Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
N Engl J Med ; 376(17): 1615-1626, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28445677

RESUMO

BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).


Assuntos
Fator Ativador de Células B/genética , Mutação INDEL , Lúpus Eritematoso Sistêmico/genética , Esclerose Múltipla/genética , Autoimunidade , Fator Ativador de Células B/metabolismo , Estudos de Casos e Controles , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Itália , Lúpus Eritematoso Sistêmico/imunologia , MicroRNAs , Esclerose Múltipla/imunologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Risco , Análise de Sequência de RNA , Transcrição Genética
3.
Cell ; 155(1): 242-56, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-24074872

RESUMO

The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ∼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.


Assuntos
Citometria de Fluxo/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doenças do Sistema Imunitário/genética , Polimorfismo de Nucleotídeo Único , Humanos , Fenótipo
4.
PLoS One ; 6(8): e22319, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21829614

RESUMO

BACKGROUND: Epidemiological evidence indicates that atopic asthma correlates with high serum IgE levels though the contribution of allergen specific IgE to the pathogenesis and the severity of the disease is still unclear. METHODS: We developed a microarray immunoassay containing 103 allergens to study the IgE reactivity profiles of 485 asthmatic and 342 non-asthmatic individuals belonging to families whose members have a documented history of asthma and atopy. We employed k-means clustering, to investigate whether a particular IgE reactivity profile correlated with asthma and other atopic conditions such as rhinitis, conjunctivitis and eczema. RESULTS: Both case-control and parent-to-siblings analyses demonstrated that while the presence of specific IgE against individual allergens correlated poorly with pathological conditions, particular reactivity profiles were significantly associated with asthma (p<10E-09). An artificial neural network (ANN)-based algorithm, calibrated with the profile reactivity data, correctly classified as asthmatic or non-asthmatic 78% of the individual examined. Multivariate statistical analysis demonstrated that the familiar relationships of the study population did not affect the observed correlations. CONCLUSIONS: These findings indicate that asthma is a higher-order phenomenon related to patterns of IgE reactivity rather than to single antibody reactions. This notion sheds new light on the pathogenesis of the disease and can be readily employed to distinguish asthmatic and non-asthmatic individuals on the basis of their serum reactivity profile.


Assuntos
Asma/sangue , Imunoglobulina E/sangue , Adolescente , Adulto , Idoso , Algoritmos , Alérgenos/imunologia , Criança , Estudos de Coortes , Feminino , Humanos , Imunoensaio , Masculino , Pessoa de Meia-Idade
5.
BMC Med Genet ; 9: 73, 2008 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-18662385

RESUMO

BACKGROUND: Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of disease genes. In these populations the disease allele reveals Linkage Disequilibrium (LD) with markers over significant genetic intervals, therefore facilitating disease locus identification. In a previous study we examined the LD extension on the Xq13 region in three Corsican sub-populations from the inner mountainous region of the island. On the basis of those previous results we have proposed a multistep procedure to carry out studies aimed at the identification of genes involved in complex diseases in Corsica. A prerequisite to carry out the proposed multi-step procedure was the presence of different degrees of LD on the island and a common genetic derivation of the different Corsican sub-populations. In order to evaluate the existence of these conditions in the present paper we extended the analysis to the Corsican coastal populations. METHODS: Samples were analyzed using seven dinucleotide microsatellite markers on chromosome Xq13-21: DXS983, DXS986, DXS8092, DXS8082, DXS1225, DXS8037 and DXS995 spanning approximately 4.0 cM (13.3 Mb). We have also investigated the distribution of the DXS1225-DXS8082 haplotype which has been recently proposed as a good marker of population genetic history due to its low recombination rate. RESULTS: the results obtained indicate a decrease of LD on the island from the central mountainous toward the coastal sub-populations. In addition the analysis of the DXS1225-DXS8082 haplotype revealed: 1) the presence of a particular haplotype with high frequency; 2) the derivation from a common genetic pool of the sub-populations examined in the present study. CONCLUSION: These results indicate the Corsican sub-populations useful for the fine mapping of genes contributing to complex diseases.


Assuntos
Efeito Fundador , Variação Genética , Desequilíbrio de Ligação , Cromossomos Humanos X , França , Geografia , Humanos , Repetições de Microssatélites
6.
Haematologica ; 93(10): 1473-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18603562

RESUMO

BACKGROUND: Hepcidin plays a key role in body iron metabolism by preventing the release of iron from macrophages and intestinal cells. Defective hepcidin synthesis causes iron loading, while overproduction results in defective reticuloendothelial iron release and iron absorption. DESIGN AND METHODS: We studied a Sardinian family in which microcytic anemia due to defective iron absorption and utilization is inherited as a recessive character. Five members showed iron deficiency anemia that was not responsive to oral iron and only partially responsive to parenteral iron administration. To investigate the involvement of known genes implicated in iron metabolism we carried out linkage analysis with microsatellite markers mapping close to these genes. Afterwards, a genome-wide search was performed. RESULTS: No linkage was found between the phenotype of the patients and several known human genes involved in iron metabolism (DMT1, TF, TFRC, ZIRTL, HAMP, HJV). Genome-wide scanning by microsatellites and single nucleotide polymorphisms showed a multipoint LOD score of 5.6 on chromosome 22q12.3-13.1, where the matriptase-2 (also known as transmembrane protease, serine 6 or TMPRSS6) gene is located. Its murine counterpart (Tmprss6) has recently been found to be an essential component of a pathway that detects iron deficiency and suppresses hepcidin production. Sequencing analysis of TMPRSS6 revealed a homozygous causal mutation, predicting a splicing error and a truncated TMPRSS6 protein in affected members. Homozygous subjects had inappropriately elevated levels of serum and urinary hepcidin. CONCLUSIONS: The findings of this study suggest that the observed TMPRSS6 mutation leads to overproduction of hepcidin and, in turn, to defective iron absorption and utilization. More generally, they confirm in humans the inhibitory effect of matriptase-2 on hepcidin synthesis already demonstrated in mice.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/enzimologia , Peptídeos Catiônicos Antimicrobianos/biossíntese , Membrana Celular/enzimologia , Predisposição Genética para Doença/genética , Ferro/uso terapêutico , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Administração Oral , Adolescente , Adulto , Anemia Ferropriva/genética , Sequência de Bases , Feminino , Hemoglobinas/metabolismo , Hepcidinas , Humanos , Ferro/administração & dosagem , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Serina Endopeptidases/genética
7.
Am J Hum Genet ; 82(6): 1270-80, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18514160

RESUMO

Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10(-11)) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 muIU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10(-20)). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287, p = 7.3 x 10(-5)), GNAQ (rs10512065, p = 2.0 x 10(-4)), TG (rs2252696, p = 2.2 x 10(-3)), POU1F1 (rs1976324, p = 3.9 x 10(-3)), PDE4D (rs27178, p = 8.3 x 10(-3)), and TSHR (rs4903957, p = 8.6 x 10(-3)) loci. Overall, the results suggest a primary effect of PDE8B variants on cAMP levels in the thyroid. This would affect production of T4 and T3 and feedback to alter TSH release by the pituitary. PDE8B may thus provide a candidate target for the treatment of thyroid dysfunction.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/genética , Variação Genética , Glândula Tireoide/enzimologia , Glândula Tireoide/fisiologia , Tireotropina/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , AMP Cíclico/metabolismo , Retroalimentação , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Hipófise/fisiologia , Polimorfismo de Nucleotídeo Único , Doenças da Glândula Tireoide/enzimologia , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/fisiopatologia , Tiroxina/biossíntese , Tri-Iodotironina/biossíntese
8.
Am J Hum Genet ; 80(6): 1103-14, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17503328

RESUMO

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF- kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.


Assuntos
Asma/epidemiologia , Asma/etiologia , Asma/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Adolescente , Idade de Início , Alelos , Processamento Alternativo , Substituição de Aminoácidos , Asma/diagnóstico , Asma/patologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Estudos de Coortes , Feminino , Efeito Fundador , Frequência do Gene , Ligação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Haplótipos , Humanos , Imuno-Histoquímica , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Itália/epidemiologia , Desequilíbrio de Ligação , Escore Lod , Pulmão/metabolismo , Pulmão/cirurgia , Masculino , Repetições de Microssatélites , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Irmãos
9.
G Ital Cardiol (Rome) ; 8(2): 115-22, 2007 Feb.
Artigo em Italiano | MEDLINE | ID: mdl-17402356

RESUMO

BACKGROUND: It has been observed that in patients with ST-elevation myocardial infarction (STEMI) the presence of ST-segment depression (ST) in heterozonal electrocardiographic leads (remote STI) worsens the patient's prognosis. The aim of this study was to observe in an unselected population with a first STEMI the incidence of remote STI and the risk factors related to this condition. METHODS: We evaluated retrospectively 350 patients with a first STEMI; we excluded from our analysis 139 patients because no data about their coronary anatomy was available. ST-segment depression in the heterozonal myocardium was considered significant if > 0.1 mV at 60 ms from the J point, in at least two electrocardiographic leads. RESULTS: Patients were classified according to the presence (group 1, 117 patients) or absence (group II, 94 patients) of remote ST. The two groups did not differ for age, sex and coronary anatomy. In group I we found more heterozonal wall motion abnormalities than group II (32 vs. 18%, p = 0.018). In this group there was a higher incidence of smokers (56 vs. 33%, p = 0.025) and less patients were treated with statins when the STEMI occurred (6 vs. 14%, p = 0.047). Patients with remote ST had higher total cholesterol (214.6 +/- 48.9 vs. 192.3 +/- 29.8 mg/dl, p < 0.001) and low-density lipoprotein cholesterol (138.7 +/- 40.7 vs. 123.2 +/- 22.9 mg/dl, p < 0.0001) levels. Conclusions. In patients with STEMI the presence of remote ST is rather frequent, and seems to indicate a real heterozonal ischemia, independently of an epicardial coronary stenosis of the non-infarct-related artery. Remote ST. is associated with a higher incidence of risk factors related to microcirculatory dysfunction, such as cigarette smoking, a worse lipid profile and less protective factors, such as the use of statins prior to acute myocardial infarction.


Assuntos
Eletrocardiografia , Infarto do Miocárdio/diagnóstico , Isquemia Miocárdica/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioplastia Coronária com Balão , Colesterol/sangue , LDL-Colesterol/sangue , Interpretação Estatística de Dados , Ecocardiografia Doppler , Feminino , Humanos , Hipolipemiantes/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/terapia , Isquemia Miocárdica/fisiopatologia , Seleção de Pacientes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fumar/epidemiologia , Terapia Trombolítica
10.
J Hum Genet ; 51(11): 1030-6, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16955230

RESUMO

In mammals, X-linked gene products can be dosage compensated between males and females by inactivation of one of the two X chromosomes in the developing female embryos. X inactivation choice is usually random in embryo mammals, but several mechanisms can influence the choice determining skewed X inactivation. As a consequence, females heterozygous for X-linked recessive disease can manifest the full phenotype. Herein, we report a family with extremely skewed X inactivation that produced the full phenotype of Lowe syndrome, a recessive X-linked disease, in a female. The X chromosome inactivation studies detected an extremely skewed inactivation pattern with a ratio of 100:0 in the propositus as well as in five out of seven unaffected female relatives in four generations. The OCRL1 "de novo" mutation resides in the active paternally inherited X chromosome. X chromosome haplotype analysis suggests the presence of a locus for the familial skewed X inactivation in chromosome Xq25 most likely controlling X chromosome choice in X inactivation or cell proliferation. The description of this case adds Lowe syndrome to the list of X-linked disorders which may manifest the full phenotype in females because of the skewed X inactivation.


Assuntos
Cromossomos Humanos X , Monoéster Fosfórico Hidrolases/genética , RNA não Traduzido/genética , Inativação do Cromossomo X , Citogenética , Saúde da Família , Feminino , Marcadores Genéticos , Haplótipos , Humanos , Cariotipagem , Masculino , Síndrome Oculocerebrorrenal , Linhagem , RNA Longo não Codificante , Análise de Sequência de DNA
11.
Eur J Hum Genet ; 12(8): 613-9, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15114371

RESUMO

Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of genes involved in the pathogenesis of multifactorial diseases. In these populations, the disease allele reveals linkage disequilibrium (LD) with markers over significant genetic intervals, therefore facilitating disease locus identification. This study has been designed to examine the background LD extension in some subpopulations of Corsica. Our interest in the island of Corsica is due to its geographical and genetic proximity to the other Mediterranean island of Sardinia. Sardinian isolates in which the extension of the background LD is particularly high have been recently identified and are now the object of studies aimed at the mapping of genes involved in complex diseases. Recent evidence has highlighted that the genetic proximity between the populations of Corsica and Sardinia is particularly true for the internal conservative populations. Given these considerations, Sardinia and Corsica may represent a unique system to carry out parallel association studies whose results could be validated by comparison. In the present study, we have analyzed the LD extension on the Xq13 genomic region in three subpopulations of Corsica: Corte, Niolo and Bozio, all located in the mountainous north-center of the island. Our results show a strong degree of LD over long distance for the population of Bozio and to a less extent for the population of Niolo. Their LD extent is comparable to or higher than that reported for other isolates.


Assuntos
Cromossomos Humanos X/genética , Efeito Fundador , Variação Genética , Genética Populacional , Desequilíbrio de Ligação/genética , Alelos , França , Geografia , Humanos , Masculino , Repetições de Microssatélites/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA