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Search Results: 1 - 10 of 355481 matches for " Emilio G de la Concha "
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Evidence for the association of the SLC22A4 and SLC22A5 genes with Type 1 Diabetes: a case control study
Jose Santiago, Alfonso Martínez, Hermenegildo de la Calle, Miguel Fernández-Arquero, M ángeles Figueredo, Emilio G de la Concha, Elena Urcelay
BMC Medical Genetics , 2006, DOI: 10.1186/1471-2350-7-54
Abstract: A case-control study was performed in the Spanish population with 295 T1D patients and 508 healthy control subjects. Maximum-likelihood haplotype frequencies were estimated by applying the Expectation-Maximization (EM) algorithm implemented by the Arlequin software.When independently analyzed, one of the tested polymorphisms in the SLC22A4 gene at 1672 showed significant association with T1D in our Spanish cohort. The overall comparison of the inferred haplotypes was significantly different between patients and controls (χ2 = 10.43; p = 0.034) with one of the haplotypes showing a protective effect for T1D (rs3792876/rs1050152/rs2631367/rs274559, CCGA: OR = 0.62 (0.41–0.93); p = 0.02).The haplotype distribution in the carnitine transporter locus seems to be significantly different between T1D patients and controls; however, additional studies in independent populations would allow to confirm the role of these genes in T1D risk.Type 1 diabetes (T1D) is a multifactorial autoimmune T-cell-mediated disease resulting from selective destruction of the insulin producing β cells in the pancreatic islets, leading to an absolute insulin deficiency. The risk of developing T1D is determined by a complex interaction between multiple genetic and environmental factors. Although susceptibility to disease is strongly associated with alleles in the major histocompatibility complex (MHC) [1,2], there are more than 20 putative T1D susceptibility regions identified by linkage and association studies [3,4]. At present, several non-MHC susceptibility loci with modest genetic effects have been clearly defined. However, it is well known that many non-MHC loci predisposing to T1D remain as yet undefined [5].Type 1 diabetes is a chronic degenerative disease, with altered metabolism characterized by hyperglycemia and ketoacidosis and T1D patients depend on exogenous insulin to sustain life. The role of the carnitine system in cell metabolism is mainly known in the mitochondria, where the intera
Susceptibility to type 1 diabetes conferred by the PTPN22 C1858T polymorphism in the Spanish population
Jose Santiago, Alfonso Martínez, Hermenegildo de la Calle, Miguel Fernández-Arquero, M ángeles Figueredo, Emilio G de la Concha, Elena Urcelay
BMC Medical Genetics , 2007, DOI: 10.1186/1471-2350-8-54
Abstract: A case-control was performed with 316 Spanish white T1D patients consecutively recruited and 554 healthy controls, all of them from the Madrid area. The PTPN22 C1858T SNP was genotyped in both patients and controls using a TaqMan Assay in a 7900 HT Fast Real-Time PCR System.We replicated for the first time in a Spanish population the association of the 1858T allele with an increased risk for developing T1D [carriers of allele T vs. CC: OR (95%) = 1.73 (1.17–2.54); p = 0.004]. Furthermore, this allele showed a significant association in female patients with diabetes onset before age 16 years [carriers of allele T vs. CC: OR (95%) = 2.95 (1.45–6.01), female patients vs female controls p = 0.0009]. No other association in specific subgroups stratified for gender, HLA susceptibility or age at onset were observed.Our results provide evidence that the PTPN22 1858T allele is a T1D susceptibility factor also in the Spanish population and it might play a different role in susceptibility to T1D according to gender in early-onset T1D patients.Type 1 diabetes (T1D) is an autoimmune disorder resulting from destruction of the insulin-producing β cells of the pancreas. T1D is a complex trait with both genetic and environmental factors contributing to the etiology of this disease. Several susceptibility loci involved in disease development have been identified and were consistently replicated in independent populations [1]. These efforts contribute to a better definition of the molecular pathways leading to increased T1D risk and this knowledge, in turn, may help in understanding the genetic basis of the disease. The MHC class II, the CTLA4 and the PTPN22 loci have all been proved important in the pathogenesis of autoimmunity globally considered, whereas the insulin gene is a disease-specific T1D predisposition locus. Most of the new general susceptibility loci identified in the past few years have a clear role in the modulation of T cell development and activation, indicating that
Early B-cell Factor gene association with multiple sclerosis in the Spanish population
Alfonso Martínez, Ana Mas, Virginia de las Heras, Rafael Arroyo, Miguel Fernández-Arquero, Emilio G de la Concha, Elena Urcelay
BMC Neurology , 2005, DOI: 10.1186/1471-2377-5-19
Abstract: The role of the EBF1 gene in multiple sclerosis susceptibility was analyzed by performing a case-control study with 356 multiple sclerosis patients and 540 ethnically matched controls comparing the EBF1 polymorphism rs1368297 and the microsatellite D5S2038.Significant association of an EBF1-intronic polymorphism (rs1368297, A vs. T: p = 0.02; OR = 1.26 and AA vs. [TA+TT]: p = 0.02; OR = 1.39) was discovered. This association was even stronger after stratification for the well-established risk factor of multiple sclerosis in the Major Histocompatibility Complex, DRB1*1501 (AA vs. [TA+TT]: p = 0.005; OR = 1.78). A trend for association in the case-control study of another EBF1 marker, the allele 5 of the very informative microsatellite D5S2038, was corroborated by Transmission Disequilibrium Test of 53 trios (p = 0.03).Our data support EBF1 gene association with MS pathogenesis in the Spanish white population. Two genetic markers within the EBF1 gene have been found associated with this neurological disease, indicative either of their causative role or that of some other polymorphism in linkage disequilibrium with them.Multiple sclerosis (MS) is one of the most common neurological diseases of young adults in Europe and North America [1]. Similarly to other common complex diseases, the interplay of genome and environment as MS susceptibility factors seems to determine the final outcome. Its precise etiology is at present unknown, even though the first genetic association with the MHC was published more than thirty years ago [2]. Genomic screens support the hypothesis that susceptibility to develop MS is determined by multiple genes with small individual contributions. To decipher those combinations of genes resulting in MS is a major goal of research. Association of MS with the HLA-DRB1*1501-DQB1*0602 haplotype has been unambiguously demonstrated [3]. The diversity of the predisposition genes is evident if we consider that the major risk allele HLA-DRB1*1501 is present
Interleukin-10 polymorphisms in Spanish IgA deficiency patients: a case-control and family study
Javier Ortiz, Miguel Fernández-Arquero, Elena Urcelay, Raquel López-Mejías, Antonio Ferreira, Gumersindo Fontán, Emilio G de la Concha, Alfonso Martínez
BMC Medical Genetics , 2006, DOI: 10.1186/1471-2350-7-56
Abstract: We genotyped 278 patients with IgAD and 573 ethnically matched controls for the microsatellites IL-10R and IL-10G and for three single nucleotide polymorphisms at positions -1082, -819 and -592 in the proximal promoter of the gene. We also included in this study the parents of 194 patients in order to study the IL-10 haplotypes transmitted and not transmitted to the affected offspring.The only allele where a significant difference was observed in the comparison between IgA deficiency patients and controls was the IL-10G12 allele (OR = 1.58 and p = 0.021). However, this p value could not withstand a Bonferroni correction. None of the IL-10R or promoter SNP alleles was found at a different frequency when patients were compared with controls.Our data do not show any significant difference in IL-10 polymorphism frequencies between control and IgAD patient samples. Their haplotype distribution among patients and controls was also equivalent and therefore these microsatellites and SNPs do not seem to influence IgAD susceptibility.IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians and is sometimes associated with deficiency of IgG2, IgG3, IgG4 and IgE [1]. Genetic studies indicate that IgAD may have an inherited component and the disease is associated with certain susceptibility genes located in the major histocompatibility complex region [2,3]. Celiac disease and selective IgA deficiency are frequently associated, and share a similar genetic background [4,5]. Environmental factors also play a role in the occurrence of IgAD. The most usual consequence of this disease is an increased susceptibility to infection [6].Although the basic immunologic defect that underlies IgAD is unknown, a number of in vitro immunological alterations have been identified: arrest in the B cell differentiation pathway [7], and a decrease in T helper lymphocyte function [8,9].IL-10 is a regulatory cytokine that has several functions; it is a potent stimulator of NK cel
Interleukin-10 haplotypes in Celiac Disease in the Spanish population
Concepción Nú?ez, Diana Alecsandru, Jezabel Varadé, Isabel Polanco, Carlos Maluenda, Miguel Fernández-Arquero, Emilio G de la Concha, Elena Urcelay, Alfonso Martínez
BMC Medical Genetics , 2006, DOI: 10.1186/1471-2350-7-32
Abstract: A case-control and a familial study were performed. Positions -1082, -819 and -592 of the IL-10 promoter were typed by TaqMan and allele specific PCR. IL10R and IL10G microsatellites were amplified with labelled primers, and they were subsequently run on an automatic sequencer. In this study 446 patients and 573 controls were included, all of them white Spaniards. Extended haplotypes encompassing microsatellites and SNPs were obtained in families and estimated in controls by the Expectation-Maximization algorithm.No significant associations after Bonferroni correction were observed in the SNPs or any of the microsatellites. Stratification by HLA-DQ2 (DQA1*0501-DQB1*02) status did not alter the results. When extended haplotypes were analyzed, no differences were apparent either.The IL-10 polymorphisms studied are not associated with celiac disease. Our data suggest that the IL-10 alteration seen in patients may be more consequence than cause of the disease.Celiac disease (CD) is a chronic inflammatory disorder characterized by a pathological response after exposure to gluten in genetically susceptible individuals [1]. HLA class II genes, mainly the alleles DQA1*0501 and DQB1*02 (HLA-DQ2) but also DQA1*0301 and DQB1*0302 (HLA-DQ8), have been found to play an important role in the development of celiac disease. However, HLA genes do not explain the totality of CD cases detected and other genes must be involved in CD onset. In fact, the sibling familial risk attributed to HLA is approximately half of the sibling risk for CD [2].The histological lesions typical of CD seem to be associated with a predominant T helper type 1 (Th1) cell response. Thus, cytokines characteristic of a Th1 inflammatory response as interferon gamma, are produced by lamina propria T cells isolated from the intestine of CD patients after gluten stimulation [3]. The complex homeostatic regulation of immune processes involves numerous interacting cells and molecules. The prototypic regulatory cytoki
Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammatory diseases
Alfonso Martínez, Jose Santiago, Jezabel Varadé, Ana Márquez, José Lamas, Juan Mendoza, Hermenegildo de la Calle, Manuel Díaz-Rubio, Emilio G de la Concha, Benjamín Fernández-Gutiérrez, Elena Urcelay
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-329
Abstract: Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171) were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study.Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.The human gene SEPS1, located on chromosome 15q26.3, encodes selenoprotein S which participates in the retro-translocation of misfolded proteins from the endoplasmic reticulum (ER) to the cytosol for their degradation [1]. This ER membrane protein functions in stress responses to prevent the deleterious consequences of accumulation of misfolded proteins, accumulation that has been linked to immune and inflammatory processes [2]. A study identified the strong association of the proximal promoter SEPS1 polymorphism at -105G/A with circulating levels of three pro-inflammatory cytokines, interleukin (IL)-6, IL-1β and TNF-α [3]. Moreover, these authors reported that the mutant variant significantly reduced the promoter activity of the SEPS1 gene in stressed HepG2 cells and that the suppression of this gene by short interfering RNA increased the release of pro-inflammatory cytokines in a macrophage cell line. A regulatory loop has been recently proposed whereby cytokines stimulate the expression of SEPS1, which in turn diminishes cytokine production [4].The murine homolog gene of the human SEPS1 is the Tanis gene, which encodes a serum amyloid A receptor [5]. Acute phase serum amyloid A proteins (SAAs) are multifunctional apolipoproteins produced in large amounts during the acute phase of inflammation and also during the development of chronic inflammatory diseases. SAAs are involved in the pathogenesis of several chronic inflammatory diseases, such as rheumatoid arthritis (RA) [6-9], multiple sclerosis (MS)[10
Type 1 Diabetes in the Spanish Population: additional factors to Class II HLA-DR3 and -DR4
Elena Urcelay, José L Santiago, Hermenegildo de la Calle, Alfonso Martínez, Julián Méndez, José M Ibarra, Carlos Maluenda, Miguel Fernández-Arquero, Emilio G de la Concha
BMC Genomics , 2005, DOI: 10.1186/1471-2164-6-56
Abstract: Genetic MHC markers were analysed in a case-control study with 302 T1D patients and 529 ethnically matched controls. DR3-TNFa1b5 carrier rate was significantly higher in DR3-positive heterozygous T1D patients than in DR3-positive heterozygous controls (p = 0.0019; odds ratio OR [95% confidence interval CI] = 2.26 [1.3–3.93]). This data was confirmed analysing the allelic frequency, which includes the information corresponding to the DR3-homozygous individuals (p = 0.001; OR = 2.09) and by using the Arlequin software to check the DR3-positive haplotypes (p = 0.004;OR = 1.93). The present results provide strong evidence of a second susceptibility region in the ancestral haplotype 18.2 in the Spanish population.Moreover, we searched for T1D susceptibility factors in addition to the MHC classical ones, within the DR2-DQ6/DR3-DQ2/DR4-DQ8 negative population. Several genetic markers in both MHC class II (DQA1*0101-DQB1*0501 [p = 0.007;OR = 2.81], DQA1*0201-DQB1*0202 [p = 0.03; OR = 2.35]) and III (TNFa2b1 [p = 0.01 OR = 2.74], BAT-2*2 [p = 0.004; OR = 3.19]) were found. These different alleles associated with T1D were not independent and we observed linkage disequilibrium among them leading us to describe two new risk haplotypes (DQA1*0101-DQB1*0501-TNFa2b1 and DQA1*0201-DQB1*0202- BAT-2*2). Finally, we studied a T1D susceptibility/protection marker located in extended class I, D6S2223; however, no association was observed in our population.Our results suggest that other associated MHC haplotypes might present susceptibility factors in loci different from HLA-class II and that the class II molecules are not necessarily the universal etiologic factor in every MHC haplotype.Type 1 diabetes is a multifactorial autoimmune disease characterised by insulin deficiency, due to the T cell mediated destruction of pancreatic β-cells [1]. Among the genetic determinants of susceptibility, with more than 18 putative loci identified to date, a region in chromosome 6p21 (IDDM1) containin
CD209 in inflammatory bowel disease: a case-control study in the Spanish population
Concepción Nú?ez, Javier Oliver, Juan Mendoza, María Gómez-García, Carlos Taxonera, Luis M Gómez, Miguel A López-Nevot, Emilio G de la Concha, Elena Urcelay, Alfonso Martínez, Javier Martín
BMC Medical Genetics , 2007, DOI: 10.1186/1471-2350-8-75
Abstract: We performed a case-control study with 515 CD patients, 497 UC patients and 731 healthy controls, all of them white Spaniards. Samples were typed for the CD209 single nucleotide polymorphism (SNP) rs4804803 by TaqMan technology. Frequency comparisons were performed using χ2 tests.No association between CD209 and UC or CD was observed initially. However, stratification of UC patients by HLA-DR3 status, a strong protective allele, showed that carriage of the CD209_G allele could increase susceptibility in the subgroup of HLA-DR3-positive individuals (p = 0.03 OR = 1.77 95% CI 1.04–3.02, vs. controls).A functional variant in the CD209 gene, rs4804803, does not seem to be influencing Crohn's disease susceptibility. However, it could be involved in the etiology or pathology of Ulcerative Colitis in HLA-DR3-positive individuals but further studies are necessary.Inflammatory bowel diseases comprise two distinct entities, Crohn's disease (CD) and Ulcerative Colitis (UC). Both forms are characterized by a chronic inflammation of the intestine, but several clinical and immunological profiles differ between them. IBD is a multifactorial disease: environmental factors seem to be involved in disease onset in genetically susceptible individuals. Common susceptibility genetic components exist for both diseases as evidenced apparently by the higher risk of developing UC in relatives of patients with CD or vice versa, but also specific genes seem to play an important role in the development or course of each disease. For CD, CARD15 mutations are the main susceptibility factors described in Caucasian populations [1]. On the other hand, HLA genes show stronger effects on UC in our population, specifically HLA-DR3 seems to have a protective role in the development of this disease [2]. However, a complex genetic contribution exists in both diseases and new etiological genes remain to be discovered.DC-SIGN (dendritic cell-specific ICAM3-grabbing non-integrin), also named CD209, is a type
DRB1*03:01 Haplotypes: Differential Contribution to Multiple Sclerosis Risk and Specific Association with the Presence of Intrathecal IgM Bands
Emilio G. de la Concha, María L. Cavanillas, M. Carmen Cénit, Elena Urcelay, Rafael Arroyo, óscar Fernández, José C. álvarez-Cerme?o, Laura Leyva, Luisa M. Villar, Concepción Nú?ez
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031018
Abstract: Background Multiple sclerosis (MS) is a multifactorial disease with a genetic basis. The strongest associations with the disease lie in the Human Leukocyte Antigen (HLA) region. However, except for the DRB1*15:01 allele, the main risk factor associated to MS so far, no consistent effect has been described for any other variant. One example is HLA-DRB1*03:01, with a heterogeneous effect across populations and studies. We postulate that those discrepancies could be due to differences in the diverse haplotypes bearing that allele. Thus, we aimed at studying the association of DRB1*03:01 with MS susceptibility considering this allele globally and stratified by haplotypes. We also evaluated the association with the presence of oligoclonal IgM bands against myelin lipids (OCMB) in cerebrospinal fluid. Methods Genotyping of HLA-B, -DRB1 and -DQA1 was performed in 1068 MS patients and 624 ethnically matched healthy controls. One hundred and thirty-nine MS patients were classified according to the presence (M+, 58 patients)/absence (M?, 81 patients) of OCMB. Comparisons between groups (MS patients vs. controls and M+ vs. M?) were performed with the chi-square test or the Fisher exact test. Results Association of DRB1*03:01 with MS susceptibility was observed but with different haplotypic contribution, being the ancestral haplotype (AH) 18.2 the one causing the highest risk. Comparisons between M+, M? and controls showed that the AH 18.2 was affecting only M+ individuals, conferring a risk similar to that caused by DRB1*15:01. Conclusions The diverse DRB1*03:01-containing haplotypes contribute with different risk to MS susceptibility. The AH 18.2 causes the highest risk and affects only to individuals showing OCMB.
A functional PTPN22 polymorphism associated with several autoimmune diseases is not associated with IgA deficiency in the Spanish population
Concepción Nú?ez, Raquel López-Mejías, Alfonso Martínez, M Cruz García-Rodríguez, Miguel Fernández-Arquero, Emilio G de la Concha, Elena Urcelay
BMC Medical Genetics , 2006, DOI: 10.1186/1471-2350-7-25
Abstract: A total of 259 IgAD patients and 455 unrelated matched controls, and 128 families were used for each approach. Comparisons were performed using Chi-Square tests or Fisher's exact test when necessary.No association between the PTPN22 1858C/T SNP and IgA deficiency was found in any case (allelic frequencies 8% vs. 6% in patients and controls, respectively, OR= 1.14 (0.72–1.79), p= 0.56; TDT p = 0.08).The result obtained seems to reinforce the consideration of IgA deficiency as a primary immunodeficiency rather than an autoimmune disease.Selective IgA deficiency (IgAD) is the most prevalent primary immunodeficiency in white populations, with values around one out of 600 [1]. This disease is characterized by a severe deficiency or total absence of IgA class immunoglobulins in the serum and secretions. Their clinical symptoms are very variable, and thus some IgAD patients are relatively healthy while others show significant illness, mainly a higher susceptibility to infections, autoimmune diseases and allergies. IgAD shows a multifactorial origin, with genetic and environmental factors involved. Class II and class III HLA genes have been implicated in the origin of this disease (see [2] and references therein). However, these HLA genetic components can not explain the totality of the genetic influence in this disease.The molecular bases underlying the origin of IgAD are not completely understood. Although it has been recently shown that a mutation in TACI is involved in the origin of the disease in some patients [3], other genetic and environmental factors remain to be discovered. Despite IgAD has been traditionally considered as an immunodeficiency, some authors [4] have pointed out that it could be an autoimmune disease.Recently, a single-nucleotide polymorphism (SNP) of the PTPN22 (protein tyrosine phosphatase, non-receptor type 22) gene, 1858C/T, has been found associated with many autoimmune diseases [5,6]. This gene, located on chromosome 1p13, encodes a lymphoid p
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