverage over 98.6% of sites previously reported as mutated in these genes. In the prospective cohort, we achieved a diagnosis in 22 out of 58 patients (38%). Genetically undiagnosed HLH patients had a later age at onset and manifested higher frequencies of known secondary HLH triggers. Rare, putatively pathogenic monoallelic variants were identified in nine patients. However, such monoallelic variants were not enriched compared with healthy individuals. CONCLUSIONS: We have established a comprehensive high-throughput platform for genetic screening of patients with HLH. Almost all cases with reduced natural killer cell function received a diagnosis, but the majority of the prospective cases remain genetically unexplained, highlighting genetic heterogeneity and environmental impact within HLH. Moreover, in silico analyses of the genetic variation affecting HLH-related genes in the general population suggest caution with respect to interpreting causality between monoallelic mutations and HLH. A complete understanding of the genetic susceptibility to HLH thus requires further in-depth investigations, including genome sequencing and detailed immunological characterization.


Assuntos
Sequência de Bases , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Análise de Sequência de DNA , Adulto Jovem
6.
Am J Hum Genet ; 95(1): 96-107, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-24931394

RESUMO

Human phosphoglucomutase 3 (PGM3) catalyzes the conversion of N-acetyl-glucosamine (GlcNAc)-6-phosphate into GlcNAc-1-phosphate during the synthesis of uridine diphosphate (UDP)-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways. We identified three unrelated children with recurrent infections, congenital leukopenia including neutropenia, B and T cell lymphopenia, and progression to bone marrow failure. Whole-exome sequencing demonstrated deleterious mutations in PGM3 in all three subjects, delineating their disease to be due to an unsuspected congenital disorder of glycosylation (CDG). Functional studies of the disease-associated PGM3 variants in E. coli cells demonstrated reduced PGM3 activity for all mutants tested. Two of the three children had skeletal anomalies resembling Desbuquois dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability. However, these additional features were absent in the third child, showing the clinical variability of the disease. Two children received hematopoietic stem cell transplantation of cord blood and bone marrow from matched related donors; both had successful engraftment and correction of neutropenia and lymphopenia. We define PGM3-CDG as a treatable immunodeficiency, document the power of whole-exome sequencing in gene discoveries for rare disorders, and illustrate the utility of genomic analyses in studying combined and variable phenotypes.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Defeitos Congênitos da Glicosilação/genética , Síndromes de Imunodeficiência/genética , Mutação , Fosfoglucomutase/genética , Feminino , Humanos , Masculino , Linhagem
7.
Nutr Cancer ; 60(5): 652-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18791929

RESUMO

Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25-0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Polimorfismo Genético/genética , Simportadores/genética , Idoso , Estudos de Casos e Controles , Feminino , Variação Genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transportadores de Sódio Acoplados à Vitamina C , Inquéritos e Questionários , Estados Unidos
9.
Am J Epidemiol ; 163(3): 245-54, 2006 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-16357110

RESUMO

Vitamin C has been the focus of epidemiologic investigation in preterm delivery (<37 weeks' gestation), which is a leading cause of neonatal mortality and birth-related morbidity. There are two sodium-dependent membrane transporters encoded by SLC23A1 and SLC23A2, which have key roles in human vitamin C metabolism and which control dietary uptake, reabsorption, and tissue distribution of vitamin C. Using maternal DNA, the authors evaluated common single-nucleotide polymorphisms (SNPs) in SLC23A1 and SLC23A2 in a nested case-control analysis of the Pregnancy, Infection, and Nutrition Study (1995-2000) cohort. Of the associations observed for both haplotypes in SLC23A1 and individual SNPs in SLC23A2, the most robust finding is with an intron 2 variant in SLC23A2. Heterozygotes and homozygotes for this variant had a 1.7-fold (95% confidence interval: 0.9, 3.3) and a 2.7-fold (95% confidence interval: 1.2, 6.3) elevation in the risk of spontaneous preterm birth, respectively. Semi-Bayesian hierarchical regression analysis, which simultaneously adjusted for multiple SNPs within the same gene, gave comparable results. The authors' findings link genetic variants in the vitamin C transporters to spontaneous preterm birth, which may explain previous dietary associations. If the findings from this study are confirmed, they may serve as the foundation for genetic risk assessment of nutritional pathways in preterm birth.


Assuntos
Ácido Ascórbico/metabolismo , Variação Genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Polimorfismo de Nucleotídeo Único , Nascimento Prematuro/genética , Simportadores/genética , Adulto , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Haplótipos , Humanos , North Carolina , Gravidez , Fatores de Risco , Transportadores de Sódio Acoplados à Vitamina C
10.
Epidemiology ; 16(4): 469-77, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15951664

RESUMO

BACKGROUND: Preliminary data suggest that common genetic variation in immune response genes can contribute to the risk for spontaneous preterm birth and possibly small-for-gestational age (SGA). METHODS: We investigated the relationship of polymorphisms in 6 cytokine genes associated with inflammation-interleukin (IL)1alpha, IL1beta, IL2, IL6, tumor necrosis factor (TNF), and lymphotoxin alpha (LTA)-with spontaneous preterm and SGA birth in a nested case-control study drawn from a prospective pregnancy cohort. Women were recruited between 24 and 29 weeks' gestation at the Wake County and University of North Carolina, Chapel Hill obstetric clinics between February 1996 and June 2000. We inferred haplotypes using the EM algorithm and the Bayesian method, PHASE. We then compared haplotype frequency distributions and implemented semi-Bayesian hierarchical logistic regression analyses to obtain odds ratio (OR) estimates and 95% confidence intervals (CIs) for each polymorphism. RESULTS: Two haplotypes spanning the TNF/LTA genes were associated with increased risk for spontaneous preterm birth in white subjects (for the AGG haplotype, OR = 1.5 [95% CI=0.8-2.6]; for the GAC haplotype, 1.6 [0.9-2.9]). Additionally, carriers of the GAG haplotype were found to have decreased risk of spontaneous preterm birth (0.6; 0.3-1.0). The TNF(-488)A and LTA(IVS1-82)C variants, constituents of the AGG and GAC haplotypes respectively, were also strongly associated with increased risk of spontaneous preterm birth. CONCLUSIONS: Our results suggest that common genetic variants in proinflammatory cytokine genes could influence the risk for spontaneous preterm birth. Selected TNF/LTA haplotypes were associated with spontaneous preterm birth in both African-American and white subjects. Our data do not support an inflammatory etiology for SGA.


Assuntos
Afro-Americanos/genética , Citocinas/genética , Grupo com Ancestrais do Continente Europeu/genética , Polimorfismo Genético , Nascimento Prematuro/genética , Nascimento Prematuro/imunologia , Teorema de Bayes , Feminino , Frequência do Gene , Idade Gestacional , Haplótipos/genética , Humanos , Modelos Logísticos , North Carolina/epidemiologia , Polimorfismo Genético/imunologia , Gravidez , Nascimento Prematuro/etnologia , Estudos Prospectivos , Fatores de Risco , Esfregaço Vaginal , Vaginose Bacteriana/diagnóstico , Vaginose Bacteriana/etnologia
11.
Epidemiology ; 16(4): 478-86, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15951665

RESUMO

BACKGROUND: Anti-inflammatory cytokines play a key role in pregnancy maintenance. Genetic variation in anti-inflammatory cytokines could influence a woman's risk of adverse reproductive outcomes. METHODS: We investigated the relationship of polymorphisms in interleukin 4 (IL4), IL5, IL10, IL13, and transforming growth factor (TGFbeta1) with spontaneous preterm birth and small-for-gestational age (SGA) in a nested case-control study of a prospective pregnancy cohort. Women were recruited between 24 and 29 weeks' gestation at the Wake County and University of North Carolina, Chapel Hill obstetric clinics between February 1996 and June 2000. We inferred haplotypes using the EM algorithm and the Bayesian method, PHASE. Semi-Bayesian hierarchical logistic regression was used to obtain odds ratio (OR) estimates and 95% confidence intervals (CIs) for each polymorphism. RESULTS: African-American mothers who carried the IL4 GCC haplotype had greater risk of spontaneous preterm birth (OR = 2.9; 95% CI = 1.2-7.4). In white mothers, carriers of the "low-producing" IL4 CC and IL10 ATA haplotypes had markedly reduced risk of SGA (for the CC haplotype, 0.2 [0.0-1.2]; for the ATA haplotype, 0.5 [0.3-0.8]), whereas carriers of the "high-producing" IL4(-589)T variant had increased risk of SGA in both African-American and white mothers. CONCLUSIONS: Variants related to decreased anti-inflammatory cytokine production may lower risk of SGA. Furthermore, the same mechanism that protects against SGA might increase risk of spontaneous preterm birth.


Assuntos
Afro-Americanos/genética , Citocinas/genética , Grupo com Ancestrais do Continente Europeu/genética , Haplótipos/genética , Recém-Nascido Pequeno para a Idade Gestacional , Nascimento Prematuro/genética , Algoritmos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Recém-Nascido , Interleucinas/genética , North Carolina/epidemiologia , Polimorfismo Genético , Gravidez , Nascimento Prematuro/etnologia , Fator de Crescimento Transformador beta/genética
12.
Hum Genet ; 115(4): 285-94, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15316768

RESUMO

Vitamin C (L-ascorbic acid) is an essential co-factor for eight mammalian enzymes and quenches reactive oxygen species. Sodium-dependent vitamin C transport is mediated by two transporters, SVCT 1 and SVCT 2, encoded by SLC23A1 and SLC23A2. We characterized the genomic structures of SLC23A1 and SLC23A2, determined the extent of genetic variation and linkage disequilibrium across each gene, analyzed nucleotide diversity to estimate the effect of selective pressure, and compared sequence variation across species. In SLC23A1, the majority of single nucleotide polymorphisms (SNPs) are population-specific in either African Americans or Caucasians, including three of four non-synonymous SNPs. In contrast, most SNPs in SLC23A2 are shared between African Americans and Caucasians, and there are no non-synonymous SNPs in SLC23A2. Our analysis, combined with previous in vitro and in vivo studies, suggests that non-synonymous variation appears to be tolerated in SLC23A1 but not SLC23A2, and that this may be a consequence of different selective pressures following past gene duplication of the sodium-dependent vitamin C transporters. Genetic association studies of these two genes will need to account for the differences in haplotype structure and the population-specific variants. Our data represent a fundamental step toward the application of genetics to refining nutrient recommendations, specifically for vitamin C, and may serve as a paradigm for other vitamins.


Assuntos
Variação Genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Filogenia , Simportadores/genética , Composição de Bases , Componentes do Gene , Genômica , Humanos , Funções Verossimilhança , Desequilíbrio de Ligação , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Transportadores de Sódio Acoplados à Vitamina C , Especificidade da Espécie
13.
J Infect Dis ; 187(7): 1153-6, 2003 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-12660931

RESUMO

Chronic disseminated candidiasis (CDC) is a form of Candida species infection observed primarily in patients with acute leukemia. To investigate possible genetic factors associated with CDC, we conducted a pilot study of 40 patients with both leukemia and CDC and 50 control patients with leukemia only. A common haplotype of the IL4 promoter (-1098T/-589C/-33C) was overrepresented in patients with CDC (P= .01; odds ratio [OR], 2.16), whereas another common haplotype (-1098T/-589T/-33T) appeared to be protective against CDC (P= .018; OR, 0.47). Genetic variants of IL4 could contribute to the development of CDC in patients with acute leukemia.


Assuntos
Candidíase/complicações , Candidíase/genética , Predisposição Genética para Doença , Haplótipos , Interleucina-4/genética , Leucemia/complicações , Leucemia/genética , Regiões Promotoras Genéticas/genética , Adolescente , Adulto , Idoso , Candida/isolamento & purificação , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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