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1.
Brief Bioinform ; 18(3): 394-402, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27178992

RESUMO

The era of genome-wide association studies (GWAS) has led to the discovery of numerous genetic variants associated with disease. Better understanding of whether these or other variants interact leading to differential risk compared with individual marker effects will increase our understanding of the genetic architecture of disease, which may be investigated using the family-based study design. We present M-TDT (the multi-locus transmission disequilibrium test), a tool for detecting family-based multi-locus multi-allelic effects for qualitative or quantitative traits, extended from the original transmission disequilibrium test (TDT). Tests to handle the comparison between additive and epistatic models, lack of independence between markers and multiple offspring are described. Performance of M-TDT is compared with a multifactor dimensionality reduction (MDR) approach designed for investigating families in the hypothesis-free genome-wide setting (the multifactor dimensionality reduction pedigree disequilibrium test, MDR-PDT). Other methods derived from the TDT or MDR to investigate genetic interaction in the family-based design are also discussed. The case of three independent biallelic loci is illustrated using simulations for one- to three-locus alternative hypotheses. M-TDT identified joint-locus effects and distinguished effectively between additive and epistatic models. We showed a practical example of M-TDT based on three genes already known to be implicated in malaria susceptibility. Our findings demonstrate the value of M-TDT in a hypothesis-driven context to test for multi-way epistasis underlying common disease etiology, whereas MDR-PDT-based methods are more appropriate in a hypothesis-free genome-wide setting.


Assuntos
Epistasia Genética , Genoma , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Linhagem
2.
J Exp Med ; 212(10): 1641-62, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26304966

RESUMO

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/ß, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/ß. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.


Assuntos
Síndrome de Job/etiologia , TYK2 Quinase/deficiência , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interferon gama/metabolismo , Interleucina-10/farmacologia , Interleucina-12/metabolismo , Interleucina-12/farmacologia , Interleucina-23/farmacologia , Interleucina-6/farmacologia , Síndrome de Job/complicações , Síndrome de Job/genética , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Mutação , Infecções por Mycobacterium/etiologia , Linfócitos T/metabolismo , Linfócitos T/patologia , TYK2 Quinase/genética , TYK2 Quinase/metabolismo , Viroses/etiologia , Adulto Jovem
3.
BMC Immunol ; 16: 14, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25887595

RESUMO

BACKGROUND: Malaria remains a major worldwide public health problem with ~207 million cases and ~627,000 deaths per year, mainly affecting children under five years of age in Africa. Recent efforts at elaborating a genetic architecture of malaria have focused on severe malaria, leading to the identification of two new genes and confirmation of previously known variants in HBB, ABO and G6PD, by exploring the whole human genome in genome-wide association (GWA) studies. Molecular pathways controlling phenotypes representing effectiveness of host immunity, notably parasitemia and IgG levels, are of particular interest given the current lack of an efficacious vaccine and the need for new treatment options. RESULTS: We propose a global causal framework of malaria phenotypes implicating progression from the initial infection with Plasmodium spp. to the development of the infection through liver and blood-stage multiplication cycles (parasitemia as a quantitative trait), to clinical malaria attack, and finally to severe malaria. Genetic polymorphism may control any of these stages, such that preceding stages act as mediators of subsequent stages. A biomarker of humoral immunity, IgG levels, can also be integrated into the framework, potentially mediating the impact of polymorphism by limiting parasitemia levels. Current knowledge of the genetic basis of parasitemia levels and IgG levels is reviewed through key examples including the hemoglobinopathies, showing that the protective effect of HBB variants on malaria clinical phenotypes may partially be mediated through parasitemia and cytophilic IgG levels. Another example is the IgG receptor FcγRIIa, encoded by FCGR2A, such that H131 homozygotes displayed higher IgG2 levels and were protective against high parasitemia and onset of malaria symptoms as shown in a causal diagram. CONCLUSIONS: We thus underline the value of parasitemia and IgG levels as phenotypes in the understanding of the human genetic architecture of malaria, and the need for applying GWA approaches to these phenotypes.


Assuntos
Vacinas Antimaláricas , Malária Falciparum/imunologia , Malária/imunologia , Sistema do Grupo Sanguíneo ABO/genética , Animais , Pré-Escolar , Estudo de Associação Genômica Ampla , Glucosefosfato Desidrogenase/genética , Humanos , Imunidade Humoral/genética , Malária/genética , Parasitemia/genética
4.
J Infect Dis ; 210(4): 611-8, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24610875

RESUMO

BACKGROUND: Only a minority of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis. Genetic epidemiological evidence suggests that pulmonary tuberculosis has a strong human genetic component. Previous genetic findings in Mendelian predisposition to more severe mycobacterial infections, including by M. tuberculosis, underlined the importance of the interleukin 12 (IL-12)/interferon γ (IFN-γ) circuit in antimycobacterial immunity. METHODS: We conducted an association study in Morocco between pulmonary tuberculosis and a panel of single-nucleotide polymorphisms (SNPs) covering 14 core IL-12/IFN-γ circuit genes. The analyses were performed in a discovery family-based sample followed by replication in a case-control population. RESULTS: Out of 228 SNPs tested in the family-based sample, 6 STAT4 SNPs were associated with pulmonary tuberculosis (P = .0013-.01). We replicated the same direction of association for 1 cluster of 3 SNPs encompassing the promoter region of STAT4. In the combined sample, the association was stronger among younger subjects (pulmonary tuberculosis onset <25 years) with an odds ratio of developing pulmonary tuberculosis at rs897200 for GG vs AG/AA subjects of 1.47 (1.06-2.04). Previous functional experiments showed that the G allele of rs897200 was associated with lower STAT4 expression. CONCLUSIONS: Our present findings in a Moroccan population support an association of pulmonary tuberculosis with STAT4 promoter-region polymorphisms that may impact STAT4 expression.


Assuntos
Predisposição Genética para Doença/genética , Interferon gama/genética , Interleucina-12/genética , Fator de Transcrição STAT4/genética , Tuberculose Pulmonar/genética , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Interferon gama/imunologia , Interleucina-12/imunologia , Masculino , Pessoa de Meia-Idade , Marrocos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Polimorfismo de Nucleotídeo Único , Risco , Fator de Transcrição STAT4/imunologia , Tuberculose Pulmonar/imunologia , Adulto Jovem
5.
Hum Genet ; 133(7): 883-93, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24563210

RESUMO

Leprosy is caused by infection with Mycobacterium leprae and is classified clinically into paucibacillary (PB) or multibacillary (MB) subtypes based on the number of skin lesions and the bacillary index detected in skin smears. We previously identified a major PB susceptibility locus on chromosome region 10p13 in Vietnamese families by linkage analysis. In the current study, we conducted high-density association mapping of the 9.5 Mb linkage peak on chromosome region 10p13 covering 39 genes. Using leprosy per se and leprosy subtypes as phenotypes, we employed 294 nuclear families (303 leprosy cases, 63 % MB, 37 % PB) as a discovery sample and 192 nuclear families (192 cases, 55 % MB, 45 % PB) as a replication sample. Replicated significant association signals were revealed in the genes for cubilin (CUBN) and nebulette (NEBL). In the combined sample, the C allele (frequency 0.26) at CUBN SNP rs10904831 showed association [p = 1 × 10(-5); OR 0.52 (0.38-0.7)] with MB leprosy only. Likewise, allele T (frequency 0.42) at NEBL SNP rs11012461 showed association [p = 4.2 × 10(-5); OR 2.51 (1.6-4)] with MB leprosy only. These associations remained valid for the CUBN signal when taking into account the effective number of tests performed (type I error significance threshold = 2.4 × 10(-5)). We used the results of our analyses to propose a new model for the genetic control of polarization of clinical leprosy.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 10/genética , Proteínas do Citoesqueleto/genética , Ligação Genética , Predisposição Genética para Doença , Proteínas com Domínio LIM/genética , Hanseníase Multibacilar/genética , Receptores de Superfície Celular/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Mapeamento Cromossômico , Feminino , Frequência do Gene , Genética Populacional , Genótipo , Humanos , Masculino , Mycobacterium leprae , Polimorfismo de Nucleotídeo Único , Vietnã
6.
Am J Hum Genet ; 92(3): 407-14, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23415668

RESUMO

Only a small fraction of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis (TB) in their lifetime. Genetic epidemiological evidence suggests a genetic determinism of pulmonary TB (PTB), but the molecular basis of genetic predisposition to PTB remains largely unknown. We used a positional-cloning approach to carry out ultrafine linkage-disequilibrium mapping of a previously identified susceptibility locus in chromosomal region 8q12-13 by genotyping 3,216 SNPs in a family-based Moroccan sample including 286 offspring with PTB. We observed 44 PTB-associated SNPs (p < 0.01), which were genotyped in an independent set of 317 cases and 650 controls from Morocco. A single signal, consisting of two correlated SNPs close to TOX, rs1568952 and rs2726600 (combined p = 1.1 × 10(-5) and 9.2 × 10(-5), respectively), was replicated. Stronger evidence of association was found in individuals who developed PTB before the age of 25 years (combined p for rs1568952 = 4.4 × 10(-8); odds ratio of PTB for AA versus AG/GG = 3.09 [1.99-4.78]). The association with rs2726600 (p = 0.04) was subsequently replicated in PTB-affected subjects under 25 years in a study of 243 nuclear families from Madagascar. Stronger evidence of replication in Madagascar was obtained for additional SNPs in strong linkage disequilibrium with the two initial SNPs (p = 0.003 for rs2726597), further confirming the signal. We thus identified around rs1568952 and rs2726600 a cluster of SNPs strongly associated with early-onset PTB in Morocco and Madagascar. SNP rs2726600 is located in a transcription-factor binding site in the 3' region of TOX, and further functional explorations will focus on CD4 T lymphocytes.


Assuntos
Cromossomos Humanos Par 8 , Ligação Genética , Proteínas de Grupo de Alta Mobilidade/genética , Tuberculose Pulmonar/genética , Adulto , Fatores Etários , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Feminino , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Madagáscar , Masculino , Marrocos , Mycobacterium tuberculosis/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Tuberculose Pulmonar/microbiologia
7.
J Infect Dis ; 206(11): 1763-7, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22984114

RESUMO

A genomewide association study in Chinese patients with leprosy detected association signals in 16 single-nucleotide polymorphisms (SNPs) belonging to 6 loci, of which 4 are related to the NOD2 signaling pathway and are Crohn's disease susceptibility loci. Here, we studied these 16 SNPs as potential leprosy susceptibility factors in 474 Vietnamese leprosy simplex families. We replicated SNPs at HLA-DR-DQ, RIPK2, CCDC122-LACC1, and NOD2 as leprosy susceptibility factors in Vietnam. These results validated the striking overlap in the genetic control of Crohn's disease and leprosy.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doença de Crohn/genética , Hanseníase/genética , Família , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Hanseníase/epidemiologia , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Vietnã/epidemiologia
8.
Science ; 337(6102): 1684-8, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-22859821

RESUMO

ISG15 is an interferon (IFN)-α/ß-inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. Here, we describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases. The lack of intracellular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses that we tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes-granulocyte, in particular-reduced the production of IFN-γ by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-γ-inducing secreted molecule for optimal antimycobacterial immunity.


Assuntos
Citocinas/imunologia , Interferon gama/imunologia , Infecções por Mycobacterium/imunologia , Ubiquitinas/imunologia , Viroses/imunologia , Animais , Anticorpos Antivirais/sangue , Citocinas/genética , Feminino , Granulócitos/imunologia , Humanos , Imunidade , Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Infecções por Mycobacterium/sangue , Infecções por Mycobacterium/genética , Linhagem , Linfócitos T/imunologia , Ubiquitinas/genética , Viroses/sangue
9.
PLoS One ; 7(5): e35863, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22574126

RESUMO

BACKGROUND: IL-13 is a signature cytokine of the helper T cell type 2 (TH2) pathway which underlies host defense to helminthic infection and activates production of IgE in both parasitized populations and in urban settings after allergen exposure. METHODOLOGY/PRINCIPAL FINDINGS: Two functional polymorphisms in IL13, rs1800925 (or c.1-1111C>T) and rs20541 (or R130Q) were previously found to be associated with Schistosoma hematobium infection intensity. They have not been thoroughly explored in S. mansoni-endemic populations, however, and were selected along with 5 tagging SNPs for genotyping in 812 individuals in 318 nuclear families from a schistosomiasis-endemic area of Conde, Bahia, in Brazil. Regression models using GEE to account for family membership and family-based quantitative transmission disequilibrium tests (QTDT) were used to evaluate associations with total serum IgE (tIgE) levels and S. mansoni fecal egg counts adjusted for non-genetic covariates. We identified a protective effect for the T allele at rs20541 (P = 0.005) against high S. mansoni egg counts, corroborated by QTDT (P = 0.014). Our findings also suggested evidence for protective effects for the T allele at rs1800925 and A allele at rs2066960 after GEE analysis only (P = 0.050, 0.0002). CONCLUSIONS/SIGNIFICANCE: The two functional variants in IL13 are protective against high S. mansoni egg counts. These markers showed no evidence of association with tIgE levels, unlike tIgE levels previously studied in non-parasitized or atopic study populations.


Assuntos
Interleucina-13/genética , Polimorfismo de Nucleotídeo Único , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/genética , Esquistossomose mansoni/prevenção & controle , Adulto , Animais , Brasil/epidemiologia , Doenças Endêmicas/prevenção & controle , Feminino , Humanos , Imunoglobulina E/sangue , Desequilíbrio de Ligação , Masculino , Esquistossomose mansoni/epidemiologia , Esquistossomose mansoni/imunologia , Células Th2/imunologia
10.
J Pediatr ; 160(6): 1055-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22402565

RESUMO

We describe a Turkish patient with tyrosine kinase 2 deficiency who suffered from disseminated Bacille Calmette-Guerin infection, neurobrucellosis, and cutaneous herpes zoster infection. Tyrosine kinase 2 deficiency should be considered in patients susceptible to herpes viruses and intramacrophage pathogens even in the absence of atopy, high serum IgE, and staphylococcal disease.


Assuntos
Síndromes de Imunodeficiência/enzimologia , TYK2 Quinase/deficiência , Criança , Diagnóstico Diferencial , Seguimentos , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndrome de Job/diagnóstico , Imagem por Ressonância Magnética , Masculino , TYK2 Quinase/sangue
11.
PLoS One ; 7(1): e29708, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22238637

RESUMO

We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the 'rescue' role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic.


Assuntos
Mutação da Fase de Leitura , Histiocitose/genética , Doenças Nasais/genética , Proteínas de Transporte de Nucleosídeos/genética , RNA não Traduzido/genética , Deleção de Sequência , Adulto , Feminino , Mutação da Fase de Leitura/genética , Humanos , Masculino , Linhagem , Fenótipo , Biossíntese de Proteínas/genética , Isoformas de RNA/genética , Sítios de Splice de RNA/genética , Índice de Gravidade de Doença , Irmãos , Adulto Jovem
12.
PLoS One ; 6(4): e18524, 2011 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-21533230

RESUMO

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rß1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rß1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rß1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rß1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rß1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity.


Assuntos
Subunidade beta 1 de Receptor de Interleucina-12/genética , Tuberculose/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Lactente , Irã (Geográfico) , Masculino , Marrocos , Linhagem , Índice de Gravidade de Doença , Turquia
13.
J Med Genet ; 48(8): 567-71, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21572128

RESUMO

INTRODUCTION: Genome-wide homozygosity mapping is a powerful method for locating rare recessive Mendelian mutations. However, statistical power decreases dramatically in the presence of genetic heterogeneity. METHODS: The authors applied an empirical approach to test for linkage accounting for genetic heterogeneity by calculating the sum of positive per-family multipoint LOD scores (S) across all positions, and obtaining corresponding empirical p values (EmpP) through permutations. RESULTS: The statistical power of the approach was found to be consistently higher than the classical heterogeneity LOD by simulations. Among 21 first-cousin matings with a single affected child, for five families linked to a locus of interest and 16 families to other loci, S/EmpP achieved a power of 40% versus 28% for heterogeneity LOD at an α level of 0.001. The mean size of peak linkage regions was markedly higher for true loci than false positive regions. The S/EmpP approach was applied to a sample of 17 consanguineous families with Mendelian susceptibility to mycobacterial disease, leading to the identification of two mutations in IL12RB1 and TYK2 from the largest of six linkage regions at p<10(-3). CONCLUSIONS: The S/EmpP approach is a flexible and powerful approach that can be applied to linkage analysis of families with suspected Mendelian disorders.


Assuntos
Heterogeneidade Genética , Predisposição Genética para Doença , Homozigoto , Infecções por Mycobacterium/genética , Família , Estudo de Associação Genômica Ampla , Humanos , Escore Lod
14.
Nat Immunol ; 12(3): 213-21, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21278736

RESUMO

Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.


Assuntos
Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Macrófagos/imunologia , Glicoproteínas de Membrana/genética , NADPH Oxidases/genética , Tuberculose/genética , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Mutação , NADPH Oxidase 2 , NADPH Oxidases/imunologia
15.
Am J Med Genet A ; 152A(3): 622-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20186794

RESUMO

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency associated with clinical disease caused by weakly virulent mycobacterial species. Interferon gamma receptor 1 (IFN-gammaR1) deficiency is a genetic etiology of MSMD. We describe the clinical and genetic features of a 7-year-old Italian boy suffering from MSMD associated with a complex phenotype, including neonatal hyperglycemia, neuromuscular disease, and dysmorphic features. The child also developed necrotizing pneumonia caused by Rhodococcus equi. The child is homozygous for a nonsense mutation in exon 3 of IFNGR1 as a result of paternal uniparental disomy (UPD) of the entire chromosome 6. This is the first reported case of uniparental disomy resulting in a complex phenotype including MSMD.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 6/genética , Infecções por Mycobacterium/genética , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Dissomia Uniparental/genética , Infecções por Actinomycetales/genética , Criança , Códon sem Sentido , Análise Mutacional de DNA , Éxons , Pai , Feminino , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Rhodococcus equi , Síndrome
16.
Eur J Hum Genet ; 18(6): 713-9, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20087405

RESUMO

Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits FcvarepsilonRI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P=8.8 x 10(-5)) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P=0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P=0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P=0.016), and replicated among the Brazilian families (P=0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6'-sulfo-sLe(x), a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma.


Assuntos
Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos B/genética , Asma/genética , Predisposição Genética para Doença , Lectinas/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Afro-Americanos/genética , Grupo com Ancestrais do Continente Asiático/genética , Asma/etnologia , Brasil , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
17.
J Allergy Clin Immunol ; 125(2): 336-346.e4, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19910028

RESUMO

BACKGROUND: Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. OBJECTIVES: We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma. METHODS: We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. RESULTS: A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. CONCLUSIONS: This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Asma/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Adulto , Afro-Americanos/genética , Barbados , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
J Allergy Clin Immunol ; 124(3 Suppl 2): R7-R12, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19720210

RESUMO

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene encoding filaggrin in a subset of patients with AD. OBJECTIVE: We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. METHODS: Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. RESULTS: Compared with normal skin, filaggrin expression was significantly reduced (P < .05) in acute AD skin, with further reduction seen in acute lesions from 3 European American subjects with AD who were heterozygous for the 2282del4 mutation. This was confirmed by using immunohistochemistry. AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression (0.04 +/- 0.01 ng filaggrin/ng glyceraldehyde 3-phosphate dehydrogenase; P < .05) compared with media alone (0.16 +/- 0.03). CONCLUSION: Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. CLINICAL IMPLICATIONS: The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.

19.
Am J Respir Crit Care Med ; 178(10): 1017-22, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18827265

RESUMO

RATIONALE: Asthma prevalence and severity are high among underserved minorities, including those of African descent. The Duffy antigen/receptor for chemokines is the receptor for Plasmodium vivax on erythrocytes and functions as a chemokine-clearing receptor. Unlike European populations, decreased expression of the receptor on erythrocytes is common among populations of African descent, and results from a functional T-46C polymorphism (rs2814778) in the promoter. This variant provides an evolutionary advantage in malaria-endemic regions, because Duffy antigen/receptor for chemokines-negative erythrocytes are more resistant to infection by P. vivax. OBJECTIVES: To determine the role of the rs2814778 polymorphism in asthma and atopy as measured by total serum IgE levels among four populations of African descent (African Caribbean, African American, Brazilian, and Colombian) and a European American population. METHODS: Family-based association tests were performed in each of the five populations to test for association between the rs2814778 polymorphism and asthma or total IgE concentration. MEASUREMENTS AND MAIN RESULTS: Asthma was significantly associated with the rs2814778 polymorphism in the African Caribbean, Colombian, and Brazilian families (P < 0.05). High total IgE levels were associated with this variant in African Caribbean and Colombian families (P < 0.05). The variant allele was not polymorphic among European Americans. CONCLUSIONS: Susceptibility to asthma and atopy among certain populations of African descent is influenced by a functional polymorphism in the gene encoding Duffy antigen/receptor for chemokines. This genetic variant, which confers resistance to malarial parasitic infection, may also partially explain ethnic differences in morbidity of asthma.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Asma/genética , Sistema do Grupo Sanguíneo Duffy/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Barbados , Brasil , Estudos de Casos e Controles , Colômbia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Estados Unidos
20.
J Infect Dis ; 198(8): 1227-36, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18717640

RESUMO

BACKGROUND: Evidence of genetic control for total serum IgE (tIgE) level has been reported in multiple populations, although populations with substantial exposure to helminths have yielded lower estimates of heritability, despite evidence suggesting that genes also control a significant portion of the variation in the number of Schistosoma mansoni eggs per gram of fecal matter. METHODS: By use of a whole-population ascertainment scheme, 822 individuals were enrolled from a schistosomiasis-endemic area in Conde, Bahia, in Brazil. Heritability was estimated by using an additive polygenic model, and segregation analysis was performed for 2 quantitative traits, tIgE level and egg count. RESULTS: After adjusting for nongenetic covariates, the heritability of log-transformed tIgE level and log-transformed egg count was estimated at 60% and 31%, respectively. No evidence for a single major gene controlling tIgE level or egg count was observed in segregation analysis for 781 individuals and 403 individuals, respectively, in 318 families, however, which suggests complex biological control. CONCLUSIONS: The high heritability of tIgE level indicates that genetic factors are likely to control tIgE level even in the presence of helminthic infection. Substantial heritability for the burden of S. mansoni infection was confirmed in these Brazilian families. Further genetic studies will be needed to dissect the specific genetic factors that underlie these traits.


Assuntos
Doenças Endêmicas , Imunoglobulina E/sangue , Schistosoma mansoni/imunologia , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/epidemiologia , Esquistossomose mansoni/genética , Adolescente , Adulto , Idoso , Animais , Anticorpos Anti-Helmínticos/sangue , Brasil/epidemiologia , Criança , Fezes/parasitologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Ovos de Parasitas , Schistosoma mansoni/crescimento & desenvolvimento , Schistosoma mansoni/isolamento & purificação , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/parasitologia
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