Papers by Concepción Nuñez
Annals of Human Genetics, 2018
Autoimmune diseases like celiac disease (CeD) and ulcerative colitis (UC) show a common genetic b... more Autoimmune diseases like celiac disease (CeD) and ulcerative colitis (UC) show a common genetic background defined by the existence of shared susceptibility loci. We aimed to go deeper into this common genetic background through performing a cross‐disease study based on gene expression. We measured the expression of 21 genes located in 13 CeD‐UC susceptibility regions, and 10 genes in five CeD risk regions. Determinations were carried out in colon/rectum samples from 13 UC patients (inflamed and uninflamed tissue) and four colon samples from controls. Duodenal samples from 19 CeD patients and 12 controls were used for comparisons. Differences were analyzed using the Bayesian method. The shared chromosomal regions containing TNFAIP3, PTPN2, ICOSLG, C1orf106, and IL21 showed similar results in both diseases. FASLG, PLEK, CCR4, and TAGAP, all located in CeD risk loci, were up‐regulated in both CeD and UC patients. Finally, ZFP36L1, ZMIZ1, PUS10, UBE2L3, and BACH2 showed opposite result...
Tissue Antigens, 2007
Inflammatory bowel disease (IBD), which comprises ulcerative colitis (UC) and Crohn&#... more Inflammatory bowel disease (IBD), which comprises ulcerative colitis (UC) and Crohn's disease (CD), shows a multifactorial origin, with genetic and environmental factors involved. Although the genetic influence is clear for both diseases, the genetics involved is complex and epistatic interactions with other genes probably exist. The Fc receptor-like 3 gene (FCRL3) maps to the human chromosome 1q21-22 and certain single nucleotide polymorphisms (SNPs) in its promoter have been associated with some autoimmune diseases. Our aim was to study the role of two promoter SNPs of the FCRL3 gene (-169A>G, rs7528684 and -110C>T, rs11264799) in patients with IBD and their interaction with HLA-DRB1 and CARD15 in patients with UC and CD, respectively. A case-control study with 311 patients with CD, 324 patients with UC and 497 healthy controls was performed. All the individuals were White Spaniards. No significant associations were found between any FCRL3 SNP and CD or UC, but the stratification in patients with UC by human leukocyte antigen (HLA) showed a significant increase in heterozygosity at the FCRL3 locus, especially -169 AG (AG vs AA+GG, P= 0.0027, odds ratio = 3.6, 95% confidence interval 1.4-2.9), when HLA-DRB1*0103 carrier patients were compared with HLA-DRB1*0103 noncarriers. Our data suggest an epistatic interaction between genes in chromosomes 6p21 and 1q21-22, marked, respectively, by HLA-DRB1*0103 and FCRL3-169 AG.
Tissue Antigens, 2010
Alterations in intestinal epithelial permeability could underlie inflammatory bowel disease (IBD)... more Alterations in intestinal epithelial permeability could underlie inflammatory bowel disease (IBD) and celiac disease (CeD) etiology, as supported by previous association studies. One related gene, DLG5 [discs, large homologue 5 (Drosophila)], has been associated with IBD in several populations and with CeD in the Dutch population. We tried to confirm the involvement of DLG5 in CeD performing a case-control study (725 CeD patients and 803 controls) by analysing the R30Q variant (rs1248696). Genetic frequencies did not significantly differ between groups (P > 0.80) and the meta-analysis with the Dutch data did not show any association. Additionally, we evaluated the effect of R30Q in IBD risk (858 patients), as discordant results were previously obtained. No association was detected. Our study does not support the effect of the R30Q DLG5 variant in CeD or IBD predisposition in the Spanish population.
Tissue Antigens, 2009
Celiac disease (CD) is a multifactorial disease characterized by intestinal inflammation after gl... more Celiac disease (CD) is a multifactorial disease characterized by intestinal inflammation after gluten exposure in genetically susceptible individuals. A strong influence of certain human leukocyte antigen (HLA) alleles (those coding the HLA‐DQ2 and DQ8 heterodimers) is well established, but they cannot explain the overall genetic risk. CIITA could be a good candidate gene for CD because it is mainly transcriptionally regulated, and it encodes the master regulator of major histocompatibilty complex class II gene transcription. CIITA is located in 16p13, a region also containing KIAA0350 (CLEC16A), associated with two autoimmune diseases in genome‐wide association studies. We aimed at studying the involvement of polymorphisms in CIITA and KIAA0350 in CD susceptibility, with special attention to evaluate the possible presence of more than one risk factor in the region. We performed a case–control study with 607 CD patients and up to 794 healthy controls, all Spaniards. All samples were...
Neurogastroenterology & Motility, 2010
Idiopathic achalasia is a primary esophageal motor disorder of unknown etiology. Different eviden... more Idiopathic achalasia is a primary esophageal motor disorder of unknown etiology. Different evidences have been reported in support of achalasia as the result of an autoimmune and inflammatory process leading to neuronal cell loss. According to this, idiopathic achalasia has been significantly associated with specific alleles of the human leukocyte antigen system class II, although few reports studying association with other loci can be found in the literature. Recent studies have shown association of a non-synonymous polymorphism within the IL23R gene with different chronic inflammatory disorders, including Barrett's esophagus. The purpose of this study was to assess whether the IL23R coding variant Arg381Gln polymorphism is involved in susceptibility to idiopathic achalasia. We performed a case-control study including 262 patients with idiopathic achalasia and 802 healthy subjects, all of them white Spaniards. Achalasia patients were diagnosed on the basis of clinical, radiographic, endoscopic, and manometric criteria. All samples were genotyped for the IL23R Arg381Gln polymorphism using TaqMan technology. The minor allele of the Arg381Gln polymorphism was significantly increased in patients compared with healthy controls (OR = 1.46, 95% CI = 1.01-2.11, P = 0.036). This association seems to be specific to male patients with disease onset after 40 years (OR = 2.33, 95% CI = 1.29-4.16, P = 0.002). Our results suggest a role of IL23R in idiopathic achalasia predisposition and extend the evidence of the general influence of this gene in autoimmune and inflammatory diseases.
Journal of Medical Genetics, 2014
Recombinant interferon β (IFNβ) is a first-line therapy for relapsing-remitting multiple sclerosi... more Recombinant interferon β (IFNβ) is a first-line therapy for relapsing-remitting multiple sclerosis (MS), with a proven effect on the inflammatory activity. Neutralising antibodies against IFNβ (NAbs) promote a loss of IFNβ bioactivity in a titre-dependent way and their development was associated with certain human leucocyte antigen (HLA) alleles. We investigated the contribution conferred by HLA alleles on the development of NAbs in independent cohorts of Southern Europe. Serum NAbs from 610 MS patients with HLA-genotype data were evaluated by cytopathic effect assay: negative tests included at least one negative result (NAb titres<20 NU/mL) after 1 year treatment; NAb-titres ≥20 NU/mL were positive tests and NAb titres ≥150 NU/mL in any test were classified as high-titre positives. The combined presence of DRB1*07/DQA1*02 with A*26 or B*14 was found in 20% of patients with NAbs at high titres, but only in 5.4% of NAb-negative patients (p=0.00052, OR (95% CI) 4.34 (1.85 to 10.13)). The DRB1*04:01 allele was also more frequently carried by patients with high titres of NAbs (10% vs 4.5%; p=0.046, OR (95% CI) 2.38 (0.93 to 5.92)). The alleles carried at a significantly lower frequency in patients with high persistent NAbs corresponded to the A*11 allele (3.3% vs 13.8%; p=0.023, OR (95% CI) 0.22 (0.02 to 0.87)), as well as the DRB1*03/DQA1*05/DQB1*02 haplotype (16.3% vs 26.8%; p=0.02, OR (95% CI) 0.53 (0.27 to 1.03)) and the DRB1*13/DQA1*01:03/DQB1*06:03 haplotype (2.5% vs 9.1%; p=0.045, OR (95% CI) 0.25 (0.03 to 1.02)). 50% of the studied MS patients carried some of the five independently associated HLA allele/allele combinations described in this work. This relevant percentage of patients could benefit a therapeutic decision.
Human Immunology, 2010
The etiology of selective IgA deficiency (IgAD) is clearly influenced by human leukocyte antigen ... more The etiology of selective IgA deficiency (IgAD) is clearly influenced by human leukocyte antigen (HLA) genetic composition, although the susceptibility observed has not been ascribed to any specific gene/s. A possible role of the MSH5 gene, mapping on this chromosomal region, has been proposed based on its function and on the association of some MSH5 polymorphisms (L85F/P786S and rs3131378) with the disease. However, the extensive linkage disequilibrium in the HLA region makes mandatory additional analyses. We aimed at evaluating the role of those MSH5 polymorphisms on IgAD susceptibility considering their linkage with other classically associated HLA markers, specifically DRB1*0102 and B*08-DRB1*03. We studied 146 trios composed by IgAD patient and parents to unambiguously establish the gametic phase. Association of those MSH5 variants with IgAD is observed but stratified analyses considering other HLA alleles rule out the role of MSH5 per se as a predisposing factor. However, the minor allele of one of the studied polymorphisms, 85F, defines the subgroup of DRB1*0102 haplotypes carrying susceptibility. The causal factor present on this haplotype (MSH5 85F-DRB1*0102) seems to be at the telomeric end of HLA class II or in Class I or III, as the allele composition in more centromeric markers is shared by all the haplotypes containing DRB1*0102.
Human Immunology, 2005
Recent findings have demonstrated that the single nucleotide polymorphism 1858C¡T located at the ... more Recent findings have demonstrated that the single nucleotide polymorphism 1858C¡T located at the P1 motif of the PTPN22 (protein tyrosine phosphatase nonreceptor 22) gene has functional relevance and is associated with a variety of autoimmune diseases. The aim of this study was to assess the role of the PTPN22 1858C¡T polymorphism in the genetic predisposition to celiac disease (CD). We analyzed a case-control cohort composed by 534 patients with CD and 653 healthy controls and additionally a panel of 271 celiac families. The PTPN22 1858C¡T genotyping was performed by TaqMan 5= allelic discrimination assay. We did not observed any statistically significant deviation after comparing allele and genotypic frequencies of PTPN22 1858C¡T between patients with CD and controls. Accordingly, the familial analysis did not reach statistically significant deviation in the transmission of PTPN22 1858C¡T alleles to the affected offspring. Therefore, our data suggest that the PTPN22 1858 single nucleotide polymorphism has no, or only a negligible, effect on CD susceptibility in this Spanish population.
Human Immunology, 2009
The etiology of selective immunoglobulin A deficiency (IgAD) is not yet unraveled, but genetics s... more The etiology of selective immunoglobulin A deficiency (IgAD) is not yet unraveled, but genetics seem to play an important role. Defects in processes during B-cell differentiation into plasma cells could exist in these patients, turning the genes controlling these processes into interesting candidate genes for IgAD predisposition, as PRDM1 (encoding Blimp-1) and XBP1. We studied the involvement of several polymorphisms located in PRDM1 and XBP1 on IgAD susceptibility. We performed a case-control study with 331 Spanish IgAD patients and 717 healthy controls, by analyzing five single nucleotide polymorphisms (SNPs) in these genes. Genetic frequencies of the studied SNPs did not significantly differ between patients and controls, even after stratifying by the known human leukocyte antigen risk factors or clinical phenotypes. Interaction between PRDM1 and XBP1 to confer disease predisposition was not detected either. In conclusion, the polymorphisms studied in the PRDM1 and XBP1 genes do not seem to be involved in IgAD predisposition in the Spanish population.
Human Immunology, 2008
Celiac disease (CD) is a chronic intestinal inflammatory disease that develops in genetically sus... more Celiac disease (CD) is a chronic intestinal inflammatory disease that develops in genetically susceptible individuals after gluten ingestion. The ICAM1 gene, located in the CD linkage region 19p13, encodes an intercellular adhesion molecule (ICAM-1) involved in inflammatory processes. Increased levels of ICAM-1 were observed in intestinal biopsies and in sera of CD patients. In addition, an association between the ICAM1 polymorphism G241R and CD patients has been recently described in a French population. Our aim in this study was to analyze the role of ICAM1 polymorphisms in CD susceptibility in the Spanish population. We performed a case-control study with 608 CD patients and 537 healthy control individuals and a family study including 231 trios. Four ICAM1 single nucleotide polymorphisms (SNPs) were analyzed: three nonsynonymous, R478W (rs5030400), P352L (rs1801714) and G241R (rs1799969); and one intronic, rs281432. Despite having above 98% statistical power to detect the association described in the French population (odds ratio ϭ 1.7), we did not find any differences in genotypic or allelic frequencies of the G241R polymorphism between our CD patients and controls, and no differences were observed when the other SNPs were analyzed. Therefore, in our population our results discard the important previously described role of ICAM1 G241R in celiac disease.
Human Immunology, 2008
Selective immunoglobulin-A deficiency (IgAD) is the most common immunodeficiency in Caucasian pop... more Selective immunoglobulin-A deficiency (IgAD) is the most common immunodeficiency in Caucasian populations. Genetic factors are important in its etiology; however human leukocyte antigen (HLA) genes, which explain 40% of the genetic risk for IgAD, are the only susceptibility factors commonly agreed upon at this time. Because interleukin-6 (IL-6) plays an important role in B-lymphocyte differentiation from plasma cells, we aimed to address the IL-6 genetic influence on IgAD susceptibility. We performed a case-control study that included 305 Caucasian Spanish IgAD patients and 529 ethnically matched healthy control subjects, as well as a familial study with 128 IgAD trios. We genotyped the functional promoter polymorphism Ϫ174GϾC and nine additional single nucleotide polymorphisms. For the case-control analyses the 2 test or Fisher's exact test were used, and for the family study the transmission disequilibrium test was used. We observed an increased frequency of the Ϫ174C allele in IgAD patients (p ϭ 0.005, odds ratio [OR] ϭ 1.51, 95% confidence interval [CI] ϭ 1.12-2.04) and a protective effect of the rs2069849_C allele (p ϭ 0.007, odds ratio ϭ 0.29, 95% CI ϭ 0.09-0.76). In conclusion, we described for the first time an association between IL6 polymorphisms and IgAD. Although it is not clear which genetic variants are causing susceptibility/protection, this intriguing finding is remarkable because of the role of IL-6 in antibody production.
Human Immunology, 2009
Evidence about the presence of susceptibility factors shared among different autoimmune diseases ... more Evidence about the presence of susceptibility factors shared among different autoimmune diseases is increasing. Based on this idea, NKX2-3, ATG16L1, and IRGM which are well-established inflammatory bowel disease risk factors, could be new celiac disease (CD) candidate genes. NKX2-3 encodes a transcription factor that in mice seems to be involved in gut development. The ATG16L1 and IRGM genes act in autophagy, a process related to innate and adaptive immunity. We aimed to study the implication of five polymorphisms in these genes in CD susceptibility: rs10883365 and rs888208 in the NKX2-3 gene, rs2241880 in ATG16L1, and rs10065172 and rs4958847 in IRGM. Association studies were performed using 725 Spanish CD patients and 956 ethnically matched healthy controls, as well as 309 parent-child trios. Genetic frequencies were compared with the 2 test and the familial study used the transmission disequilibrium test. Differences between CD patients and controls did not reach significance when genotypic and allelic frequencies were compared. No differential transmission of alleles or haplotypes from heterozygous parents to affected children was observed in the familial study. In conclusion, no evidence of association with CD has been reported for the Crohn's disease susceptibility polymorphisms studied in the NKX2-3, ATG16L1, and IRGM genes.
Human Immunology, 2006
Ulcerative colitis is often accompanied by the development of extraintestinal, mainly articular, ... more Ulcerative colitis is often accompanied by the development of extraintestinal, mainly articular, manifestations. Genetic differences could be underlying that clinical heterogeneity. We performed a case-control study to determine whether TNFab microsatellites or HLA-DR alleles were associated with the development of articular manifestations in patients with ulcerative colitis. With that aim, a total of 84 ulcerative colitis patients with articular manifestations and 172 without them were genotyped for TNFab microsatellites and HLA-DR. A healthy control sample (n ϭ 595) was also included for comparative purposes. Haplotypes were inferred with the Arlequin software. The influence of HLA-DRB1*0103 and HLA-B27, factors previously known to be associated with extraintestinal manifestations, was specifically addressed. We observed that TNFa6b5 minihaplotype increases the susceptibility to developing articular manifestations in ulcerative colitis patients (p ϭ 0.003, OR ϭ 2.39). The locus HLA-DR does not appear to be involved in these extraintestinal manifestations by itself; however, the frequency of subjects carrying TNFa6b5 in combination with DR1, DR7, or DR11 is very significantly increased in patients with articular manifestations (p ϭ 3.9ϫ10 Ϫ8). The associations found were independent of DRB1*0103 and HLA-B27. Thus, it seems that the development of articular manifestations in ulcerative colitis patients appears to be influenced by some genetic factor(s) present in some major histocompatibility complex haplotypes.
Clinical Immunology, 2006
Clinical Immunology, 2006
Objective: To evaluate the efficacy and safety of injections is Polymerized-Type I Collagen (coll... more Objective: To evaluate the efficacy and safety of injections is Polymerized-Type I Collagen (collagen polyvinylpyrrolidone or collagen-PVP) in patients with severe knee osteoartritis (OA). Methods: Patients (n = 53) were treated with 12 intraarticular injections of 2 ml of collagen-PVP (16.6 mg of collagen) (n = 27) or 2 ml of placebo (n = 26) during 6 months. The primary endpoints included Western Ontario and MacMaster University Osteoarthritis Index (WOMAC), Lequesne index, pain intensity on a visual analogue scale (VAS). Secondary outcomes were patient global score, investigator global score and drug evaluation. Clinical improvement was determined if the decrease in pain exceeds 19.9 mm on VAS and patients achieved at least 20% of improvement of the scores from baseline. Statistical analysis was performed by the non-parametric double tailed Mann-Whitney U test and paired Student t test. Data were expressed as the mean + ES. The p values smaller than or equal to 0.05 were considered as significant. Results: Collagen-PVP was safe and well tolerated. Patients had a statistically significant improvement (p b 0.05) in baseline vs. collagen-PVP-treated and vs. placebo at 6 months of treatment in: Lequesne Index (13.1 + 0.5vs.7.1 + 0.7vs.9.6 + 0.8; p = 0.027), WOMAC (51.9 + 3.4vs.22.9 + 2.9vs.33.0 + 3.4; p = 0.032), patient VAS (60.0 + 2.6vs.20.6 + 2.4vs.36.2 + 4.2; p = 0.003), physician VAS (49.4 + 1.9vs.16.8 + 2.9vs.29.8 + 2.9; p = 0.002), patient global score (2.7 + 0.3vs.7.0 + 0.4vs.5.5 + 0.4; p = 0.028) and physician drug evaluation (2.7 + 0.3vs.7.4 + 0.4vs.5.1 + 0.4; p = 0.001). No differences between groups were observed with respect to incidence of adverse events. Conclusion: Our findings indicate that Collagen-PVP is safe and effective in the treatment of OA of the knee.
Clinical Immunology, 2006
BACKGROUND: APCs in the human gut are highly heterogeneous and involved in active immunity and in... more BACKGROUND: APCs in the human gut are highly heterogeneous and involved in active immunity and induction of oral tolerance. The phenotype of APCs in human colon and their involvement in immunological responses are poorly characterized. We recently reported that normal human colonic myofibroblasts (CMFs), which are located in the lamina propria just beneath the epithelial layer, are novel non professional APCs that are capable of inducing allogeneic and antigen-specific CD4+ T-cell proliferation in a MHC class IIdependent manner. CMFs express low levels of CD80 and CD86 co-stimulatory molecules in situ, but have high expression of negative co-stimulators PD-L1 and PD-L2 and can suppress proliferation of CD3-activated CD4+ T-cells. We hypothesize that CMFs are novel, local negative regulators of T-cell responses in the colon that may limit immune responses to luminal antigens and thus participate in the maintenance of mucosal tolerance. METHODS: In present work, we have evaluated role of PD-L1 in CMF-mediated suppression of CD3activated CD4+ T-cells by using RT-PCR, ELISA, flow cytometry and lymphoproliferation assays. RESULTS: We demonstrated that~15% of freshly isolated lamina propria mononuclear cells from normal mucosa constitutively express PD-L1. CMFs represented~80% of this PD-L1-expressing population. In vitro functional analyses demonstrated that CMFs suppress proliferation of CD3-activated CD45RA+CD7+T-cells via cellcontact-dependent mechanisms. Blockade of PD-L1 on CMFs partially, but significantly reversed the inhibition of the T-cell proliferation induced by CMFs. CONCLUSIONS: Our data indicate that CMFs act as suppressors of activated CD4+ T effector cell responses in the colonic mucosa of healthy individuals. Moreover, expression of PD-L1 by CMFs contributes to the CMF-mediated suppressive capacity. Supported by NIDDK, GRIP, Gulf Coast DDC, McLaughlin Endowment.
Revista Española de Enfermedades Digestivas, 2005
Objective: the aim of this study is to assess the importance of NOD2/CARD15 gene mutations as pro... more Objective: the aim of this study is to assess the importance of NOD2/CARD15 gene mutations as prognostic factors for surgical indications in Crohn's disease. Patients and experimental design: a total of 165 Crohn's disease patients were studied, considering previous surgery related to Crohn´s disease. We analyzed for previous surgery in global procedures as well as separately for the two main surgical indications: ileal resection and fistula treatment. The need for appendectomy was also studied. All patients were genotyped for the three CARD15 mutations, and association studies were developed using Chi-square statistics and Fisher's exact test whenever appropriate. Results: carriers of the G908R or 1007fs mutation needed surgery more frequently, both for ileal resection and fistula repair. In contrast, appendectomy was not associated with CARD15 mutations. Conclusions: as previously reported in this population, the R702W mutation does influence parameters of disease or need of surgery. The need for Crohn's disease-related surgery is higher in carriers of the G908R or 1007fs CARD15 mutation in the Galician population. Nevertheless, the frequency of these mutations does not allow their use to predict the course of disease.
Frontiers in Immunology
Accurate celiac disease (CD) diagnosis is still challenging for some specific patients or circums... more Accurate celiac disease (CD) diagnosis is still challenging for some specific patients or circumstances. Thus, much effort has been expended last decades focused on seronegative or low grade enteropathy CD and, especially, on enable early diagnosis of individuals on a gluten-free diet (GFD). We discuss here two diagnostic approaches based on immunophenotyping by flow cytometry that we expect to reduce the persistent low diagnostic rates and the common diagnostic delay. The intraepithelial lymphogram is based on determining the percentage of TCRγδ+ and surface CD3- lymphocytes in the intestinal epithelium. The concomitant increase in TCRγδ+ and decrease in surface CD3- intraepithelial lymphocytes has been termed the celiac lymphogram and has been proved to be discriminative in seronegative, low grade enteropathy and potential CD, as well as in most CD patients on a GFD. A blood lymphogram based on the analysis of activated gut-homing CD8+ T cells combined with a 3-day gluten challeng...
Nutrients
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Annals of hepatology, 2016
Autoimmune polyglandular syndrome (APS) is a combination of different autoimmune diseases. The cl... more Autoimmune polyglandular syndrome (APS) is a combination of different autoimmune diseases. The close relationship between immune-mediated disorders makes it mandatory to perform serological screening periodically in order to avoid delayed diagnosis of additional autoimmune diseases. We studied a patient with type 1 diabetes (T1D) who later developed an autoimmune thyroid disease (ATD) and was referred to our hospital with a serious condition of his clinical status. The patient was suffering from an advance stage of celiac disease (CD), the delay in its diagnosis and in the establishment of a gluten-free dietled the patient to a severe proteincalorie malnutrition. Later, the patient developed an autoimmune hepatitis (AIH). We consider that clinical deterioration in patients with APS should alert physicians about the possible presence of other immune-mediated diseases. Periodic screening for autoantibodies would help to prevent delayed diagnosis and would improve patient's quality...
Uploads
Papers by Concepción Nuñez