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Cenit M.C.,Hospital Clinico S Carlos | Alcina A.,Institute Parasitologia y Biomedicina Lopez Neyra | Marquez A.,Hospital Clinico S Carlos | Mendoza J.L.,Hospital Clinico S Carlos | And 8 more authors.
Genes and Immunity | Year: 2010

STAT3 (signal transducer and activator of transcription 3) signaling is a critical component of Th17-dependent autoimmune processes. Genome-wide association studies (GWAS) have revealed the role of the STAT3 gene in inflammatory bowel disease (IBD) susceptibility, although confirmation in clinical subphenotypes is warranted. Mice with targeted deletion of Stat3 in T cells are resistant to experimental autoimmune encephalomyelitis, which is a multiple sclerosis (MS) model. Moreover, increased phosphorylated STAT3 was reported in T cells of patients evolving from clinically isolated syndrome to defined MS and in relapsing patients. These evidences led us to analyze the role of STAT3 in Crohn's disease (CD), ulcerative colitis (UC) and MS risk. Polymorphisms in the STAT3 region (rs3809758/rs744166/rs1026916/rs12948909) were genotyped and the inferred haplotypes were subsequently analyzed in 860 IBD and 1540 MS Spanish patients and 1720 ethnically matched controls. The haplotype conformed by the risk alleles of each polymorphism was significantly associated with both clinical phenotypes of IBD (CD: P0.005, odds ratio 1.25, 95% confidence interval 1.06-1.46; and UC: P0.002, odds ratio 1.19, 95% confidence interval 1.02-1.38). No evidence of association was detected for MS. The originally described association of IBD with STAT3 polymorphisms is corroborated for the two clinical phenotypes, CD and UC, in an independent population. A major role of this gene in MS seems unlikely. © 2010 Macmillan Publishers Limited All rights reserved.


Prieto L.,University of Valencia | Ruiz-Jimenez L.,Hospital Clinico S Carlos | Marin J.,University of Valencia
Journal of Asthma | Year: 2013

Objective. The effect of spirometric maneuvers on exhaled nitric oxide (NO) at the constant flow rate of 50 ml/s (FENO) has been studied with equivocal results. Furthermore, the effects of spirometry on bronchial NO flux (J'awNO) and alveolar NO (CANO), two measurements increasingly being used in clinical and research protocols, are unknown. The aim of this study was to evaluate the effect of spirometry on FENO, J'awNO, and CANO in adults with asthma. Methods. Forty-four adults with asthma were studied. To assess the impact of exhaled NO measurement itself on exhaled NO values, FENO, J'awNO, and CANO were obtained twice, at baseline and after a resting period of 10 min. Then spirometry (with or without bronchodilator) was performed followed by exhaled NO measurements at 10 min. Results. In the group with pre-bronchodilator study only (n = 26), mean (95% CI) values before spirometry were 37.3 ppb (22.2-52.4) for FENO, 2375 pl/s (1613-3137) for J'awNO, and 1.65 ppb (0.95-2.35) for CANO, compared with 35.5 ppb (21.1-49.0, p = .10), 2402 pl/s (1663-3141, p = .85), and 1.60 ppb (0.64-2.56, p = .87) after spirometry, respectively. Spirometry-induced changes in exhaled NO values were also not significant in the group with both pre- and post-bronchodilators (n = 18). Furthermore, changes in FENO, J'awNO, and CANO values were similar in the two groups. Conclusions. Our findings demonstrate that spirometry (with or without bronchodilator) does not induce significant changes in bronchial NO flux or alveolar NO values. Therefore, exhaled NO values may be obtained after spirometric maneuvers. © 2013 Informa Healthcare USA, Inc.


Hurtado Del Pozo C.,Institute Investigaciones Biomedicas Alberto Sols | Vesperinas-Garcia G.,Hospital Universitario La Paz | Rubio M.-A.,Hospital Clinico S Carlos | Corripio-Sanchez R.,Hospital Universitario La Paz | And 3 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2011

ChREBP is an essential transcription factor for lipogenesis. Its physiological role in adipose tissue has been studied only to a small extent and the control of its expression remains unknown in human adipocytes. We have studied ChREBP mRNA and protein expression levels in the liver and the omental (OM) and subcutaneous (SC) adipose tissues from obese and lean subjects, as well as in human differentiated preadipocytes. Liver and OM and SC adipose tissue biopsies were obtained from lean and obese patients. Human preadipocytes were isolated from the adipose tissues from obese patients and differentiated under adipogenic conditions. ChREBP expression levels were quantified by RT-PCR and Western blot analysis. We found opposing results in terms of ChREBP regulation in the liver and adipose samples. ChREBP increased in the liver from obese compared to lean subjects, whereas the expression decreased in both adipose tissues. The mRNAs of other adipogenic markers were checked in these tissues. The pattern of FASN was similar to the one for ChREBP, ADCY3 decreased in both adipose tissues from obese patients, AP2 decreased only in OM adipose tissue of obese patients and ATGL did not change. The levels of ChREBP mRNA and protein showed dramatic increases during the differentiation of human OM and SC preadipocytes. In conclusion, ChREBP expression has an opposite regulation in the liver and adipose tissue from obese subjects which is compatible with the increased hepatic lipogenesis and decreased adipocytic lipogenesis found in these patients. The dramatic increase of ChREBP mRNA and protein levels during preadipocyte differentiation suggests a role in adipogenesis. © 2011 Elsevier B.V. All rights reserved.


Hurtado Del Pozo C.,Institute Investigaciones Biomedicas Alberto Sols | Hurtado Del Pozo C.,CIBER ISCIII | Calvo R.M.,Institute Investigaciones Biomedicas Alberto Sols | Calvo R.M.,CIBER ISCIII | And 8 more authors.
Obesity Surgery | Year: 2011

The adipose tissue is a highly regulated endocrine and paracrine organ that secretes a wide variety of biologically active molecules involved in the control of energy balance and the regulation of body weight. Our work aimed to analyze the dysregulation of the adipocyte metabolism and compare the gene expression patterns between omental (OM) and subcutaneous (SC) adipose tissue from obese and lean subjects by using whole-genome DNA microarrays. OM and SC adipose tissues were obtained from 43 obese subjects undergoing bariatric surgery and from six lean individuals. Gene expression analysis was performed by whole-genome microarrays and Taqman RT-PCR. The analysis of microarrays showed upregulation of 545 genes in OM and 47 in SC adipose tissue, whereas 723 and 27 genes were downregulated in OM and SC tissue, respectively, in obese patients. Significantly altered genes showed at least a twofold change of p<0.05. Validation of the arrays with 28 genes was carried out by using low density microfluidic cards which confirmed the changes found in most genes. We focused on the altered expression of gene coding for enzymes and transcription factors involved in lipid metabolism. Interestingly, some of these genes have not been previously described in obesity. Our results show that adipose tissue from obese subjects entails defense mechanisms against an excessive expansion and fat accumulation, repressing both lipogenesis and lipolysis. © 2010 Springer Science+Business Media, LLC.


Vandenbroeck K.,University of the Basque Country | Vandenbroeck K.,Ikerbasque | Alvarez J.,CIC BioGUNE | Swaminathan B.,University of the Basque Country | And 17 more authors.
Genes and Immunity | Year: 2012

Cytokine and cytokine receptor genes, including IL2RA, IL7R and IL12A, are known risk factors for multiple sclerosis (MS). Excitotoxic oligodendroglial death mediated by glutamate receptors contributes to demyelinating reactions. In the present study, we screened 368 single-nucleotide polymorphisms (SNPs) in 55 genes or gene clusters coding for cytokines, cytokine receptors, suppressors of cytokine signaling (SOCS), complement factors and glutamate receptors for association with MS in a Spanish-Basque resident population. Top-scoring SNPs were found within or nearby the genes coding for SOCS-1 (P=0.0005), interleukin-28 receptor, alpha chain (P=0.0008), oncostatin M receptor (P=0.002) and interleukin-22 receptor, alpha 2 (IL22RA2; P=0.003). The SOCS1 rs243324 variant was validated as risk factor for MS in a separate cohort of 3919 MS patients and 4003 controls (combined Cochran-Mantel-Haenszel P=0.00006; odds ratio (OR)=1.13; 95% confidence interval (CI)=1.07-1.20). In addition, the T allele of rs243324 was consistently increased in relapsing-remitting/secondary progressive versus primary-progressive MS patients, in each of the six data sets used in this study (P CMH 0.0096; OR1.24; 95% CI 1.05-1.46). The association with SOCS1 appears independent from the chr16MS risk locus CLEC16A. © 2012 Macmillan Publishers Limited All rights reserved.


Hurtado Del Pozo C.,Institute Investigaciones Biomedicas | Hurtado Del Pozo C.,CIBER ISCIII | Calvo R.M.,Institute Investigaciones Biomedicas | Calvo R.M.,CIBER ISCIII | And 9 more authors.
Obesity | Year: 2010

Housekeeping genes frequently used in gene expression studies are highly regulated in human adipose tissue. To ensure a correct interpretation of results, it is critical to select appropriate reference genes. Subcutaneous (SC) and omental (OM) adipose tissue expression was analyzed from lean and obese subjects using whole genome complementary DNA (cDNA) microarrays to identify stably expressed genes and commercial TaqMan low density arrays (LDAs), with 16 common control genes. The best candidate gene from microarrays analysis was F-box and leucine-rich repeat protein-10 (FBXL10) (fold-change 10-3 P <0.01), an ubiquitous nucleolar protein evolutionarily conserved. Hypoxanthine phosphoribosyltransferase 1 (HPRT1) and importin 8 (IPO8), were the best reference genes among the 16 genes in the LDAs with coefficient of variation (CV) of 4.51 and 4.55%, respectively. However, when the LDAs data were further analyzed by the geNorm and NormFinder softwares, IPO8, a nuclear protein mediating import of proteins, was the first and the third better reference gene, respectively. IPO8 and FBXL10 were further validated by real-time PCR in additional OM and SC fat samples and primary cultured preadipocytes. According to their CV, IPO8 resulted more suitable than FBXL10 in both adipose tissue depots and SC preadipocytes, whereas FBXL10 performed better than IPO8 in OM cultured preadipocytes. Both genes expression levels did not change throughout adipogenesis. Thus, we provide clear evidence that IPO8 and FBXL10 are good candidates to use as reference genes in gene expression studies in human OM and SC adipose tissues as well as differentiated primary preadipocytes. © 2010 The Obesity Society.


Trynka G.,University of Groningen | Hunt K.A.,Queen Mary, University of London | Bockett N.A.,Queen Mary, University of London | Romanos J.,University of Groningen | And 62 more authors.
Nature Genetics | Year: 2011

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease. © 2011 Nature America, Inc. All rights reserved.


Vandenbroeck K.,University of the Basque Country | Vandenbroeck K.,Ikerbasque | Alloza I.,University of the Basque Country | Swaminathan B.,University of the Basque Country | And 11 more authors.
Genes and Immunity | Year: 2011

In recent reports, IRF5 polymorphisms showed significant association with multiple sclerosis (MS) susceptibility in three studied populations and Irf5-deficient mice exhibited an increased susceptibility to viral infection, linked to a significant decrease in the induction of serum type I interferon (IFN). In the present study, we evaluated the association of two IRF5 polymorphisms with MS predisposition and we also addressed whether these polymorphisms were associated with active replication of human herpes virus-6 (HHV-6) observed in a subgroup of MS patients, and/or with response to IFN-β therapy. A total of 1494 MS patients and 1506 ethnically matched controls were genotyped for rs4728142 and rs3807306 with TaqMan pre-designed assays. One hundred and six patients were classified as responders to IFN-β therapy (no relapses/increases in EDSS over the 2-year follow-up) and 112 as non-responders (at least two relapses or an increase in expanded disability status scale (EDSS) of at least one point during the same period). The combined analysis of available datasets yielded an effect size on MS with odds ratio (OR) MantelHaenszel 1.14 (P<0.002) for the IRF5 polymorphisms rs4728142 and rs3807306. Additionally, trends for association were observed between rs3807306T and infection with HHV-6 p0.05, OR (95% CI)1.56 (1.00-2.44) and response to IFN-β therapy P0.09, OR (95% CI)1.39 (0.95-2.05). © 2011 Macmillan Publishers Limited All rights reserved.


Diaz-Gallo L.-M.,Institute Parasitologia y Biomedicina Lopez Neyra | Medrano L.M.,Hospital Clinico S Carlos | Gomez-Garcia M.,Hospital Virgen Of Las Nieves | Cardena C.,Hospital Clinico San Cecilio | And 9 more authors.
Human Immunology | Year: 2011

The aim of this study was to evaluate the possible implication of CD24 gene in the genetic predisposition to inflammatory bowel disease (IBD). Our study population consisted of 1321 female Spanish individuals (369 Crohn's disease [CD] patients, 323 ulcerative colitis [UC] patients, and 629 healthy matched controls). Two putative functional polymorphisms, a C to T coding polymorphism (rs8734) and a TG deletion in the 3' untranslated region (rs3838646), were used as CD24 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. The "del" allele of the dinucleotide deletion was associated with an increased risk of CD (odds ratio = 1.61, 95% confidence interval = 1.17-2.21, p FDR = 6.4E-03) but not with UC. Moreover, this allele was significant associated with the age of CD diagnosis between 17 and 40 years, the ileocolonic location, and the inflammatory behavior of CD. We observed no significant differences between the allelic or genotypic frequencies of the A57V polymorphism in our studied IBD cohort. Our results suggest that the rs3838646 CD24 polymorphism is part of the genetic background of CD. © 2011 American Society for Histocompatibility and Immunogenetics.


Villar L.M.,Hospital Ramon y Cajal | Espino M.,Hospital Ramon y Cajal | Cavanillas M.L.,Hospital Clinico S Carlos | Roldan E.,Hospital Ramon y Cajal | And 7 more authors.
Clinical Immunology | Year: 2010

We described previously that multiple sclerosis (MS) patients with oligoclonal IgM against myelin lipids (M+) develop an aggressive disease. Our aim was to assess possible mechanisms regulating the production of these antibodies. We studied B cell subsets in 180 patients with MS, and 69 with other neurological diseases. M+ MS patients showed a moderate increase of CD5+ B-cell percentage in peripheral blood and a considerable augment of these cells in cerebrospinal fluid (CSF) that correlated with intrathecal IgM production. The appearance of CD5+ B cells into the central nervous system (CNS) was related to increased CXCL13 and TNF-alpha levels in CSF. Moreover, the presence of oligoclonal IgM associated with a SNP at position -376 of the TNF-alpha promoter.These results help to elucidate the B lymphocytes responsible for intrathecal IgM secretion in MS and the origin of this abnormal B-cell response in patients with aggressive MS. © 2010 Elsevier Inc.

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