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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.

Diaz-Gallo L.-M.,Institute Parasitologia y Biomedicina Lopez Neyra | Espino-Paisan L.,Hospital Clinico S. Carlos | Fransen K.,University of Groningen | Gomez-Garcia M.,Hospital Virgen de Las Nieves | And 22 more authors.
Inflammatory Bowel Diseases | Year: 2011

Background: The PTPN22 gene is an important risk factor for human autoimmunity. The aim of this study was to evaluate for the first time the role of the R263Q PTPN22 polymorphism in ulcerative colitis (UC) and Crohn's disease (CD), and to reevaluate the association of the R620W PTPN22 polymorphism with both diseases. Methods: A total of 1677 UC patients, 1903 CD patients, and 3111 healthy controls from an initial case-control set of Spanish Caucasian ancestry and two independent sample sets of European ancestry (Dutch and New Zealand) were included in the study. Genotyping was performed using TaqMan SNP assays for the R263Q (rs33996649) and R620W (rs2476601) PTPN22 polymorphisms. Meta-analysis was performed on 6977 CD patients, 5695 UC patients, and 9254 controls to test the overall effect of the minor allele of R620W and R263Q polymorphisms. Results: The PTPN22 263Q loss-of-function variant showed initial evidence of association with UC in the Spanish cohort (P = 0.026, odds ratio [OR] = 0.61, 95% confidence interval [CI]: 0.39-0.95), which was confirmed in the meta-analysis (P = 0.013 pooled, OR = 0.69, 95% CI: 0.51-0.93). In contrast, the 263Q allele showed no association with CD (P = 0.22 pooled, OR = 1.16, 95% CI: 0.91-1.47). We found in the pooled analysis that the PTPN22 620W gain-of-function variant was associated with reduced risk of CD (P = 7.4E-06 pooled OR = 0.81, 95% CI: 0.75-0.89) but not of UC (P = 0.88 pooled, OR = 0.98, 95% CI: 0.85-1.15). Conclusions: Our data suggest that two autoimmunity- associated polymorphisms of the PTPN22 gene are differentially associated with CD and UC. The R263Q polymorphism only associated with UC, whereas the R620W was significantly associated with only CD. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

Alcina A.,Institute Parasitologia y Biomedicina Lopez Neyra | Vandenbroeck K.,University of the Basque Country | Vandenbroeck K.,Ikerbasque | Otaegui D.,Institute Investigacion Sanitaria BIODONOSTIA | And 19 more authors.
Genes and Immunity | Year: 2010

Genome-wide association studies (GWAS) have revealed that different diseases share susceptibility variants. Twelve single-nucleotide polymorphisms (SNPs) previously associated with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls. Three SNPs were found to be associated with MS: rs1678542 in KIF5A (P0.001, odds ratio (OR)1.13, 95% confidence interval (CI)1.05-1.23); rs3184504 in SH2B3 (P0.00001, OR1.19, 95% CI1.10-1.27) and rs763361 in CD226 (P0.00007, OR1.16, 95%CI1.08-1.25). These variants have previously been associated with rheumatoid arthritis and type 1 diabetes. The SH2B3 polymorphism has additionally been associated with systemic lupus erythematosus. Our results, in addition to validating some of these loci as risk factors for MS, are consistent with shared genetic mechanisms underlying different immune-mediated diseases. These data may help to shape the contribution of each pathway to different disorders. © 2010 Macmillan Publishers Limited All rights reserved.

Swaminathan B.,University of the Basque Country | Matesanz F.,Institute Parasitologia y Biomedicina Lopez Neyra | Cavanillas M.L.,Hospital Clinico S. Carlos | Alloza I.,University of the Basque Country | And 10 more authors.
Journal of Neuroimmunology | Year: 2010

A recent meta-analysis of genome-wide association screens coupled to a replication exercise in a combined US/UK collection led to the identification of 4 single nucleotide polymorphisms (SNPs) in three gene loci, i.e. TNFRSF1A, CD6 and IRF8, as novel risk factors for multiple sclerosis with genome-wide level of significance. In the present study, using a combined all-Spain collection of 2515 MS patients and 2942 healthy controls, we demonstrate significant association of rs17824933 in CD6 (P CMH=0.004; OR=1.14; 95% CI 1.04-1.24) and of rs1860545 in TNFRSF1A (P CMH=0.001; OR=1.15; 95% CI 1.06-1.25) with MS, while the low-frequency coding non-synonymous SNP rs4149584 in TNFRSF1A displayed a trend for association (P CMH=0.062; OR=1.27; 95% CI 0.99-1.63). This data reinforce a generic role for CD6 and TNFRSF1A in susceptibility to MS, extending to populations of southern European ancestry. © 2010 Elsevier B.V.

Diaz-Gallo L.-M.,Institute Parasitologia y Biomedicina Lopez Neyra | Medrano L.M.,Hospital Clinico S. Carlos | Gomez-Garcia M.,Hospital Virgen de 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.

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