Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Med Genomics ; 12(1): 143, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651322

RESUMO

BACKGROUND: Attention-Deficit Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder (NDD) which may significantly impact on the affected individual's life. ADHD is acknowledged to have a high heritability component (70-80%). Recently, a meta-analysis of GWAS (Genome Wide Association Studies) has demonstrated the association of several independent loci. Our main aim here, is to apply PASCAL (pathway scoring algorithm), a new gene-based analysis (GBA) method, to the summary statistics obtained in this meta-analysis. PASCAL will take into account the linkage disequilibrium (LD) across genomic regions in a different way than the most commonly employed GBA methods (MAGMA or VEGAS (Versatile Gene-based Association Study)). In addition to PASCAL analysis a gene network and an enrichment analysis for KEGG and GO terms were carried out. Moreover, GENE2FUNC tool was employed to create gene expression heatmaps and to carry out a (DEG) (Differentially Expressed Gene) analysis using GTEX v7 and BrainSpan data. RESULTS: PASCAL results have revealed the association of new loci with ADHD and it has also highlighted other genes previously reported by MAGMA analysis. PASCAL was able to discover new associations at a gene level for ADHD: FEZF1 (p-value: 2.2 × 10- 7) and FEZF1-AS1 (p-value: 4.58 × 10- 7). In addition, PASCAL has been able to highlight association of other genes that share the same LD block with some previously reported ADHD susceptibility genes. Gene network analysis has revealed several interactors with the associated ADHD genes and different GO and KEGG terms have been associated. In addition, GENE2FUNC has demonstrated the existence of several up and down regulated expression clusters when the associated genes and their interactors were considered. CONCLUSIONS: PASCAL has been revealed as an efficient tool to extract additional information from previous GWAS using their summary statistics. This study has identified novel ADHD associated genes that were not previously reported when other GBA methods were employed. Moreover, a biological insight into the biological function of the ADHD associated genes across brain regions and neurodevelopmental stages is provided.

2.
Arthritis Res Ther ; 17: 233, 2015 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-26330155

RESUMO

INTRODUCTION: DNA methylation is an epigenetic mechanism regulating gene expression that has been insufficiently studied in the blood of rheumatoid arthritis (RA) patients, as only T cells and total peripheral blood mononuclear cells (PBMCs) from patients with established RA have been studied and with conflicting results. METHOD: Five major blood cell subpopulations: T, B and NK cells, monocytes, and polymorphonuclear leukocytes, were isolated from 19 early RA patients and 17 healthy controls. Patient samples were taken before and 1 month after the start of treatment with methotrexate (MTX). Analysis included DNA methylation with high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring (HPLC-ESI-MS/MS-SRM) and expression levels of seven methylation-specific enzymes by quantitative polymerase chain reaction (qPCR). RESULTS: Disease-modifying anti-rheumatic drug (DMARD)-naïve early RA patients showed global DNA hypomethylation in T cells and monocytes, together with a lower expression of DNA methyltrasnferase 1 (DNMT1), the maintenance DNA methyltransferase, which was also decreased in B cells. Furthermore, significantly increased expression of ten-eleven translocation1 (TET1), TET2 and TET3, enzymes involved in demethylation, was found in monocytes and of TET2 in T cells. There was also modest decreased expression of DNMT3A in B cells and of growth arrest and DNA-damage-inducible protein 45A (GADD45A) in T and B cells. Treatment with MTX reverted hypomethylation in T cells and monocytes, which were no longer different from controls, and increased global methylation in B cells. In addition, DNMT1 and DNMT3A showed a trend to reversion of their decreased expression. CONCLUSIONS: Our results confirm global DNA hypomethylation in patients with RA with specificity for some blood cell subpopulations and their reversal with methotrexate treatment. These changes are accompanied by parallel changes in the levels of enzymes involved in methylation, suggesting the possibility of regulation at this level.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Metotrexato/uso terapêutico , Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Linfócitos B/metabolismo , Proteínas de Ciclo Celular/genética , Cromatografia Líquida de Alta Pressão , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas por Ionização por Electrospray , Linfócitos T/metabolismo , Fatores de Tempo
3.
Arthritis Rheumatol ; 67(11): 2861-5, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26246227

RESUMO

OBJECTIVE: Results of a recent study suggested that the excess cardiovascular (CV) risk observed in patients with rheumatoid arthritis (RA) could be partially explained by the presence of immune complexes of antibodies against citrullinated proteins that locally promote and perpetuate inflammation and progression of atherosclerotic plaques. The present study was undertaken to attempt to replicate one of the observations supporting this hypothesis, i.e., association between anti-citrullinated fibrinogen (anti-Cit-fibrinogen) positivity and subclinical atherosclerosis. METHODS: Three surrogate markers of atherosclerosis were assessed in 124 RA patients with no previous history of CV events: carotid intima-media thickness (CIMT) assessed by carotid ultrasonography, carotid plaques assessed by carotid ultrasonography, and Coronary Artery Calcification Score (CACS) determined by multidetector computed tomography (CT) scanning. We analyzed the relationship of these 3 subclinical atherosclerosis markers to the presence and levels of autoantibodies, including anti-Cit-fibrinogen, anti-cyclic citrullinated peptide 2 (anti-CCP-2), and rheumatoid factor (RF). RESULTS: Carotid plaques and CIMT >0.90 mm were present in 69.4% and 15.3%, of the patients, respectively, and the CACS was moderate or high in 21.0%. None of these surrogate markers of atherosclerosis showed a significant association with positivity for or the level of anti-Cit-fibrinogen antibodies (either against the whole protein [present in 33.9% of the patients] or against an immunodominant peptide [present in 23.4%]), anti-CCP-2 (present in 60.7%), or RF (present in 58.1%) in this series of patients with RA. CONCLUSION: Our results do not support the notion that there is a relationship between anti-Cit-fibrinogen antibodies and subclinical atherosclerosis in RA, thus calling into question the claim that these antibodies have a role in the increased risk of CV disease observed in patients with RA.


Assuntos
Artrite Reumatoide/complicações , Aterosclerose/complicações , Autoanticorpos/sangue , Fibrinogênio/imunologia , Peptídeos Cíclicos/imunologia , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Aterosclerose/sangue , Aterosclerose/imunologia , Espessura Intima-Media Carotídea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/sangue
4.
Arthritis Res Ther ; 16(5): 436, 2014 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-25260880

RESUMO

INTRODUCTION: Approximately 100 loci have been definitively associated with rheumatoid arthritis (RA) susceptibility. However, they explain only a fraction of RA heritability. Interactions between polymorphisms could explain part of the remaining heritability. Multiple interactions have been reported, but only the shared epitope (SE) × protein tyrosine phosphatase nonreceptor type 22 (PTPN22) interaction has been replicated convincingly. Two recent studies deserve attention because of their quality, including their replication in a second sample collection. In one of them, researchers identified interactions between PTPN22 and seven single-nucleotide polymorphisms (SNPs). The other showed interactions between the SE and the null genotype of glutathione S-transferase Mu 1 (GSTM1) in the anti-cyclic citrullinated peptide-positive (anti-CCP+) patients. In the present study, we aimed to replicate association with RA susceptibility of interactions described in these two high-quality studies. METHODS: A total of 1,744 patients with RA and 1,650 healthy controls of Spanish ancestry were studied. Polymorphisms were genotyped by single-base extension. SE genotypes of 736 patients were available from previous studies. Interaction analysis was done using multiple methods, including those originally reported and the most powerful methods described. RESULTS: Genotypes of one of the SNPs (rs4695888) failed quality control tests. The call rate for the other eight polymorphisms was 99.9%. The frequencies of the polymorphisms were similar in RA patients and controls, except for PTPN22 SNP. None of the interactions between PTPN22 SNPs and the six SNPs that met quality control tests was replicated as a significant interaction term--the originally reported finding--or with any of the other methods. Nor was the interaction between GSTM1 and the SE replicated as a departure from additivity in anti-CCP+ patients or with any of the other methods. CONCLUSIONS: None of the interactions tested were replicated in spite of sufficient power and assessment with different assays. These negative results indicate that whether interactions are significant contributors to RA susceptibility remains unknown and that strict standards need to be applied to claim that an interaction exists.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Epistasia Genética , Feminino , Genótipo , Glutationa Transferase/genética , Cadeias HLA-DRB1/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética
5.
BMC Genomics ; 15: 408, 2014 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-24884992

RESUMO

BACKGROUND: Some association studies, as the implemented in VEGAS, ALIGATOR, i-GSEA4GWAS, GSA-SNP and other software tools, use genes as the unit of analysis. These genes include the coding sequence plus flanking sequences. Polymorphisms in the flanking sequences are of interest because they involve cis-regulatory elements or they inform on untyped genetic variants trough linkage disequilibrium. Gene extensions have customarily been defined as ±50 Kb. This approach is not fully satisfactory because genetic relationships between neighbouring sequences are a function of genetic distances, which are only poorly replaced by physical distances. RESULTS: Standardized recombination rates (SRR) from the deCODE recombination map were used as units of genetic distances. We searched for a SRR producing flanking sequences near the ±50 Kb offset that has been common in previous studies. A SRR≥2 was selected because it led to gene extensions with median length=45.3 Kb and the simplicity of an integer value. As expected, boundaries of the genes defined with the ±50 Kb and with the SRR≥2 rules were rarely concordant. The impact of these differences was illustrated with the interpretation of top association signals from two large studies including many hits and their detailed analysis based in different criteria. The definition based in genetic distance was more concordant with the results of these studies than the based in physical distance. In the analysis of 18 top disease associated loci form the first study, the SRR≥2 genes led to a fully concordant interpretation in 17 loci; the ±50 Kb genes only in 6. Interpretation of the 43 putative functional genes of the second study based in the SRR≥2 definition only missed 4 of the genes, whereas the based in the ±50 Kb definition missed 10 genes. CONCLUSIONS: A gene definition based on genetic distance led to results more concordant with expert detailed analyses than the commonly used based in physical distance. The genome coordinates for each gene are provided to maintain a simple use of the new definitions.


Assuntos
Estudos de Associação Genética/métodos , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Recombinação Genética , Software
6.
Arthritis Res Ther ; 16(3): R128, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24946689

RESUMO

INTRODUCTION: We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE. METHODS: Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRS(s)). RESULTS: Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRS(s). GRS(s) were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10(-16)) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10(-7)), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results. CONCLUSION: Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women.


Assuntos
Carga Genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Alelos , Estudos de Casos e Controles , Europa (Continente) , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Razão de Chances , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Fatores Sexuais
7.
Arthritis Rheumatol ; 66(4): 940-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24757145

RESUMO

OBJECTIVE: To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA. METHODS: A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant. RESULTS: SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. CONCLUSION: Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.


Assuntos
Predisposição Genética para Doença , Osteoartrite do Quadril/genética , Osteoartrite do Joelho/genética , Polimorfismo de Nucleotídeo Único , Colágeno Tipo XI/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fator A de Crescimento do Endotélio Vascular/genética
8.
Endocrinology ; 154(12): 4757-67, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24064358

RESUMO

Nesfatin-1, a satiety-inducing peptide identified in hypothalamic regions that regulate energy balance, is an integral regulator of energy homeostasis and a putative glucose-dependent insulin coadjuvant. We investigated its production by human cardiomyocytes and its effects on glucose uptake, in the main cardiac glucose transporter GLUT-4 and in intracellular signaling. Quantitative RT-PCR, Western blots, confocal immunofluorescence microscopy, and ELISA of human and murine cardiomyocytes and/or cardiac tissue showed that cardiomyocytes can synthesize and secrete nesfatin-1. Confocal microscopy of cultured cardiomyocytes after GLUT-4 labeling showed that nesfatin-1 mobilizes this glucose transporter to cell peripherals. The rate of 2-deoxy-D-[(3)H]glucose incorporation demonstrated that nesfatin-1 induces glucose uptake by HL-1 cells and cultured cardiomyocytes. Nesfatin-1 induced dose- and time-dependent increases in the phosphorylation of ERK1/2, AKT, and AS160. In murine and human cardiac tissue, nesfatin-1 levels varied with diet and coronary health. In conclusion, human and murine cardiomyocytes can synthesize and secrete nesfatin-1, which is able to induce glucose uptake and the mobilization of the glucose transporter GLUT-4 in these cells. Nesfatin-1 cardiac levels are regulated by diet and coronary health.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ração Animal/análise , Animais , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Proteínas de Ligação a DNA/genética , Dieta , Gorduras na Dieta/farmacologia , Feminino , Regulação da Expressão Gênica/fisiologia , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Humanos , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Arthritis Res Ther ; 15(4): R82, 2013 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-23941291

RESUMO

BACKGROUND: Polymorphisms in the interferon regulatory factor 5 (IRF5) gene are associated with susceptibility to systemic lupus erythematosus, rheumatoid arthritis and other diseases through independent risk and protective haplotypes. Several functional polymorphisms are already known, but they do not account for the protective haplotypes that are tagged by the minor allele of rs729302. METHODS: Polymorphisms in linkage disequilibrium (LD) with rs729302 or particularly associated with IRF5 expression were selected for functional screening, which involved electrophoretic mobility shift assays (EMSAs) and reporter gene assays. RESULTS: A total of 54 single-nucleotide polymorphisms in the 5' region of IRF5 were genotyped. Twenty-four of them were selected for functional screening because of their high LD with rs729302 or protective haplotypes. In addition, two polymorphisms were selected for their prominent association with IRF5 expression. Seven of these twenty-six polymorphisms showed reproducible allele differences in EMSA. The seven were subsequently analyzed in gene reporter assays, and three of them showed significant differences between their two alleles: rs729302, rs13245639 and rs11269962. Haplotypes including the cis-regulatory polymorphisms correlated very well with IRF5 mRNA expression in an analysis based on previous data. CONCLUSION: We have found that three polymorphisms in LD with the protective haplotypes of IRF5 have differential allele effects in EMSA and in reporter gene assays. Identification of these cis-regulatory polymorphisms will allow more accurate analysis of transcriptional regulation of IRF5 expression, more powerful genetic association studies and deeper insight into the role of IRF5 in disease susceptibility.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença/genética , Fatores Reguladores de Interferon/genética , Polimorfismo de Nucleotídeo Único/genética , Doenças Reumáticas/genética , Western Blotting , Ensaio de Desvio de Mobilidade Eletroforética , Haplótipos , Humanos , Técnicas In Vitro , Desequilíbrio de Ligação , Reação em Cadeia da Polimerase Multiplex
11.
PLoS One ; 7(9): e45356, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23049788

RESUMO

INTRODUCTION: Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question. METHODS: European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication. RESULTS: THERE WERE THREE NEW ASSOCIATIONS: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR=0.76 and 1.30, P(corr) =0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci. CONCLUSION: Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.


Assuntos
Grupo com Ancestrais do Continente Europeu , Loci Gênicos , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idade de Início , Autoanticorpos/imunologia , Europa (Continente)/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/imunologia , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/imunologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Fenótipo , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/imunologia
12.
Arthritis Rheum ; 64(10): 3102-10, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22674012

RESUMO

OBJECTIVE: To determine whether the anti-citrullinated vimentin peptide 60-75 (anti-Cit-vimentin) and the immunodominant anti-citrullinated α-enolase peptide 1 (anti-CEP-1) antibodies are associated with subsets of patients with rheumatoid arthritis (RA) independently of the associations between anti-cyclic citrullinated peptide (anti-CCP) antibodies and clinical features of RA. METHODS: The 3 antibody types were quantified by enzyme-linked immunosorbent assay (ELISA) in serum samples from 521 patients with RA and 173 healthy controls of Spanish ancestry. Genotypes for HLA-DRB1 alleles and rs2476601 in PTPN22 were available for these patients and controls plus an additional 106 healthy controls. A combined analysis of the 3 antibodies was conducted using stratified contingency tables and logistic regression models. RESULTS: A differential, particularly strong, and independent association was observed between the presence of anti-Cit-vimentin antibodies and the presence of shared epitope (SE) alleles, specifically in patients carrying 2 SE alleles, and between the presence of anti- Cit-vimentin antibodies and the prevalence of joint erosion. Associations were observed between anti-CEP-1 positivity and the presence of HLA-DRB1 and PTPN22 risk alleles and their additive interaction. These associations were not accounted for by the anti-CCP status. CONCLUSION: Our results indicate that the 2 antibodies against citrullinated peptides analyzed in this study add specific information beyond that obtained with the anti-CCP status. They define subgroups of patients with RA in which genetic factors have different weight and there is an observed difference in the prevalence of erosions.


Assuntos
Artrite Reumatoide/imunologia , Peptídeos Cíclicos/imunologia , Fosfopiruvato Hidratase/imunologia , Vimentina/imunologia , Adulto , Alelos , Anticorpos/imunologia , Artrite Reumatoide/genética , Progressão da Doença , Epitopos/genética , Epitopos/imunologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fosfopiruvato Hidratase/genética , Vimentina/genética
13.
PLoS One ; 7(6): e37505, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22701570

RESUMO

BACKGROUND: Heart failure (HF) involves alterations in metabolism, but little is known about cardiomyopathy-(CM)-specific or diabetes-independent alterations in gene expression of proteins involved in fatty-acid (FA) uptake and oxidation or in calcium-(Ca(2+))-handling in the human heart. METHODS: RT-qPCR was used to quantify mRNA expression and immunoblotting to confirm protein expression in left-ventricular myocardium from patients with HF (n = 36) without diabetes mellitus of ischaemic (ICM, n = 16) or dilated (DCM, n = 20) cardiomyopathy aetiology, and non-diseased donors (CTL, n = 6). RESULTS: Significant increases in mRNA of genes regulating FA uptake (CD36) and intracellular transport (Heart-FA-Binding Protein (HFABP)) were observed in HF patients vs CTL. Significance was maintained in DCM and confirmed at protein level, but not in ICM. mRNA was higher in DCM than ICM for peroxisome-proliferator-activated-receptor-alpha (PPARA), PPAR-gamma coactivator-1-alpha (PGC1A) and CD36, and confirmed at the protein level for PPARA and CD36. Transcript and protein expression of Ca(2+)-handling genes (Two-Pore-Channel 1 (TPCN1), Two-Pore-Channel 2 (TPCN2), and Inositol 1,4,5-triphosphate Receptor type-1 (IP3R1)) increased in HF patients relative to CTL. Increases remained significant for TPCN2 in all groups but for TPCN1 only in DCM. There were correlations between FA metabolism and Ca(2+)-handling genes expression. In ICM there were six correlations, all distinct from those found in CTL. In DCM there were also six (all also different from those found in CTL): three were common to and three distinct from ICM. CONCLUSION: DCM-specific increases were found in expression of several genes that regulate FA metabolism, which might help in the design of aetiology-specific metabolic therapies in HF. Ca(2+)-handling genes TPCN1 and TPCN2 also showed increased expression in HF, while HF- and CM-specific positive correlations were found among several FA and Ca(2+)-handling genes.


Assuntos
Cálcio/metabolismo , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/fisiologia , Insuficiência Cardíaca/fisiopatologia , Redes e Vias Metabólicas/genética , Miocárdio/metabolismo , Antígenos CD36/metabolismo , Canais de Cálcio/metabolismo , Estudos de Casos e Controles , Primers do DNA/genética , Feminino , Regulação da Expressão Gênica/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/citologia , Proteínas de Choque Térmico/metabolismo , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Fatores de Transcrição/metabolismo
14.
Arthritis Res Ther ; 14(2): R94, 2012 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-22541939

RESUMO

INTRODUCTION: We aimed to investigate whether the effect size of the systemic lupus erythematosus (SLE) risk alleles varies across European subpopulations. METHODS: European SLE patients (n = 1,742) and ethnically matched healthy controls (n = 2,101) were recruited at 17 centres from 10 different countries. Only individuals with self-reported ancestry from the country of origin were included. In addition, participants were genotyped for top ancestry informative markers and for 25 SLE associated SNPs. The results were used to compare effect sizes between the Central Eureopan and Southern European subgroups. RESULTS: Twenty of the 25 SNPs showed independent association with SLE, These SNPs showed a significant bias to larger effect sizes in the Southern subgroup, with 15/20 showing this trend (P = 0.019) and a larger mean odds ratio of the 20 SNPs (1.46 vs. 1.34, P = 0.02) as well as a larger difference in the number of risk alleles (2.06 vs. 1.63, P = 0.027) between SLE patients and controls than for Central Europeans. This bias was reflected in a very significant difference in the cumulative genetic risk score (4.31 vs. 3.48, P = 1.8 × 10-32). Effect size bias was accompanied by a lower number of SLE risk alleles in the Southern subjects, both patients and controls, the difference being more marked between the controls (P = 1.1 × 10-8) than between the Southern and Central European patients (P = 0.016). Seven of these SNPs showed significant allele frequency clines. CONCLUSION: Our findings showed a bias to larger effect sizes of SLE loci in the Southern Europeans relative to the Central Europeans together with clines of SLE risk allele frequencies. These results indicate the need to study risk allele clines and the implications of the polygenic model of inheritance in SLE.


Assuntos
Alelos , Loci Gênicos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Viés , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
15.
J Orthop Res ; 30(6): 905-9, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22102359

RESUMO

To test whether a higher genetic risk load for knee osteoarthritis (OA) is associated with an earlier age at symptom onset. Six polymorphisms in GDF5, PTGS2, 7q22 locus, DVWA, DIO3, and ASPN that have been associated with knee OA were analyzed in 255 patients that had undergone total knee replacement (TKR) because of primary OA and in 457 healthy controls. We looked for association between the number of risk alleles in each patient and his age at symptom onset with linear regression and t-tests between the upper and lower quartiles. There was not even a weak trend in the direction of a younger age at symptom onset in the patients carrying more risk alleles. Patients in the upper quartile of age at symptom onset (67.0 ± 2.8 years) carried the same number of OA risk alleles (5.4 ± 1.4 vs. 5.3 ± 1.0) than patients in the lower quartile (44.6 ± 5.5 years). We did not find any evidence in support of the hypothesis of an earlier knee OA symptom onset associated with higher genetic risk load as determined by the six loci. This result suggests that old age and genetic risk act as independent factors in the pathogenesis of OA. It also indicates that designing OA genetic studies with patients selected for early symptom onset will not provide any substantial power gain.


Assuntos
Predisposição Genética para Doença , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/genética , Polimorfismo de Nucleotídeo Único , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/epidemiologia , Fatores de Risco , Espanha/epidemiologia
16.
PLoS One ; 6(12): e29033, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22194982

RESUMO

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8×10(-4)), oral ulcers (P = 6.9×10(-4)) and photosensitivity (P = 0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Genética Populacional , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Adulto , Feminino , Frequência do Gene/genética , Marcadores Genéticos , Geografia , Humanos , Masculino , Filogenia , Análise de Componente Principal
17.
Arthritis Res Ther ; 13(3): R80, 2011 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-21627826

RESUMO

INTRODUCTION: Interferon regulatory factor 5 gene (IRF5) polymorphisms are strongly associated with several diseases, including systemic lupus erythematosus (SLE). The association includes risk and protective components. They could be due to combinations of functional polymorphisms and related to cis-regulation of IRF5 expression, but their mechanisms are still uncertain. We hypothesised that thorough testing of the relationships between IRF5 polymorphisms, expression data from multiple experiments and SLE-associated haplotypes might provide useful new information. METHODS: Expression data from four published microarray hybridisation experiments with lymphoblastoid cell lines (57 to 181 cell lines) were retrieved. Genotypes of 109 IRF5 polymorphisms, including four known functional polymorphisms, were considered. The best linear regression models accounting for the IRF5 expression data were selected by using a forward entry procedure. SLE-associated IRF5 haplotypes were correlated with the expression data and with the best cis-regulatory models. RESULTS: A large fraction of variability in IRF5 expression was accounted for by linear regression models with IRF5 polymorphisms, but at a different level in each expression data set. Also, the best models from each expression data set were different, although there was overlap between them. The SNP introducing an early polyadenylation signal, rs10954213, was included in the best models for two of the expression data sets and in good models for the other two data sets. The SLE risk haplotype was associated with high IRF5 expression in the four expression data sets. However, there was also a trend towards high IRF5 expression with some protective and neutral haplotypes, and the protective haplotypes were not associated with IRF5 expression. As a consequence, correlation between the cis-regulatory best models and SLE-associated haplotypes, regarding either the risk or protective component, was poor. CONCLUSIONS: Our analysis indicates that although the SLE risk haplotype of IRF5 is associated with high expression of the gene, cis-regulation of IRF5 expression is not enough to fully account for IRF5 association with SLE susceptibility, which indicates the need to identify additional functional changes in this gene.


Assuntos
Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos/fisiologia , Linhagem Celular , Expressão Gênica/imunologia , Teste de Complementação Genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Modelos Lineares , Lúpus Eritematoso Sistêmico/epidemiologia , Linfócitos/citologia , Polimorfismo Genético/imunologia , Medição de Risco/métodos , Fatores de Risco
18.
Arthritis Rheum ; 63(3): 654-61, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21360494

RESUMO

OBJECTIVE: To confirm that the presence of anti-citrullinated α-enolase peptide 1 (anti-CEP-1) antibodies identifies a subgroup of patients with rheumatoid arthritis (RA). METHODS: DNA and serum samples were obtained from 451 patients with RA and 279 healthy control subjects, all of whom were of Spanish ancestry. Antibodies to cyclic citrullinated peptide (CCP) and CEP-1 were measured by enzyme-linked immunosorbent assay. HLA-DRB1 and the R620W single-nucleotide polymorphism of PTPN22 were genotyped. RESULTS: Anti-CEP-1 and anti-CCP antibodies were observed in 26.8% and 71.2% of the patients with RA, respectively. Most of the patients (86.6%) with anti-CEP-1 antibodies also had anti-CCP antibodies. Erosive arthritis, rheumatoid factor (RF) positivity, and the presence of the HLA shared epitope (especially the DRB1*04 alleles) were disproportionately associated with the group of patients with both antibodies. In addition, evidence of a significant interaction between the shared epitope and the risk allele of PTPN22 was observed only in these patients. In contrast, the association with these clinical and genetic features was weaker in patients with anti-CCP antibodies but lacking anti-CEP-1 antibodies. These results were obtained in patients in whom the prevalence of RA risk factors differed from that in other previously studied patients. CONCLUSION: We observed that autoimmunity against citrullinated α-enolase may identify a subset of patients with a higher frequency of joint erosions and RF positivity. In addition, we confirmed the disproportionately large effect of the susceptibility alleles of HLA-DRB1 and their interaction with PTPN22 in this subset of patients. These results extend, confirm, and generalize the evidence supporting the specificity of the anti-CEP-1 antibody-positive subgroup of patients with RA among anti-CCP antibody-positive patients with RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Biomarcadores Tumorais/imunologia , Proteínas de Ligação a DNA/imunologia , Fosfopiruvato Hidratase/imunologia , Proteínas Supressoras de Tumor/imunologia , Idoso , Especificidade de Anticorpos , Artrite Reumatoide/epidemiologia , Epitopos/genética , Epitopos/imunologia , Feminino , Predisposição Genética para Doença/epidemiologia , Genótipo , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/genética , Peptídeos Cíclicos/imunologia , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/imunologia , Prevalência , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/imunologia , Fatores de Risco , Fumar/epidemiologia
19.
Arthritis Res Ther ; 12(2): R72, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20423481

RESUMO

INTRODUCTION: We aimed to replicate the strong associations that a recent genome wide association study (GWAS) has found between 16 single nucleotide polymorphisms (SNPs) and response to anti-tumour necrosis factor (TNF) treatment in 89 patients with rheumatoid arthritis (RA). This study is very important because, according to published simulations, associations as strong as the reported ones will mean that these SNPs could be used as predictors of response at the individual level. METHODS: Disease activity score (DAS28) was evaluated in 151 anti-TNF treated patients with RA of Spanish ancestry at baseline and every 3 months thereafter. Genotypes of the 16 putative predictor SNPs were obtained by single-base extension. Association between the relative change in DAS28 and SNP genotypes was tested by linear regression. In addition, logistic regression was applied to compare genotypes in non-responders (n = 34) versus good-responders (n = 61) following the EULAR response criteria. RESULTS: None of the analyses showed any significant association between the 16 SNPs and response to anti-TNF treatments at 3 or 6 months. Results were also negative when only patients treated with infliximab (66.9% of the total) were separately analyzed. These negative results were obtained in spite of a very good statistical power to replicate the reported strong associations. CONCLUSIONS: We still do not have any sound evidence of genetic variants associated with RA response to anti-TNF treatments. In addition, the possibility we had envisaged of using the results of a recent GWAS for prediction in individual patients should be dismissed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Etanercepte , Feminino , Estudo de Associação Genômica Ampla , Nível de Saúde , Humanos , Imunoglobulina G/uso terapêutico , Infliximab , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores do Fator de Necrose Tumoral/uso terapêutico , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Falha de Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA