RESUMEN
OBJECTIVE: To elucidate the prevalence of undiagnosed rheumatology-verified diagnosis of axial spondyloarthritis (RVD-axSpA) in patients attending routine secondary care IBD clinics with chronic back pain. METHODS: Screening questionnaires were sent to consecutive patients attending IBD clinics in a university teaching hospital. Patients fulling the eligibility criteria (gastroenterologist-verified diagnosis, 18-80 years old, biologic therapy naive, no previous diagnosis of axSpA); and a moderate diagnostic probability of axSpA [self-reported chronic back pain (CBP) >3 months, onset <45 years] were invited for rheumatology assessment. This included medical review, physical examination, patient reported outcome measures, human leucocyte antigen B27, C-reactive protein, pelvic radiograph and axSpA protocol magnetic resonance imaging. A diagnosis of RVD-axSpA was made by a panel of rheumatologists. RESULTS: Of the 470 patients approached, 91 had self-reported CBP >3 months, onset <45 years, of whom 82 were eligible for clinical assessment. The prevalence of undiagnosed RVD-axSpA in patients attending IBD clinics in a secondary care setting, with self-reported CBP, onset <45 years is estimated at 5% (95% CI 1.3, 12.0) with a mean symptom duration of 12 (s.d. 12.4) years. CONCLUSION: There is a significant hidden disease burden of axSpA among IBD patients. Appropriate identification and referral from gastroenterology is needed to potentially shorten the delay to diagnosis and allow access to appropriate therapy.
Asunto(s)
Espondiloartritis Axial , Enfermedades Inflamatorias del Intestino , Espondiloartritis , Espondilitis Anquilosante , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Espondiloartritis/complicaciones , Espondiloartritis/diagnóstico , Espondiloartritis/epidemiología , Estudios Transversales , Atención Secundaria de Salud , Prevalencia , Dolor de Espalda/diagnóstico , Dolor de Espalda/epidemiología , Dolor de Espalda/etiología , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/epidemiología , Espondilitis Anquilosante/diagnósticoRESUMEN
A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.
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Autofagia/genética , Enfermedad de Crohn/genética , Proteínas de Unión al GTP/genética , Predisposición Genética a la Enfermedad , Variación Genética , Animales , Estudios de Casos y Controles , Humanos , Ratones , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADNRESUMEN
Peptidoglycan (PGN) is a ubiquitous bacterial membrane product that, despite its well known pro-inflammatory properties, has also been invoked in immuno-tolerance of the gastrointestinal tract. PGN-induced mucosal IL-10 secretion and downregulation of Toll like receptors are potential mechanisms of action in the gut but there are few data on tolerogenic adaptive immune responses and PGN. Here, using blood-derived mononuclear cells, we showed that PGN induced marked cell surface expression of PD-L1 but not PD-L2 or CD80/CD86, and specifically in the CD14(+) monocytic fraction. This was reproduced at the gene level with rapid induction (<4 h) and, unlike for LPS stimulation, was still sustained at 24 h. Using transfected and native muramyl dipeptide (MDP), which is a cleavage product of PGN and a specific NOD2 agonist, in assays with wild type cells or those from patients with Crohn's disease carrying the Leu1007 frameshift mutation of NOD2, we showed that (i) both NOD2 dependent and independent signalling (appearing TLR2 mediated) occurred for PGN upregulation of PD-L1 (ii) upregulation is lost in response to MDP in patients with the homozygous mutation and (iii) PD-L1 upregulation was unaffected in patients with heterozygous mutations as previously reported for cytokine responses to MDP. The uptake of PGN and its cleavage products by the intestinal mucosa is well recognised and further work should consider PD-L1 upregulation as one potential mechanism of the commensal flora-driven intestinal immuno-tolerance. Indeed, recent work has shown that loss of PD-L1 signalling in the gut breaks CD8(+) T cell tolerance to self antigen and leads to severe autoimmune enteritis.
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Antígeno B7-H1/inmunología , Enfermedad de Crohn/inmunología , Proteína Adaptadora de Señalización NOD2/inmunología , Peptidoglicano/farmacología , Staphylococcus aureus , Antígeno B7-H1/deficiencia , Antígeno B7-H1/genética , Enfermedad de Crohn/genética , Escherichia coli , Femenino , Expresión Génica , Humanos , Lipopolisacáridos/farmacología , Masculino , Monocitos/efectos de los fármacos , Monocitos/inmunología , Mutación , Proteína Adaptadora de Señalización NOD2/genéticaRESUMEN
We describe a precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to determine the mechanisms by which SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 378 UC patients we map the regulatory effects of the SNPs to a human signalling network containing protein-protein, miRNA-mRNA and transcription factor binding interactions. With unsupervised clustering algorithms we group these patient-specific networks into four distinct clusters driven by PRKCB, HLA, SNAI1/CEBPB/PTPN1 and VEGFA/XPO5/POLH hubs. The pathway analysis identifies calcium homeostasis, wound healing and cell motility as key processes in UC pathogenesis. Using transcriptomic data from an independent patient cohort, with three complementary validation approaches focusing on the SNP-affected genes, the patient specific modules and affected functions, we confirm the regulatory impact of non-coding SNPs. iSNP identified regulatory effects for disease-associated non-coding SNPs, and by predicting the patient-specific pathogenic processes, we propose a systems-level way to stratify patients.
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Colitis Ulcerosa , MicroARNs , Algoritmos , Colitis Ulcerosa/genética , Genómica , Humanos , Carioferinas/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND AND AIMS: Historical and emerging data implicate fungi in Crohn's disease [CD] pathogenesis. However, a causal link between mycobiota, dysregulated immunity, and any impact of NOD2 variants remains elusive. This study aims to evaluate associations between NOD2 variants and faecal mycobiota in CD patients and non-CD subjects. METHODS: Faecal samples were obtained from 34 CD patients [18 NOD2 mutant, 16 NOD2 wild-type] identified from the UK IBD Genetics Consortium. To avoid confounding influence of mucosal inflammation, CD patients were in clinical remission and had a faecal calprotectinâ <250 µg/g; 47 non-CD subjects were included as comparator groups, including 22 matched household [four NOD2 mutant] and 25 non-household subjects with known NOD2 genotype [14 NOD2 mutant] identified by the NIHR BioResource Cambridge. Faecal mycobiota composition was determined using internal transcribed spacer 1 [ITS1] sequencing and was compared with 16S rRNA gene sequences and volatile organic compounds. RESULTS: CD was associated with higher numbers of fungal observed taxonomic units [OTUs] [pâ =â 0.033]. Principal coordinates analysis using Jaccard index [pâ =â 0.018] and weighted Bray-Curtis dissimilarities [pâ =â 0.01] showed Candida spp. clustered closer to CD patients whereas Cryptococcus spp. clustered closer to non-CD. In CD, we found higher relative abundance of Ascomycota [pâ =â 0.001] and lower relative abundance Basidiomycota [pâ =â 0.019] phyla. An inverse relationship was found between bacterial and fungal Shannon diversity in NOD2 wild-type which was independent of CD [râ =â -0.349; pâ =â 0.029]. CONCLUSIONS: This study confirms compositional changes in the gut mycobiota in CD and provides evidence that fungi may play a role in CD pathogenesis. No NOD2 genotype-specific differences were observed in the faecal mycobiota.
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Enfermedad de Crohn/genética , Heces/microbiología , Microbioma Gastrointestinal/genética , Micosis/genética , Micosis/microbiología , Proteína Adaptadora de Señalización NOD2/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Inducción de RemisiónRESUMEN
BACKGROUND & AIMS: Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. METHODS: We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. RESULTS: Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 x 10(-8); odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. CONCLUSIONS: Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis.
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Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Estudios de Casos y Controles , Quinasa 5 Dependiente de la Ciclina/genética , Proteínas de la Matriz Extracelular/genética , Femenino , Genotipo , Humanos , Janus Quinasa 2/genética , Masculino , Factores de Riesgo , Factor de Transcripción STAT3/genética , ARNt MetiltransferasasRESUMEN
BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis. METHODS AND FINDINGS: Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C-->G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09-1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1(+/lacZ) mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1(+/lacZ) mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model. CONCLUSIONS: HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.
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Mutación de Línea Germinal , Proteínas Hedgehog/fisiología , Enfermedades Inflamatorias del Intestino/genética , Polimorfismo de Nucleótido Simple , Transducción de Señal/genética , Factores de Transcripción/genética , Adulto , Animales , Inglaterra , Femenino , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Proteínas Hedgehog/genética , Humanos , Inflamación/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Escocia , Transducción de Señal/inmunología , Suecia , Proteína con Dedos de Zinc GLI1RESUMEN
INTRODUCTION OR BACKGROUND: It has long been recognized from epidemiological data that inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), have a strong genetic predisposition, interacting with unknown environmental drivers to render susceptible individuals at risk for relapsing intestinal inflammation. Substantial progress has been made in the last 2 years in characterizing the susceptibility genes involved. SOURCES OF DATA: The recent acceleration in understanding has resulted from the use of new technologies of genome-wide association scanning in large panels of cases and controls. AREAS OF AGREEMENT: Genome scans have robustly identified 11 susceptibility genes and loci and highlighted a number of new, previously unsuspected pathways as playing an important role in IBD pathogenesis-including the IL23 pathway in IBD overall and specific aspects of innate immunity (particularly NOD2 and the autophagy genes ATG16L1 and IRGM) in CD. AREAS OF CONTROVERSY: The next challenge is to identify specific causal variants at each of the confirmed susceptibility loci and then characterize their biological impact on gene expression and function of the protein product. GROWING POINTS: To date, most attention has focused on CD. A recent meta-analysis has increased the number of confirmed susceptibility loci to 32-more than for any other common disease to date. Attention is now turning to the use of the same techniques in UC to identify new, disease-specific genes and understand areas of overlap. AREAS TIMELY FOR DEVELOPING RESEARCH: This review explores genetic clues to the pathogenesis of IBD derived from the growing list of confirmed IBD susceptibility genes, and briefly elaborates some of the important themes and overlaps that are becoming evident both within IBD and also with other complex diseases.
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Predisposición Genética a la Enfermedad/genética , Enfermedades Inflamatorias del Intestino/genética , Predicción , Antígenos de Histocompatibilidad/genética , Humanos , Interleucinas/genética , Proteína Adaptadora de Señalización NOD2/genética , Proteínas de Transporte de Catión Orgánico/genética , Factores de Riesgo , Miembro 5 de la Familia 22 de Transportadores de SolutosRESUMEN
BACKGROUND: Identification of Crohn's disease (CD)-associated genetic variants is key to understanding pathogenic pathways underlying disease susceptibility. Recent reports of an association between TNFSF15 variants and CD have been modestly replicated in European populations, suggesting heterogeneity at this locus with stronger CD association in Japanese than European populations. METHODS: We investigated the association between variants in TNFSF15 and CD in 756 CD patients and 636 controls. Disease subphenotype associations were also investigated. RESULTS: TNFSF15 single nucleotide polymorphism (SNP) variants were associated with CD in our panel with peak odds ratio (OR) 1.2 (95% confidence interval [CI] 1.01-1.41) P = 0.033. The presence of a risk haplotype was replicated for the first time in a European population (frequency 67% in cases and 61% in controls) OR = 1.44 (95% CI 1.23-1.68) P = 0.00012. This result mirrors the UK panel in the index study (Yamazaki et al [2005] Hum Mol Genet 14:3499-3506) but is less significant than that reported in Japanese populations. There was no evidence of association with any individual CD subphenotype. CONCLUSIONS: Variants in TNFSF15 contribute to overall CD susceptibility in European populations, although to a lesser extent than that seen in the Japanese. Further studies to define the precise disease-causing variants as well as targeted functional studies are now required in human CD as TNFSF15 is a potential target for biological therapies.
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Enfermedad de Crohn/genética , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Adulto , Susceptibilidad a Enfermedades , Femenino , Variación Genética , Genotipo , Haplotipos , Humanos , Japón , Masculino , Polimorfismo de Nucleótido Simple , Reino UnidoRESUMEN
Background/Aims: Current models of Crohn's disease (CD) describe an inappropriate immune response to gut microbiota in genetically susceptible individuals. NOD2 variants are strongly associated with development of CD, and NOD2 is part of the innate immune response to bacteria. This study aimed to identify differences in fecal microbiota in CD patients and non-IBD controls stratified by NOD2 genotype. Methods: Patients with CD and non-IBD controls of known NOD2 genotype were identified from patients in previous UK IBD genetics studies and the Cambridge bioresource (genotyped/phenotyped volunteers). Individuals with known CD-associated NOD2 mutations were matched to those with wild-type genotype. We obtained fecal samples from patients in clinical remission with low fecal calprotectin (<250 µg/g) and controls without gastrointestinal disease. After extracting DNA, the V1-2 region of 16S rRNA genes were polymerase chain reaction (PCR)-amplified and sequenced. Analysis was undertaken using the mothur package. Volatile organic compounds (VOC) were also measured. Results: Ninety-one individuals were in the primary analysis (37 CD, 30 bioresource controls, and 24 household controls). Comparing CD with nonIBD controls, there were reductions in bacterial diversity, Ruminococcaceae, Rikenellaceae, and Christensenellaceae and an increase in Enterobacteriaceae. No significant differences could be identified in microbiota by NOD2 genotype, but fecal butanoic acid was higher in Crohn's patients carrying NOD2 mutations. Conclusions: In this well-controlled study of NOD2 genotype and fecal microbiota, we identified no significant genotype-microbiota associations. This suggests that the changes associated with NOD2 genotype might only be seen at the mucosal level, or that environmental factors and prior inflammation are the predominant determinant of the observed dysbiosis in gut microbiota.
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Enfermedad de Crohn/genética , Enfermedad de Crohn/microbiología , Microbioma Gastrointestinal , Proteína Adaptadora de Señalización NOD2/genética , Adulto , Anciano , Estudios de Casos y Controles , Heces/microbiología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mutación , ARN Ribosómico 16S/genéticaRESUMEN
The last 12 months have seen unprecedented progress in identifying the susceptibility genes that predispose to common disease in general and Crohn's disease in particular. Success has derived from the new technique of genome-wide association scanning in large panels of cases and controls. This has itself been made possible by the sequencing of the human genome,12 development of a map of common human haplotype structure (HapMap),3 and advances in genotyping technologies permitting ascertainment of hundreds of thousands of genetic variants in multiple individuals. Several previously unsuspected pathways particularly relating to innate immunity and the early host response to bacteria have been revealed as key determinants of Crohn's disease susceptibility. These will provide a solid foundation for directed functional and translational research. Further, the wealth of confirmed association data coming from unbiased surveys of the genome provided by genome-wide association scans provide several key pointers regarding design and analysis of inflammatory bowel disease genetics studies in the future.
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Enfermedad de Crohn/genética , Predisposición Genética a la Enfermedad , Genoma Humano , HumanosRESUMEN
To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at â¼12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.
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Adenilil Ciclasas/genética , Predisposición Genética a la Enfermedad/genética , Enfermedades Inflamatorias del Intestino/genética , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.
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Predisposición Genética a la Enfermedad/genética , Enfermedades Inflamatorias del Intestino/genética , Integrinas/genética , Alelos , Estudio de Asociación del Genoma Completo/métodos , Humanos , Inflamación/genética , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genéticaRESUMEN
BACKGROUND: Genetic variants in DLG5, which encodes a scaffolding protein on chromosome 10q23, and tumor necrosis factor (TNF)-alpha, encoding a proinflammatory cytokine on chromosome 6p, have recently been reported to be associated with inflammatory bowel disease (IBD). We studied these variants to seek evidence of association with IBD in a large independent dataset. METHODS: We genotyped 1104 unrelated white IBD subjects-496 with Crohn's disease, 512 with ulcerative colitis, and 96 with indeterminate colitis from the Cambridge/Eastern (UK) panel-and 760 healthy control subjects for DLG5_113G/A, DLG5_4136C/A, TNF-857C/T, and TNF-1031T/C polymorphisms. Known Crohn's disease-predisposing variants in CARD15/NOD2 were also genotyped to permit analysis for reported epistatic interactions. RESULTS: : TNF-857 was shown to be associated with IBD overall (P = 0.0079). A formal interaction test showed that TNF-857 is associated equally with ulcerative colitis and Crohn's disease. Neither of the DLG5 alleles, however, was associated with IBD (P = 0.32 and 0.35). Subgroup analysis also failed to show evidence of association between either DLG5 allele or genotype frequencies and ulcerative colitis or Crohn's disease. Stratification of TNF-alpha and DLG5 cases by CARD15 genotype made no significant difference in the strength of associations. CONCLUSIONS: We have confirmed an association between the TNF-857 promoter polymorphism and IBD in a large independent UK dataset but were unable to replicate an association at the previously reported loci within DLG5. This may reflect heterogeneity between the populations, a smaller effect size than originally predicted, or possibly a false-positive result in the original study. Further fine mapping studies of the TNF promoter region and studies assessing functional consequences of TNF promoter polymorphisms are now required in IBD.
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Predisposición Genética a la Enfermedad/epidemiología , Variación Genética , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/genética , Proteínas de la Membrana/genética , Factor de Necrosis Tumoral alfa/genética , Proteínas Supresoras de Tumor/genética , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Colitis Ulcerosa/epidemiología , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/genética , Enfermedad de Crohn/patología , Femenino , Marcadores Genéticos , Humanos , Incidencia , Enfermedades Inflamatorias del Intestino/patología , Masculino , Persona de Mediana Edad , Valores de Referencia , Sensibilidad y Especificidad , Reino Unido/epidemiologíaRESUMEN
BACKGROUND AND AIMS: Genetic association between inflammatory bowel disease (IBD) and NOD1 (CARD4) has recently been reported. This gene has structural similarity to NOD2 (CARD15), a confirmed susceptibility gene for Crohn"s disease (CD). The NOD1 association was strongest at novel complex indel ND1 + 32656. Our aim was to ascertain the contribution of ND1 + 32656 variants to IBD in a large independent United Kingdom dataset and to identify any subphenotype association within CD and ulcerative colitis (UC). METHODS: The presence of the ND1 + 32656 variant in our panel was confirmed by direct resequencing in 96 cases. One thousand three hundred seventy unrelated white IBD subjects (671UC, 645 CD, 54 indeterminate) and 760 regionally matched controls were then genotyped for the ND1 + 32656 variant. Data were analyzed by logistic regression methods within STATA software. RESULTS: There was no association between ND1 + 32656 and IBD in our panel. There was no heterogeneity between UC and CD, nor within the CD subgroup when conditioned by subphenotype or the presence of NOD2 variants. CONCLUSIONS: There was no overall evidence of association between IBD and the reported NOD1 susceptibility variant ND1 + 32656 in our panel. The discrepancy with the earlier report may reflect a smaller effect size than previously predicted, a false-positive result in the index study, or population heterogeneity.
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Predisposición Genética a la Enfermedad , Enfermedades Inflamatorias del Intestino/genética , Proteína Adaptadora de Señalización NOD1/genética , Polimorfismo Genético , Adulto , Colitis Ulcerosa/epidemiología , Colitis Ulcerosa/genética , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/genética , Femenino , Eliminación de Gen , Frecuencia de los Genes , Genotipo , Humanos , Enfermedades Inflamatorias del Intestino/epidemiología , Masculino , Persona de Mediana Edad , Mutagénesis Insercional , Reino Unido/epidemiologíaRESUMEN
Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
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Predisposición Genética a la Enfermedad/genética , Cadenas alfa de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Pancreatitis/genética , Polimorfismo de Nucleótido Simple , Azatioprina/efectos adversos , Azatioprina/química , Azatioprina/metabolismo , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Cadenas alfa de HLA-DQ/química , Cadenas alfa de HLA-DQ/metabolismo , Cadenas HLA-DRB1/química , Cadenas HLA-DRB1/metabolismo , Haplotipos , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/química , Inmunosupresores/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Mercaptopurina/efectos adversos , Mercaptopurina/química , Mercaptopurina/metabolismo , Modelos Moleculares , Estructura Molecular , Pancreatitis/inducido químicamente , Unión Proteica , Estructura Terciaria de Proteína , Factores de RiesgoRESUMEN
BACKGROUND: NLRP3 (formerly known as CIAS1 or NALP3) encodes a key component of the inflammasome and is a strong candidate gene for Crohn's disease (CD) susceptibility. A recent study reported significant and internally replicated association between CD and six single nucleotide polymorphisms (SNPs) in a regulatory region 5.3 kb downstream of NLRP3. Independent replication is required to verify these findings. METHODS: In all, 1298 CD cases and 1244 healthy controls were genotyped for the six SNPs using Taqman. Single locus, haplotype, and subphenotype analyses were conducted using logistic regression-based methods and PLINK, respectively. RESULTS: No significant associations were found, either on single locus, subphenotype, or haplotype analysis. CONCLUSIONS: Given our high (>90%) power to replicate findings from the index study, our data suggest either a much smaller effect size for the association between NLRP3 and CD susceptibility than previously reported or the possibility of a false-positive result in the index study. Further studies in other populations are required to determine what role, if any, NLRP3 variants play in CD susceptibility.
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Proteínas Portadoras/genética , Enfermedad de Crohn/genética , Polimorfismo de Nucleótido Simple/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR , Fenotipo , Reproducibilidad de los Resultados , Reino UnidoRESUMEN
We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.
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Biomarcadores/metabolismo , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Proteínas de la Matriz Extracelular/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Proteínas Relacionadas con la Autofagia , Proteínas Portadoras/genética , Estudios de Casos y Controles , Estudios de Cohortes , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/epidemiología , Proteínas de Unión al GTP/genética , Antígenos HLA-A/genética , Proteínas de Homeodominio/genética , Humanos , Subunidad p40 de la Interleucina-12/genética , Péptidos y Proteínas de Señalización Intracelular , Proteína Adaptadora de Señalización NOD2/genética , Proteínas Serina-Treonina Quinasas/genética , Receptores de Interleucina/genética , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: Identification of inflammatory bowel disease (IBD) susceptibility genes is key to understanding pathogenic mechanisms. Recently, the North American IBD Genetics Consortium provided compelling evidence for an association between ileal Crohn's disease (CD) and the IL23R gene using genome-wide association scanning. External replication is a priority, both to confirm this finding in other populations and to validate this new technique. We tested for association between IL23R and IBD in a large independent UK panel to determine the size of the effect and explore subphenotype correlation and interaction with CARD15. METHODS: Eight single nucleotide polymorphism markers in IL23R tested in the North American study were genotyped in 1902 cases of Crohn's disease (CD), 975 cases of ulcerative colitis (UC), and 1345 controls using MassARRAY. Data were analyzed using chi(2) statistics, and subgroup association was sought. RESULTS: A highly significant association with CD was observed, with the strongest signal at coding variant Arg381Gln (allele frequency, 2.5% in CD vs 6.2% in controls [P = 1.1 x 10(-12)]; odds ratio, 0.38; 95% confidence interval, 0.29-0.50). A weaker effect was seen in UC (allele frequency, 4.6%; odds ratio, 0.73; 95% confidence interval, 0.55-0.96). Analysis accounting for Arg381Gln suggested that other loci within IL23R also influence IBD susceptibility. Within CD, there were no subphenotype associations or evidence of interaction with CARD15. CONCLUSIONS: This study shows an association between IL23R and all subphenotypes of CD with a smaller effect on UC. This extends the findings of the North American study, providing clear evidence that genome-wide association scanning can successfully identify true complex disease genes.