Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros

Bases de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Nat Genet ; 39(4): 523-8, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17322885

RESUMO

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.


Assuntos
Bacteriemia/genética , Malária/genética , Proteínas de Membrana Transportadoras/genética , Proteínas da Mielina/genética , Infecções Pneumocócicas/genética , Polimorfismo de Nucleotídeo Único , Proteolipídeos/genética , Tuberculose/genética , África , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/fisiologia , Modelos Moleculares , Proteínas da Mielina/fisiologia , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina , Polimorfismo de Nucleotídeo Único/fisiologia , Proteolipídeos/fisiologia , Receptores de Interleucina-1/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Reino Unido , Vietnã
2.
Nat Rev Genet ; 10(7): 431-42, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19506576

RESUMO

The last few years have seen major advances in common non-syndromic obesity research, much of it the result of genetic studies. This Review outlines the competing hypotheses about the mechanisms underlying the genetic and physiological basis of obesity, and then examines the recent explosion of genetic association studies that have yielded insights into obesity, both at the candidate gene level and the genome-wide level. With obesity genetics now entering the post-genome-wide association scan era, the obvious question is how to improve the results obtained so far using single nucleotide polymorphism markers and how to move successfully into the other areas of genomic variation that may be associated with common obesity.


Assuntos
Genoma Humano , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Marcadores Genéticos , Humanos
3.
Mol Syst Biol ; 9: 649, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23511207

RESUMO

We evaluated the presence/absence of proteins encoded by 14 077 genes in adipocytes obtained from different tissue samples using immunohistochemistry. By combining this with previously published adipocyte-specific proteome data, we identified proteins associated with 7340 genes in human adipocytes. This information was used to reconstruct a comprehensive and functional genome-scale metabolic model of adipocyte metabolism. The resulting metabolic model, iAdipocytes1809, enables mechanistic insights into adipocyte metabolism on a genome-wide level, and can serve as a scaffold for integration of omics data to understand the genotype-phenotype relationship in obese subjects. By integrating human transcriptome and fluxome data, we found an increase in the metabolic activity around androsterone, ganglioside GM2 and degradation products of heparan sulfate and keratan sulfate, and a decrease in mitochondrial metabolic activities in obese subjects compared with lean subjects. Our study hereby shows a path to identify new therapeutic targets for treating obesity through combination of high throughput patient data and metabolic modeling.


Assuntos
Adipócitos/metabolismo , Modelos Biológicos , Obesidade/metabolismo , Proteoma/metabolismo , Androsterona/metabolismo , Índice de Massa Corporal , Gangliosídeo G(M2)/metabolismo , Genoma Humano , Heparitina Sulfato/metabolismo , Humanos , Imuno-Histoquímica/métodos , Sulfato de Queratano/metabolismo , Mitocôndrias/metabolismo , Obesidade/genética , Proteoma/genética , Reprodutibilidade dos Testes , Transcriptoma
4.
N Engl J Med ; 362(22): 2092-101, 2010 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-20484391

RESUMO

BACKGROUND: The interleukin-2-mediated immune response is critical for host defense against infectious pathogens. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a suppressor of cytokine signaling, controls interleukin-2 signaling. METHODS: Using a case-control design, we tested for an association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis, and severe malaria) in blood samples from 8402 persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam. We had previously tested 20 other immune-related genes in one or more of these sample collections. RESULTS: We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five single-nucleotide polymorphisms (SNPs) (at positions -639, -292, -163, +1320, and +3415 [all relative to CISH]) within the CISH-associated locus were considered together in a multiple-SNP score, we found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P=3.8x10(-11) for all comparisons), with -292 accounting for most of the association signal (P=4.58x10(-7)). Peripheral-blood mononuclear cells obtained from adult subjects carrying the -292 variant, as compared with wild-type cells, showed a muted response to the stimulation of interleukin-2 production--that is, 25 to 40% less CISH expression. CONCLUSIONS: Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signaling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.


Assuntos
Bacteriemia/genética , Predisposição Genética para Doença , Malária/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras da Sinalização de Citocina/genética , Tuberculose/genética , Adulto , Estudos de Casos e Controles , Criança , Expressão Gênica , Genótipo , Humanos , Interleucina-2/fisiologia , Desequilíbrio de Ligação , Razão de Chances , Risco , Proteínas Supressoras da Sinalização de Citocina/metabolismo
5.
Bioinformatics ; 27(13): 1873-5, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21546396

RESUMO

UNLABELLED: A program package to enable genome-wide association of copy number variants (CNVs) with quantitative phenotypes in families of arbitrary size and complexity. Intensity signals that act as proxies for the number of copies are modeled in a variance component framework and association with traits is assessed through formal likelihood testing. AVAILABILITY AND IMPLEMENTATION: The Java package is made available at www.imperial.ac.uk/medicine/people/m.falchi/. CONTACT: m.falchi@imperial.ac.uk.


Assuntos
Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Característica Quantitativa Herdável , Software , Doença/genética , Família , Frequência do Gene , Humanos , Fenótipo
6.
J Bone Miner Res ; 22(4): 544-50, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17243864

RESUMO

UNLABELLED: Leptin is emerging as a key regulator of bone remodeling. In a population-based study of 1306 postmenopausal Danish women, nonsynonymous LEPR SNPs were associated with risk of adiposity, BMD, and vertebral fracture. Smoking exacerbates this LEPR-associated fracture risk. INTRODUCTION: Nonsynonymous single nucleotide polymorphisms (SNPs) in the human LEPR gene have been associated with adiposity in a number of studies, but there have been no large-scale studies of their implications for BMD and osteoporotic fracture risk in postmenopausal women. MATERIALS AND METHODS: We carried out a population-based study of 1430 women. Three well-known nonsynonymous leptin receptor (LEPR) SNPs (Lys109Arg, Gln223Arg, and Lys656Asn) were genotyped for qualitative and quantitative association analysis. Phenotype characteristics of main interest were DXA measures of body fat and lean tissue mass, BMD, and radiographic vertebral fractures. RESULTS: Gln223Arg associated with risk of vertebral fracture (overall OR = 1.76; OR in smokers = 2.31; p = 0.0004), in addition to BMD of the femoral neck and total hip (p = 0.036 and 0.008, respectively). Heterozygote carriers showed lower BMD at both sites. Gln223Arg was also associated with adiposity (p = 0.001 for total fat mass). For adiposity, the at-risk allele was G (resulting in an arginine at position 223). CONCLUSIONS: Variation in LEPR seemed to contribute to the variation in BMD and fracture risk in Danish postmenopausal women; the heterozygous genotype was associated with increased risk of manifest osteoporosis. Further studies are needed to replicate these data and to clarify the mechanisms involved.


Assuntos
Composição Corporal/genética , Densidade Óssea/genética , Receptores de Superfície Celular/genética , Fraturas da Coluna Vertebral/genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Primers do DNA/genética , Dinamarca , Feminino , Genótipo , Humanos , Menopausa , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores para Leptina
7.
Eur J Hum Genet ; 15(3): 320-7, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17164796

RESUMO

Candidate gene analyses are often inconclusive owing to genetic or phenotypic heterogeneity, low statistical power, selection of nonfunctional SNPs, and inadequate statistical analysis of the genetic architecture. Angiotensin-converting enzyme (ACE) is involved in adipocyte growth and function and the ACE-processed angiotensin II inhibits adipocyte differentiation. Associations between body mass index (BMI) and ACE polymorphisms have been reported in general populations, but the contribution to severe obesity of this gene, which is located under an obesity genome-scan linkage peak on 17q23, is unknown. ACE is one of the most studied genes and markers responsible for variation in circulating ACE enzyme levels have been extensively characterised. Eight of these variants were genotyped in 1054 severely obese cases and 918 nonobese controls, as well as 116 nuclear families from the genome scan (n=447), enabling the known clades to be inferred. Qualitative analysis of individual single-nucleotide polymorphisms (SNPs), haplotypes, clades, and diploclades demonstrated no significant associations (P<0.05) after minimal correction for multiple testing. Quantitative analysis of clades and diploclades for BMI, waist-to-hip ratio, or ZBMI in children were also not significant. This rigorous, large-scale study of common, well-defined, severe polygenic obesity provides strong evidence that functionally relevant sequence variation in ACE, whether it is defined at the level of SNPs, haplotypes, or clades, is not associated with severe obesity in French Caucasians. Such a study design exemplifies the strategy needed to clearly define the contribution of the ACE gene to the plethora of complex genetic diseases where weak associations have been previously reported.


Assuntos
Modelos Genéticos , Obesidade Mórbida/genética , Peptidil Dipeptidase A/genética , Estudos de Casos e Controles , Humanos , Polimorfismo de Nucleotídeo Único
8.
Nat Commun ; 8(1): 428, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28874660

RESUMO

Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1ß administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth.Inflammation mediated by microglia plays a key role in brain injury associated with preterm birth, but little is known about the microglial response in preterm infants. Here, the authors integrate molecular and imaging data from animal models and preterm infants, and find that microglial expression of DLG4 plays a role.


Assuntos
Proteína 4 Homóloga a Disks-Large/metabolismo , Genômica , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido Prematuro/metabolismo , Microglia/metabolismo , Substância Branca/crescimento & desenvolvimento , Substância Branca/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Recém-Nascido , Inflamação/patologia , Interleucina-1beta/farmacologia , Imageamento por Ressonância Magnética , Camundongos , Microglia/efeitos dos fármacos , Neuropsiquiatria , Mapas de Interação de Proteínas/genética , Locos de Características Quantitativas/genética , Fator de Transcrição STAT3/metabolismo , Transcriptoma/genética
9.
Diabetes ; 54(10): 3049-55, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16186414

RESUMO

Murine models have been highly effective in identifying the monogenic forms of human obesity discovered to date. Melanin-concentrating hormone receptor 1 (MCHR1) has been shown to be significant in the downstream orexigenic activity of the leptin-melanocortin pathway by such models. In this study, the human MCHR1 gene was extensively characterized by sequencing 3.5 kb of coding, untranslated and intronic regions plus 1 kb of putative promoter region in 180 morbidly obese adults and 87 morbidly obese children, a total of >2.4 Mb of sequencing. Thirty-nine single nucleotide polymorphisms (SNPs) were found, seven of which encode an amino acid change. One mutation, R248Q, appeared to cosegregate with the obesity trait in one pedigree but was also found to be a rare polymorphism in control samples. To investigate the possible polygenic role of MCHR1, the six common SNPs (minor allele frequency >5%) found in the sequenced regions were then screened in 557 morbidly obese adults, 552 obese children, and 1,195 nonobese nondiabetic control subjects. The plausible promoter SNP, rs133068, was found to be associated with protection against obesity in obese children only (allele frequency P = 0.006 and genotype frequency P = 0.004). Most significant results were found when using a dominant model (P = 0.001, odds ratio 0.695 [95% CI 0.560-0.863]). However, similar associations were found when both adults and children were analyzed together (P = 0.006, 0.783 [0.658-0.930]), suggesting that severe forms of obesity with early onset may be associated with SNPs in MCHR1.


Assuntos
Obesidade Mórbida/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Somatostatina/genética , Adolescente , Adulto , Alelos , Sequência de Aminoácidos , Índice de Massa Corporal , Membrana Celular/química , Criança , Feminino , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Razão de Chances , Regiões Promotoras Genéticas/genética , Receptores de Somatostatina/química
10.
Brain Behav ; 6(7): e00434, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27110435

RESUMO

BACKGROUND: The consequences of preterm birth are a major public health concern with high rates of ensuing multisystem morbidity, and uncertain biological mechanisms. Common genetic variation may mediate vulnerability to the insult of prematurity and provide opportunities to predict and modify risk. OBJECTIVE: To gain novel biological and therapeutic insights from the integrated analysis of magnetic resonance imaging and genetic data, informed by prior knowledge. METHODS: We apply our previously validated pathway-based statistical method and a novel network-based method to discover sources of common genetic variation associated with imaging features indicative of structural brain damage. RESULTS: Lipid pathways were highly ranked by Pathways Sparse Reduced Rank Regression in a model examining the effect of prematurity, and PPAR (peroxisome proliferator-activated receptor) signaling was the highest ranked pathway once degree of prematurity was accounted for. Within the PPAR pathway, five genes were found by Graph Guided Group Lasso to be highly associated with the phenotype: aquaporin 7 (AQP7), malic enzyme 1, NADP(+)-dependent, cytosolic (ME1), perilipin 1 (PLIN1), solute carrier family 27 (fatty acid transporter), member 1 (SLC27A1), and acetyl-CoA acyltransferase 1 (ACAA1). Expression of four of these (ACAA1, AQP7, ME1, and SLC27A1) is controlled by a common transcription factor, early growth response 4 (EGR-4). CONCLUSIONS: This suggests an important role for lipid pathways in influencing development of white matter in preterm infants, and in particular a significant role for interindividual genetic variation in PPAR signaling.


Assuntos
Recém-Nascido Prematuro/fisiologia , Substância Branca/fisiologia , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Imagem de Difusão por Ressonância Magnética , Variação Genética , Humanos , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido Prematuro/metabolismo , Metabolismo dos Lipídeos/genética , Fenótipo , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Substância Branca/diagnóstico por imagem , Substância Branca/crescimento & desenvolvimento , Substância Branca/patologia
11.
PLoS One ; 10(6): e0131417, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26120850

RESUMO

Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76_98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans.


Assuntos
Carboxipeptidase H/genética , Diabetes Mellitus Tipo 2/complicações , Deficiência Intelectual/complicações , Síndrome de Klinefelter/complicações , Mutação/genética , Obesidade Mórbida/complicações , Obesidade Mórbida/genética , Carboxipeptidase H/metabolismo , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Exoma/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Homozigoto , Humanos , Deficiência Intelectual/genética , Síndrome de Klinefelter/enzimologia , Síndrome de Klinefelter/genética , Masculino , Obesidade Mórbida/enzimologia , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
12.
Eur J Hum Genet ; 12(2): 132-8, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14673470

RESUMO

Interleukin-1 (IL1) is a potent endogenous pyrogen and inducer of the acute phase response, and these innate immune responses are an important part of the human host's initial reaction to infection by the malaria parasite. In addition, several single-nucleotide polymorphisms (SNPs) in this region have previously been demonstrated to be associated with susceptibility to infectious disease. Therefore, a possible association with malaria susceptibility was investigated. A total of 13 polymorphic markers were used in a two-stage screening strategy to genotype a Gambian case-control study group by either restriction endonuclease digestion or the Sequenom MassARRAY assay. This involved an initial screen of 188 severe cases and 188 mild controls, and if there was a significant association with a malaria phenotype (P<0.05); this was followed by screening of the remaining 1044 samples. Two markers showed significant association with malaria: interleukin-1 alpha +4845 G --> T (P=0.035 for mild malaria versus controls) and interleukin-1 beta +3953 C --> T (P=0.030 for mild malaria versus severe malaria). Haplotypes constructed using the SNPHAP programme were not associated with any of the malaria phenotypes investigated. In summary, if IL1 variants are involved in malaria susceptibility in the Gambia at all, then the effects are small.


Assuntos
Predisposição Genética para Doença , Interleucina-1/genética , Malária/genética , Família Multigênica , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Gâmbia , Humanos
13.
Am J Trop Med Hyg ; 69(6): 565-8, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14740869

RESUMO

Malaria continues to claim the lives of more children worldwide than any other infectious disease, and improved understanding of disease immunology is a priority for the development of new therapeutic and vaccination strategies. FcgammaRIIa (CD32) contains a polymorphic variant (H/R131) that has been associated with variability in susceptibility to both bacterial diseases and Plasmodium falciparum parasitemia. We investigated the role of this polymorphism in West Africans with mild and severe malarial disease. The HH131 genotype was significantly associated with susceptibility to severe malaria (P = 0.03, odds ratio = 1.40, 95% confidence interval = 1.02-1.91). In contrast to studies of parasitemia, the presence of the R131 allele, rather than the RR131 genotype, appeared to be the important factor in protection from disease. This is the first evidence for an association between CD32 polymorphism and severe malaria and provides an example of balancing selective pressures from different infectious diseases operating at the same genetic locus.


Assuntos
Antígenos CD/genética , Predisposição Genética para Doença , Malária Cerebral/genética , Receptores de IgG/genética , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Gâmbia , Humanos , Lactente , Recém-Nascido , Malária Cerebral/patologia , Malária Cerebral/prevenção & controle , Masculino , Plasmodium falciparum , Polimorfismo Genético , Índice de Gravidade de Doença
14.
Trans R Soc Trop Med Hyg ; 96(3): 327-8, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12174790

RESUMO

The influence of haptoglobin polymorphisms on severe malaria occurrence was assessed in 1183 individuals from The Gambia. No significant association was found between severe malaria and either haptoglobin genotypes or phenotypes. The advantages of using a deoxyribonucleic acid-based haptoglobin typing method are discussed.


Assuntos
Haptoglobinas/genética , Malária Falciparum/genética , Polimorfismo Genético , Estudos de Casos e Controles , Gâmbia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Imunidade Inata/genética , Malária Falciparum/imunologia
15.
Cancer Prev Res (Phila) ; 6(12): 1348-55, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24089088

RESUMO

Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterized. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium's HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly and epigenetically regulated in this tumor type. Using a linear model for microarray data, we identified 1610 differentially methylated autosomal CpG sites, with 809 hypermethylated (representing 603 genes) and 801 hypomethylated (representing 712 genes) in cholangiocarcinoma versus adjacent normal tissues (false-discovery rate ≤ 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12, and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors.


Assuntos
Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos/patologia , Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/patologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Colangiocarcinoma/patologia , Ilhas de CpG/genética , Humanos , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Regiões Promotoras Genéticas/genética , Sulfitos/química
16.
Obesity (Silver Spring) ; 20(4): 708-14, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21852814

RESUMO

Adipocytes secrete many proteins that regulate metabolic functions. The gene inter-α (globulin) inhibitor H5 (ITIH-5) encodes a secreted protein and is known to be expressed abundantly in the placenta. However, using gene expression profiles data we observed high expression of ITIH-5 in adipose tissue. The aim of this study was to test the hypothesis that ITIH-5 is strongly expressed in human adipocytes and adipose tissue, and is related to obesity and clinical metabolic variables. ITIH-5 adipose tissue mRNA expression was analyzed with DNA microarray and real-time PCR, and its association with clinical variables was examined. ITIH-5 protein expression was analyzed using western blot. ITIH-5 mRNA expression was abundant in human adipose tissue, adipocytes, and placenta, and higher in subcutaneous (sc) compared to omental adipose tissue (P < 0.0001). ITIH-5 mRNA and protein expression in sc adipose tissue were higher in obese compared to lean subjects (P < 0.0001 and P < 0.001, respectively). ITIH-5 mRNA expression was reduced after diet-induced weight loss (P < 0.0001). ITIH-5 mRNA expression was associated with anthropometry and clinical metabolic variables. In conclusion, ITIH-5 is highly expressed in sc adipose tissue, increased in obesity, down regulated after weight loss, and associated with measures of body size and metabolism. Together, this indicates that ITIH-5 merits further investigation as a regulator of human metabolism.


Assuntos
Adipócitos/metabolismo , Obesidade/metabolismo , Proteínas Secretadas Inibidoras de Proteinases/metabolismo , Gordura Subcutânea/metabolismo , Redução de Peso , Adulto , Western Blotting , Índice de Massa Corporal , Células Cultivadas , Dieta Redutora , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Secretadas Inibidoras de Proteinases/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Gordura Subcutânea/patologia
17.
Obesity (Silver Spring) ; 20(1): 178-85, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21760635

RESUMO

Recent studies have reported associations of sirtuin 1 (SIRT1) single nucleotide polymorphisms (SNPs) to both obesity and BMI. This study was designed to investigate association between SIRT1 SNPs, SIRT1 gene expression and obesity. Case-control analyses were performed using 1,533 obese subjects (896 adults, BMI >40 kg/m(2) and 637 children, BMI >97th percentile for age and sex) and 1,237 nonobese controls, all French Caucasians. Two SNPs (in high linkage disequilibrium (LD), r(2) = 0.96) were significantly associated with adult obesity, rs33957861 (P value = 0.003, odds ratio (OR) = 0.75, confidence interval (CI) = 0.61-0.92) and rs11599176 (P value: 0.006, OR = 0.74, CI = 0.61-0.90). Expression of SIRT1 mRNA was measured in BMI-discordant siblings from 154 Swedish families. Transcript expression was significantly correlated to BMI in the lean siblings (r(2) = 0.13, P value = 3.36 × 10(-7)) and lower SIRT1 expression was associated with obesity (P value = 1.56 × 10(-35)). There was also an association between four SNPs (rs11599176, rs12413112, rs33957861, and rs35689145) and BMI (P values: 4 × 10(-4), 6 × 10(-4), 4 × 10(-4), and 2 × 10(-3)) with the rare allele associated with a lower BMI. However, no SNP was associated with SIRT1 transcript expression level. In summary, both SNPs and SIRT1 gene expression are associated with severe obesity.


Assuntos
Obesidade Mórbida/genética , PPAR gama/genética , Polimorfismo de Nucleotídeo Único , Sirtuína 1/genética , Adolescente , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Feminino , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Obesidade Mórbida/epidemiologia , Razão de Chances , Irmãos , Suécia/epidemiologia , Regulação para Cima , População Branca/genética
18.
Obesity (Silver Spring) ; 19(4): 833-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20966904

RESUMO

A recent study suggested that four CD36 polymorphisms (namely rs3211867, rs3211883, rs3211908, and rs1527483) were associated with an increased risk of obesity, an increased BMI and percentage of body fat in European adolescents. We first attempted to confirm these results in three independent case-control genome-wide association studies (GWAS) data totaling 3,509 subjects of French and German origin, but we were unable to find any association of these variants with early onset obesity risk. We then genotyped the four CD36 single-nucleotide polymorphisms (SNPs) in a large population-based study of 4,667 Finnish subjects and we did not replicate any of the recently reported associations with BMI. By combining all available data in a meta-analysis (N = 9,973), we found no evidence for an association of the reported four variants in CD36 with increased obesity risk or increased BMI (0.07 ≤ P values ≤ 0.93). Finally, we assessed the contribution of the full CD36 locus gene variation to obesity risk in 3,509 subjects and we did not detect any significant association with obesity after correction for multiple testing. In summary, we were unable to confirm the recently reported association of variants in CD36 with early onset obesity in populations of European ancestry.


Assuntos
Antígenos CD36/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , Tecido Adiposo/metabolismo , Adolescente , Adulto , Alelos , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Feminino , Finlândia , França , Loci Gênicos , Predisposição Genética para Doença/epidemiologia , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , População Branca/estatística & dados numéricos , Adulto Jovem
19.
Obesity (Silver Spring) ; 17(8): 1549-53, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19300429

RESUMO

Visfatin was recently reported as a novel adipokine encoded by the NAMPT (PBEF1) gene. This study was aimed at investigation of the possibility that single-nucleotide polymorphisms (SNPs) in the visfatin gene are associated with either obesity or type 2 diabetes (T2D). A set of eight "tag-SNPs" were selected and ABI SNPlex assays designed for genotyping purposes. A total of 1,709 severely obese subjects were typed (896 class III obese adults and 813 children) together with 2,367 T2D individuals and 2,850 controls. For quantitative trait analysis, an additional 2,362 subjects were typed for rs10487818 from a general population sample. One rare SNP, rs10487818, located in intron 4 of NAMPT was associated with severe obesity, with a minor allele frequency of 1.6% in controls, 0.4% in the class III obese adults and, remarkably, 0% in the severely obese children. A highly significant association was observed for the presence or absence of the rare allele, i.e., (A,A) vs. (A,T + T,T) genotypes, in children (P = 6 x 10(-9)) and in adults (P = 8 x 10(-5)). No other significant (P < 0.05) association was observed with obesity or T2D for this or any other SNP. No association with BMI or waist-to-hip ratio was observed in a general population sample (n = 5,212). This is one of the first rare SNPs shown to be protective against a common polygenic disease and provides further evidence that rare alleles of strong effect can contribute to complex diseases such as severe obesity.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/fisiologia , Obesidade/genética , Adulto , Índice de Massa Corporal , Criança , Estudos de Coortes , Feminino , Genótipo , Haplótipos , Humanos , Íntrons , Desequilíbrio de Ligação , Masculino , Obesidade/prevenção & controle , Razão de Chances , Polimorfismo de Nucleotídeo Único
20.
Nat Genet ; 41(1): 89-94, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19060909

RESUMO

In genome-wide association (GWA) data from 2,151 nondiabetic French subjects, we identified rs1387153, near MTNR1B (which encodes the melatonin receptor 2 (MT2)), as a modulator of fasting plasma glucose (FPG; P = 1.3 x 10(-7)). In European populations, the rs1387153 T allele is associated with increased FPG (beta = 0.06 mmol/l, P = 7.6 x 10(-29), N = 16,094), type 2 diabetes (T2D) risk (odds ratio (OR) = 1.15, 95% CI = 1.08-1.22, P = 6.3 x 10(-5), cases N = 6,332) and risk of developing hyperglycemia or diabetes over a 9-year period (hazard ratio (HR) = 1.20, 95% CI = 1.06-1.36, P = 0.005, incident cases N = 515). RT-PCR analyses confirm the presence of MT2 transcripts in neural tissues and show MT2 expression in human pancreatic islets and beta cells. Our data suggest a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptor MT2 de Melatonina/genética , Receptores de Melatonina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Criança , Cromossomos Humanos Par 11/genética , Estudos de Coortes , Diabetes Mellitus Tipo 2/enzimologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glucoquinase/genética , Humanos , Resistência à Insulina/genética , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Metanálise como Assunto , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor MT2 de Melatonina/metabolismo , Receptores de Melatonina/metabolismo , Reprodutibilidade dos Testes
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA