RESUMEN
A functional polymorphism (rs6554199) located in the c-kit gene was associated with achalasia in a Turkish cohort. Our aim was to replicate this result in a large cohort of Spanish patients and controls. A case-control study was performed with 282 Spanish white unrelated patients and 687 healthy controls. All were genotyped for SNP rs6554199 using a TaqMan Assay. No association was found in our study (T allele frequency in patients and controls: 47.3% vs. 49.4%; OR=0.92, p=0.41). The finding that the T allele of the c-kit rs6554199 polymorphism could be associated with achalasia as reported in a Turkish population could not be replicated in a Spanish cohort. Although ethnic differences might explain these data, the sample size that compromised the statistical power in the Turkish cohort and is higher in our study, led us to suggest that the reported association seems to be a false positive.
Asunto(s)
Acalasia del Esófago/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-kit/genética , Población Blanca/genética , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , EspañaRESUMEN
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.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Haplotipos/genética , Inmunoglobulina M/líquido cefalorraquídeo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/genética , Estudios de Casos y Controles , Humanos , Esclerosis Múltiple/inmunología , Factores de RiesgoRESUMEN
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.
Asunto(s)
Enfermedad Celíaca/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Mapeo Cromosómico , Frecuencia de los Genes , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Factores de RiesgoRESUMEN
Type 1 diabetes (T1D) is a multifactorial disease mainly associated with the human leukocyte antigen region. Previous studies suggested the association of interleukin-2 (IL2) gene polymorphisms and its alpha- and beta-chain receptor (IL2RA and IL2RB) variants with different autoimmune diseases such as T1D, celiac disease, multiple sclerosis, and rheumatoid arthritis. All T1D studies were conducted in diabetic patients younger than 17 years at diagnosis. The aim of our study was to replicate these associations not only in pediatric patients, but also in individuals with late onset. We performed a genetic association study of chromosomal regions 4q27, 10p15, and 22q13 containing the IL2, IL2RA, and IL2RB genes in 445 T1D subjects and 828 healthy controls. Seven single nucleotide polymorphisms (SNPs) were selected, previously described as genetic factors related to several autoimmune diseases, and were analyzed by TaqMan assays. The reported association with T1D patients of the IL2RA-rs41295061 located in the 10p15 region was replicated and our data suggest a trend of association of the polymorphisms IL2-rs17388568 and IL2-rs6822844 in 4q27. The effect of these markers was independent of the age at disease onset. Furthermore, the polymorphisms studied in 4q27 were not dependent on the presence of autoantibodies; however, the effect of the associated SNP in 10p15 (IL2RA-rs41295061) was specific of patients sera positive for diabetes antibodies. In conclusion, our results seem to indicate that late-onset and young T1D patients share most genetic factors located in the studied regions, but some markers could correlate with the presence of T1D specific autoantibodies.
Asunto(s)
Autoanticuerpos/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Edad de Inicio , Alelos , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 4 , Femenino , Orden Génico , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/genética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Idiopathic achalasia is an esophageal motor disorder of unknown etiology. A wealth of evidence supports the concept that achalasia is an immune-mediated disease. According to this evidence, achalasia has been significantly associated with specific alleles of the human leukocyte antigen class II, PTPN22 and IL23R. Several studies have demonstrated association of the IL10 gene with different inflammatory disorders. Our aim was to evaluate the role of functional IL10 promoter polymorphisms in susceptibility to idiopathic achalasia. A case-control study was performed with the -1082, -819, and -592 IL10 promoter polymorphisms in 282 patients and 529 controls and in an independent replication set of 75 patients and 575 controls. The GCC haplotype of the IL10 promoter was reported to be associated with a lower risk of achalasia in the discovery sample (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64-0.98, p = 0.029). This association was validated in a replication set (OR = 0.69, 95% CI = 0.48-1.00, p = 0.04). In the combined analysis no heterogeneity was observed between the 2 sample sets and the GCC haplotype was significantly associated with the disease (OR(MH) = 0.76, 95% CI = 0.63-0.91, p = 0.003). Our results provide the first evidence for an association between IL10 promoter polymorphisms and idiopathic achalasia, suggesting that the interleukin-10 cytokine may contribute to the pathogenesis of this disease.
Asunto(s)
Acalasia del Esófago/genética , Interleucina-10/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Inmunidad/genética , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras Genéticas , EspañaRESUMEN
The Wellcome Trust Case Control Consortium (WTCCC) genome-wide study found association of PTPN2 with three autoimmune diseases, among them is type 1 diabetes (T1D). This result was confirmed by a follow-up study that pointed to new independent signals within the region. However, both studies were performed in patients with an early-onset T1D. We aimed at replicating the previous results and studying the influence of these polymorphisms in the age at T1D debut. We genotyped 439 T1D Spanish subjects (age at onset, 1 to 65 years) and 861 controls for two PTPN2 single nucleotide polymorphisms (SNPs), rs2542151 and rs478582, and studied the effect of both polymorphisms in age at onset through stratified and continuous analyses. The frequency of rs2542151*G carriers was significantly higher in the early-onset group compared with late-onset patients (p = 0.023) and with controls (OR = 1.61 [1.14-2.26]; p = 0.005). No significant differences were found between controls and late-onset patients. The log-rank chi-square test for the Kaplan-Meier plots (carriers of susceptibility allele vs non carriers) was statistically significant (χ (1df) (2) = 4.485; p = 0.034), yielding an earlier disease debut for G carriers. The analysis of the SNP rs478582 did not reach statistical significance. In summary, we replicate the association detected by the WTCCC and propose that the rs2542151*G allele confers risk to an earlier onset of T1D.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Polimorfismo Genético , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , España , Población Blanca/genética , Adulto JovenRESUMEN
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.
Asunto(s)
Inmunoglobulina M/inmunología , Esclerosis Múltiple/inmunología , Bandas Oligoclonales/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Antígenos CD19/metabolismo , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Células Sanguíneas/citología , Células Sanguíneas/inmunología , Células Sanguíneas/metabolismo , Antígenos CD5/metabolismo , Líquido Cefalorraquídeo/citología , Líquido Cefalorraquídeo/inmunología , Líquido Cefalorraquídeo/metabolismo , Quimiocina CXCL13/líquido cefalorraquídeo , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina M/biosíntesis , Inmunoglobulina M/líquido cefalorraquídeo , Interleucina-5/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Lípidos/inmunología , Masculino , Glicoproteínas de Membrana/metabolismo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/diagnóstico , Vaina de Mielina/inmunología , Bandas Oligoclonales/biosíntesis , Bandas Oligoclonales/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Recurrencia , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
BACKGROUND: A functional polymorphism located at -1 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves' disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves' disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn's disease (CD) lesions. METHODOLOGY: Genotyping of rs1883832C>T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry. PRINCIPAL FINDINGS: The observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p = 0.025; OR (95% CI) = 1.12 (1.01-1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p = 0.002; OR (95% CI) = 1.19 (1.06-1.33)]. This increased predisposition was not detected in UC patients [p = 0.5; OR (95% CI) = 1.04 (0.93-1.17)]. CONCLUSION: The impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions.
Asunto(s)
Antígenos CD40/genética , Enfermedad de Crohn/genética , Esclerosis Múltiple/genética , Adulto , Alelos , Colitis Ulcerosa/genética , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Polimorfismo Genético/genética , Adulto JovenRESUMEN
Chromosomal region 5p13 includes regulatory elements of the prostaglandin receptor EP4 (PTGER4) gene and is associated with inflammatory bowel disease (IBD) susceptibility. We aimed at corroborating the association of the PTGER4 risk variant in IBD. Given the proinflammatory activity of prostaglandin E(2) in rheumatoid arthritis (RA), the reduction in incidence and severity of collagen-induced arthritis observed in mice deficient in the prostaglandin receptor EP4, and a modest signal of association found in an RA genome-wide scan, we proposed to extend the investigation of this locus to RA patients. A total of 709 Crohn's disease (CD) patients, 662 ulcerative colitis (UC) patients, and 1369 control subjects were genotyped for rs17234657. This polymorphism was also analyzed in 605 RA patients, and rs6871834 was studied in the RA patient group. Replication of the previous finding in CD was achieved in our independent collections, although with a milder effect (odds ratios = 1.23) than that originally described. No further association of the previously mentioned polymorphisms was detected with either UC or RA patients. We validated this 5p13 signal as a genuine susceptibility factor for CD in Caucasian populations. Our data seem to rule out a major influence of these polymorphisms on UC or RA predisposition.
Asunto(s)
Artritis Reumatoide/genética , Cromosomas Humanos Par 5/genética , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Receptores de Prostaglandina E/genética , Distribución de Chi-Cuadrado , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Subtipo EP4 de Receptores de Prostaglandina ERESUMEN
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.
Asunto(s)
Proteínas de Ciclo Celular/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA-DR/genética , Deficiencia de IgA/genética , Alelos , Antígenos HLA-B/genética , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Repeticiones de Microsatélite/genética , Padres , Polimorfismo Genético/genética , Polimorfismo Genético/inmunologíaRESUMEN
We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.
Asunto(s)
Enfermedad Celíaca/genética , Genes MHC Clase I , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Expresión Génica , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Metaanálisis como Asunto , RiesgoRESUMEN
Interleukin (IL)-2/IL-2R signalling promotes proliferation and survival of activated T cells and has an essential non-redundant role in the production of regulatory T cells. Associations with different autoimmune diseases of polymorphisms in a linkage disequilibrium block in which the IL2/IL21 genes map (4q27), and also in genes encoding the IL2RA and IL2RB subunits (located in 10p15 and 22q13, respectively), were identified through genome-wide studies. Polymorphisms in these three genes were studied in 430 multiple sclerosis (MS) patients and in 550 ethnically matched controls from Madrid (Spain). Replication and meta-analysis with results from an independent cohort of 771 MS patients and 759 controls from Andalucía (Spain) confirmed the association of polymorphisms in the IL2RA gene (P(Mantel-Haenszel,) odds ratio (OR)(M-H) (95% confidence interval, CI) for rs2104286: 0.0001, 0.75 (0.65-0.87); for rs11594656/rs35285258: 0.004, 1.19 (1.06-1.34); for rs41295061: 0.03, 0.77 (0.60-0.98)); showed a trend for association of the IL2/IL21 rs6822844 (P(M-H)=0.07, OR(M-H) (95% CI)=0.86 (0.73-1.01)), but did not corroborate the association for IL2RB. Regression analyses of the combined Spanish cohort revealed the independence of two IL2RA association signals: rs2104286 and rs11594656/rs35285258. The relevant role of the IL2RA gene on MS susceptibility adds support to its common effect on autoimmune risk and the suggestive association of IL2/IL21 warrants further investigation.
Asunto(s)
Predisposición Genética a la Enfermedad , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/genética , Interleucina-2/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Frecuencia de los Genes/genética , Humanos , Desequilibrio de Ligamiento/genética , Modelos Logísticos , Persona de Mediana Edad , España , Adulto JovenRESUMEN
OBJECTIVE: Genetic variants located close to 2 genes codifying for members of the tumor necrosis factor receptor superfamily (TNFRSF), TNFRSF14 and TNFRSF6B, have recently been associated with rheumatoid arthritis (RA) and with inflammatory bowel disease susceptibility, respectively. The TNFRSF6B protein has been related to osteoclastic activity, apoptosis inhibition, and modulation of T cell activation and differentiation. Interestingly, peptides encoded by both genes bind a common ligand called LIGHT, which is overexpressed in RA synovium. The aim of this study was to investigate the combined effect of the TNFRSF14 rs6684865 and TNFRSF6B rs4809330 polymorphisms in RA predisposition. METHODS: TaqMan genotyping of these polymorphisms was conducted in 649 patients with RA and 553 ethnically matched control subjects (first study). To validate the results, an independent replication cohort with 211 patients and 255 control subjects was additionally studied (replication study). RESULTS: The frequency of the rs6684865 G allele in the RA subgroup with the rs4809330 GG susceptibility genotype was significantly higher than that in the other patients with RA (74% versus 65%; P = 0.002) or in control subjects (74% versus 67%; P = 0.003). Because no significant differences between the control and patient groups in the first and replication studies were observed, the data were pooled. When compared with control subjects overall, the effect of the rs6684865 G allele in the group with the rs4809330 GG genotype (odds ratio [OR] 1.49) was significantly different from the effect observed in the group carrying the rs4809330 A allele (OR 0.97; P = 0.0015 by Breslow-Day test of homogeneity). CONCLUSION: We have identified and replicated a novel gene-gene interaction between 2 polymorphisms of TNFRSF members in Spanish patients with RA, based on the hypothesis of shared pathogenic pathways in complex diseases.
Asunto(s)
Artritis Reumatoide/genética , Epistasis Genética , Polimorfismo Genético , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Proteínas de Unión al ADN/genética , Deficiencia de IgA/genética , Deficiencia de IgA/inmunología , Polimorfismo de Nucleótido Simple , Proteínas Represoras/genética , Factores de Transcripción/genética , Alelos , Estudios de Casos y Controles , Proteínas de Unión al ADN/inmunología , Predisposición Genética a la Enfermedad , Humanos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de Transcripción del Factor Regulador X , Proteínas Represoras/inmunología , España , Factores de Transcripción/inmunología , Proteína 1 de Unión a la X-BoxRESUMEN
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 chi(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.
Asunto(s)
Proteínas Portadoras/genética , Enfermedad Celíaca/genética , Proteínas de Unión al GTP/genética , Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/genética , Enfermedades Inflamatorias del Intestino/genética , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genética , Proteínas Relacionadas con la Autofagia , Proteínas Portadoras/inmunología , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/inmunología , Proteínas de Unión al GTP/inmunología , Proteínas de Homeodominio/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/inmunología , Factores de Transcripción/inmunologíaRESUMEN
Previous studies have suggested that the ancestral haplotype 18.2 (AH18.2) carries additional susceptibility gene to Type 1 Diabetes (T1D) on the Major Histocompatibility Complex (MHC). We analyzed 10 DR3/TNFa1b5 homozygous subjects in order to establish the conservation of the AH18.2 and then compared this conserved region with other DR3 haplotype, the AH8.1. The Illumina's HumanHap550 Bead chip was used to perform an extensive genotyping of the MHC region. The AH18.2 was highly conserved between DDR1 and HLA-DQA1 genes; therefore most probably the second susceptibility gene is located within this region. We can exclude the region centromeric to HLA-DRA gene and telomeric to DDR1 gene. A comparison between the AH18.2 and AH8.1 haplotypes showed that 233 SNPs were different in the aforementioned conserved region. These data suggest that the 1.65 Mb MHC region between DDR1 and HLA-DRA genes is likely to carry additional susceptibility alleles for T1D on the AH18.2 haplotype.
Asunto(s)
Mapeo Cromosómico , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Haplotipos , Polimorfismo de Nucleótido Simple , Edad de Inicio , Alelos , Estudios de Casos y Controles , Cromosomas Humanos , Diabetes Mellitus Tipo 1/inmunología , Femenino , Marcadores Genéticos , Genotipo , Antígenos HLA-B , Antígeno HLA-B18 , Homocigoto , Humanos , Masculino , Repeticiones de Microsatélite , Miembro 25 de Receptores de Factores de Necrosis Tumoral/genética , EspañaRESUMEN
Nitric oxide has been described as a trigger for the synthesis of proinflammatory mediators and as a cytotoxic molecule with a pivotal role in apoptosis at the joints of rheumatoid arthritis (RA) patients. Polymorphisms in the NOS2A gene, which codes for the inducible nitric oxide synthase [(i)NOS], have been tested for association with several autoimmune diseases such as Crohn's disease or type 1 diabetes. Moreover, the existence of correlated levels of (i)NOS protein and synovial cell apoptosis in RA patients, pointed to NOS2A as a good candidate gene involved in RA predisposition. The role of NOS2A was studied in 405 Spanish RA patients and in 398 ethnically matched healthy controls, through the analysis of five SNPs: two at the NOS2A promoter (rs2779251 and 2779248), other two exonic markers (Asp(346)Asp (rs1137933) and Ser(608)Leu (rs22518)) and the last one located at intron 7 (rs3729508). We also included other two widely-used promoter polymorphisms: the insertion/deletion (TAAA/-) and the (CCTTT)n microsatellite. No individual association of each single-marker or haplotype was found with RA susceptibility. Our data show the low linkage disequilibrium between these NOS2A SNPs and the alleles of the (CCTTT)n microsatellite, corroborating in a Spanish population the observation previously described in British and Gambian population. The present data do not support a causative role of NOS2A polymorphisms in RA predisposition.
Asunto(s)
Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , EspañaRESUMEN
BACKGROUND: Thr300Ala polymorphism in ATG16L1 was reported as a susceptibility factor to Crohn's disease (CD). Inconsistently replicated associations with ulcerative colitis (UC) and specifically with ileal CD were also reported. Our aims were: to replicate the ATG16L1 Thr300Ala association with inflammatory bowel disease (IBD) in the Spanish population, to perform a meta-analysis to determine the risk conferred to the different IBD subgroups, and to test for the interaction with CARD15 or IL23R risk loci. METHODS: Thr300Ala (rs2241880) single nucleotide polymorphism (SNP) was genotyped in 712 IBD patients and 745 controls by TaqMan technology. Genetic frequencies were compared with chi-square tests. Our findings were pooled in a meta-analysis. RESULTS: In Spain, we observed an association of rs2241880 with CD (P = 0.008; odds ratio [OR, 95% confidence interval, CI] = 1.28 [1.06-1.54]), but not with UC. No significant differences emerged when patients were stratified by clinical features. Similarly, the meta-analysis demonstrated a significant association only with CD (P < 10(-4); OR [95% CI] = 1.33 [1.28-1.38]). A significant difference between ileal CD patients and controls was observed, but heterogeneity was found in comparisons involving colonic CD patients and definite conclusions cannot be drawn. No interaction between rs2241880 and the established CARD15 or IL23R susceptibility variants was observed. CONCLUSIONS: The Thr300Ala polymorphism is associated with CD, regardless of the CARD15 or IL23R status, but not with UC. Stratification by clinical phenotypes did not show definitive results because of the existing heterogeneity among studies.
Asunto(s)
Proteínas Portadoras/genética , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/genética , Polimorfismo Genético , Proteínas Relacionadas con la Autofagia , Predisposición Genética a la Enfermedad/epidemiología , Humanos , España/epidemiologíaRESUMEN
OBJECTIVES: Genome-wide association studies have reported the role of the interleukin (IL) 2-IL21 chromosomal region at 4q27 in several autoimmune conditions. Mice deficient in IL-2 develop a disease with clinical and histological similarity to ulcerative colitis (UC) in humans. Modest evidence of linkage with UC was tentatively proposed for the IL2 gene more than a decade ago. Therefore, we decide to investigate the association of polymorphisms in the IL-2 axis (IL2, IL2RA, and IL2RB genes) with inflammatory bowel diseases (IBDs). METHODS: Seven hundred and twenty-eight white Spanish unrelated IBD patients (356 Crohn's disease (CD) and 372 UC) and 549 ethnically matched controls were included in a case-control study. In addition, a Spanish replication cohort with 562 CD and 430 UC patients and 1,310 controls were analyzed. Eight single-nucleotide polymorphisms previously associated with different autoimmune diseases were analyzed using TaqMan chemistry. RESULTS: The IL2-rs6822844 polymorphism modified CD predisposition (P=0.002; odds ratio, OR (95% confidence interval, CI)=0.61 (0.44-0.84)); this was replicated in the other Spanish cohort, resulting in a strong protective effect of the minor allele in the merged samples (P=0.0002; OR (95% CI)=0.70 (0.58-0.85)). A similar effect of rs6822844 was detected for UC. Another marker, rs11938795, also showed evidence of an association with CD (P=0.006; OR (95% CI)=0.73 (0.58-0.92)). CONCLUSIONS: Polymorphisms within the IL2-IL21 linkage disequilibrium (LD) block show a novel association with IBD, this is concordant with suggestive previous results of whole genome analyses in CD and type 1 diabetes. Our data agree with the effect previously observed for other conditions and delineate a shared underlying mechanism.
Asunto(s)
Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Interleucina-2/genética , Interleucinas/genética , Polimorfismo Genético , Estudios de Casos y Controles , Humanos , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/genética , EspañaRESUMEN
Independent genome-wide association studies highlighted the function of CLEC16A/KIAA0350 polymorphisms modifying the risk to either multiple sclerosis (rs6498169) or type 1 diabetes (rs2903692). This C-type lectin gene maps to a linkage disequilibrium block at 16p13 and a functional role of this gene could be envisaged for other immune-related conditions, such as inflammatory bowel disease (IBD). The present study, aimed at investigating the association of those two polymorphisms with IBD, included 720 IBD patients and 550 ethnically matched healthy controls. The effect of rs2903692 previously described in diabetes was observed specifically for Crohn's disease (CD) patients lacking the main susceptibility factor described to date, that is, three polymorphisms within another pattern recognition gene, NOD2/CARD15 (NOD2(-) vs NOD2(+) CD patients, G vs A: P=0.008; OR (95% CI)=1.54 (1.10-2.15); NOD2(-) CD patients vs controls: P=0.008; OR (95% CI)=1.37 (1.08-1.73)). Replication of these findings was performed in independent Spanish cohorts of 544 IBD patients and 340 controls and the combined data yielded significant differences (405 NOD2(-) vs 204 NOD2(+) CD patients, G vs A: P=0.0012; OR(M-H) (95% CI)=1.49 (1.17-1.90); NOD2(-) CD patients vs controls: P=0.0007; OR(M-H) (95% CI)=1.35 (1.13-1.60)). The pooled analysis of the ulcerative colitis patients vs controls also yielded a significant risk (P=0.0005; OR (95% CI)=1.52 (1.19-1.93)). These data would suggest that microbial recognition through different pathways seems to converge in the development of these polygenic bowel diseases.