Anticipation in familial Crohn's disease.
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ABSTRACT:
SUBMITTER: Grandbastien B
PROVIDER: S-EPMC1726980 | biostudies-other | 1998 Feb
REPOSITORIES: biostudies-other
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Project description:BACKGROUND: Having a relative with inflammatory bowel disease increases the risk for Crohn's disease but may also increase its severity in affected patients. AIMS: To evaluate the influence of a family history on Crohn's disease course and severity. METHODS: 1316 patients followed in the same unit were studied retrospectively. Age at onset, duration of illness, site, and extent of disease were determined in patients with and without a family history. Additionally, disease severity was estimated by the need for medical therapy (steroid and immunosuppressive requirement) and the frequency and extent of excisional surgery. RESULTS: 152 (12%) patients had a family history of inflammatory bowel disease. Duration of follow up was longer in patients with a family history and there were more operations for perforating complications in familial cases. However, the importance of medical therapy, and the incidence and extent of excisional surgery were similar in familial and and sporadic cases. Kaplan-Meier estimated time to prescription of immunosuppressive drugs and first intestinal resection were similar in familial and sporadic cases. When the 152 patients with familial Crohn's disease were paired for sex, location of disease at onset, date of birth, and date of diagnosis with 152 patients sporadic Crohn's disease, the disease severity remained similar in the two groups of paired patients. CONCLUSION: Patients with Crohn's disease and a family history of inflammatory bowel disease do not have a more severe course.
| S-EPMC1760050 | biostudies-other
Project description:Background/aimThe underlying etiology of Crohn's disease remains unknown. The aim of this study was to identify genomic alterations associated with the development of Crohn's disease in one Japanese family with a family history of Crohn's disease.Materials and methodsWe performed whole-exome sequence and pedigree analysis of a Japanese family in which both sisters developed Crohn's disease. Whole-exome sequencing was performed using the Ion Torrent Proton™ system. Data from the Proton runs were initially processed using the Ion Torrent platform-specific pipeline software Ion Reporter. An autosomal dominant mode of inheritance was assumed, and stringent selection criteria were applied.ResultsA substitution in the NR4A1 gene at codon 293 resulting in an amino acid change from arginine to serine was identified only in the affected sisters.ConclusionThe impaired DNA-binding capacity of the NR4A1 protein due to an NR4A1 germline mutation may be a possible cause of Crohn's disease.
| S-EPMC8286521 | biostudies-literature
Project description:Crohn's disease (CD) results from a complex interplay between host genetic factors and endogenous microbial communities. In the current study, we used Ion Torrent sequencing to characterize the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in patients with CD and their nondiseased first-degree relatives (NCDR) in 9 familial clusters living in northern France-Belgium and in healthy individuals from 4 families living in the same area (non-CD unrelated [NCDU]). Principal component, diversity, and abundance analyses were conducted, and CD-associated inter- and intrakingdom microbial correlations were determined. Significant microbial interactions were identified and validated using single- and mixed-species biofilms. CD and NCDR groups clustered together in the mycobiome but not in the bacteriome. Microbiotas of familial (CD and NCDR) samples were distinct from those of nonfamilial (NCDU) samples. The abundance of Serratia marcescens and Escherichia coli was elevated in CD patients, while that of beneficial bacteria was decreased. The abundance of the fungus Candida tropicalis was significantly higher in CD than in NCDR (P = 0.003) samples and positively correlated with levels of anti-Saccharomyces cerevisiae antibodies (ASCA). The abundance of C. tropicalis was positively correlated with S. marcescens and E. coli, suggesting that these organisms interact in the gut. The mass and thickness of triple-species (C. tropicalis plus S. marcescens plus E. coli) biofilm were significantly greater than those of single- and double-species biofilms. C. tropicalis biofilms comprised blastospores, while double- and triple-species biofilms were enriched in hyphae. S. marcescens used fimbriae to coaggregate or attach with C. tropicalis/E. coli, while E. coli was closely apposed with C. tropicalis Specific interkingdom microbial interactions may be key determinants in CD. Here, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal (Candida tropicalis) and bacterial (Serratia marcescens and Escherichia coli) species that are associated with CD dysbiosis. Additionally, we found that the level of anti-Saccharomyces cerevisiae antibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis We also identified positive interkingdom correlations between C. tropicalis, E. coli, and S. marcescens in CD patients and validated these correlations using in vitro biofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays.
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Project description:The Relationship between Fecal Bile Acids and Microbiome Community Structure in Pediatric Crohn’s Disease
| PRJEB35587 | ENA
Project description:The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1beta processing. Pyrin has been shown to interact with the gene product of NLRP3, NALP3/cryopyrin, also an important active member of the inflammasome. The NLRP3 region was recently reported to be associated with Crohn's disease (CD) susceptibility. We therefore sought to evaluate MEFV as an inflammatory bowel disease (IBD) susceptibility gene.MEFV colonic mucosal gene expression was significantly increased in experimental colitis mice models (TNBS p<0.0003; DSS p<0.006), in biopsies from CD (p<0.02) and severe ulcerative colitis (UC) patients (p<0.008). Comprehensive genetic screening of the MEFV region in the Belgian exploratory sample set (440 CD trios, 137 UC trios, 239 CD cases, 96 UC cases, and 107 healthy controls) identified SNPs located in the MEFV 5' haplotype block that were significantly associated with UC (rs224217; p = 0.003; A allele frequency: 56% cases, 45% controls), while no CD associations were observed. Sequencing and subsequent genotyping of variants located in this associated haplotype block identified three synonymous variants (D102D/rs224225, G138G/rs224224, A165A/rs224223) and one non-synonymous variant (R202Q/rs224222) located in MEFV exon 2 that were significantly associated with UC (rs224222: p = 0.0005; A allele frequency: 32% in cases, 23% in controls). No consistent associations were observed in additional Canadian (256 CD trios, 91 UC trios) and Scottish (495 UC, 370 controls) sample sets. We note that rs224222 showed marginal association (p = 0.012; G allele frequency: 82% in cases, 70% in controls) in the Canadian sample, but with a different risk allele. None of the NLRP3 common variants were associated with UC in the Belgian-Canadian UC samples and no significant interactions were observed between NLRP3 and MEFV that could explain the observed flip-flop of the rs224222 risk allele.The differences in association levels observed between the sample sets may be a consequence of distinct founder effects or of the relative small sample size of the cohorts evaluated in this study. However, the results suggest that common variants in the MEFV region do not contribute to CD and UC susceptibility.
| S-EPMC2745755 | biostudies-literature
Project description:To investigate the role of TIC in the morning perception process, we performed a transcriptome analysis of the wild type and time for coffee mutant (tic-2) at dawn. An additional file is included. In this file, the expression values for the replicates are condensed in a single data point obtaining one mean and standard deviation of the expression values per genotype. The protocol for this file is: log2 fold change followed by a False Discovery Rate with a p-value equal or below 0.05.
2013-10-10 | E-MTAB-1362 | biostudies-arrayexpress
Project description:BackgroundThe relative importance of peripheral nerve injury or central pain processing in painful diverticular disease (DD) is unclear. Functional magnetic resonance imaging (fMRI) has demonstrated that dysfunctional central pain processing predominates in irritable bowel syndrome (IBS). This study aims to identify anticipatory changes in symptomatic DD (SDD) compared to asymptomatic DD (ADD) and IBS patients.MethodsGastrointestinal symptoms and somatization were evaluated via the Patient Health Question-12 Somatic Symptom and the SDD group divided into low (?6 [LSDD]) and high (?7 [HSDD]) somatization. Cued painful cutaneous thermal stimuli were delivered to the left hand and foot during fMRI. Fixed effect group analysis of the 'cued' anticipatory phase was performed.Key resultsWithin the right posterior insula, greater deactivation was found in the ADD compared to other groups. In emotion processing centers, anterior and middle insula, greater activation was identified in all patient compared to the ADD group, and in LSDD compared to IBS and HSDD groups. In comparison, amygdala deactivation was greater in ADD than the IBS and HSDD groups, and in LSDD vs HSDD groups. Descending nociceptive control centers, such as the superior medial frontal and orbitofrontal cortex, also showed greater deactivation in the ADD and LSDD compared to the HSDD and IBS groups.Conclusions & inferencesThe HSDD group have altered anticipatory responses to thermal pain, similar to IBS group. The LSDD are similar to ADD group. This suggests underlying differences in pain pathophysiology, and the need for individualized treatment strategies to target the cause of their chronic pain.
| S-EPMC4879512 | biostudies-literature
Project description:Anticipatory actions require to keep track of elapsed time and inhibitory control. These cognitive functions could be impacted in Parkinson's disease (iPD). To test this hypothesis, a saccadic reaction time task was used where a visual warning stimulus (WS) predicted the occurrence of an imperative one (IS) appearing after a short delay. In the implicit condition, subjects were not informed about the duration of the delay, disfavoring anticipatory behavior but leaving inhibitory control unaltered. In the explicit condition, delay duration was cued. This should favor anticipatory behavior and perhaps alter inhibitory control. This hypothesis was tested in controls (N = 18) and age-matched iPD patients (N = 20; ON and OFF L-DOPA). We found that the latency distribution of saccades before the IS was bimodal. The 1st mode weakly depended on temporal information and was more prominent in iPD. Saccades in this mode were premature and could result of a lack of inhibition. The 2nd mode covaried with cued duration suggesting that these movements were genuine anticipatory saccades. The explicit condition increased the probability of anticipatory saccades before the IS in controls and iPDON but not iPDOFF patients. Furthermore, in iPD patients the probability of sequences of 1st mode premature responses increased. In conclusion, the triggering of a premature saccade or the initiation of a controlled anticipatory one could be conceptualized as the output of two independent stochastic processes. Altered time perception and increased motor impulsivity could alter the balance between these two processes in favor of the latter in iPD, particularly OFF L-Dopa.
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Project description:parkin mutations are a common cause of parkinsonism. Possessing two parkin mutations leads to early-onset parkinsonism, while having one mutation may predispose to late-onset disease. This dosage pattern suggests that some parkin families should exhibit intergenerational variation in age at onset resembling anticipation. A subset of familial PD exhibits anticipation, the cause of which is unknown. The aim of this study was to determine if anticipation was due to parkin mutation dosage.We studied 19 kindreds that had early-onset parkinsonism in the offspring generation, late-onset parkinsonism in the parent generation, and > or = 20 years of anticipation. We also studied 28 early-onset parkinsonism cases without anticipation. Patients were diagnosed by neurologists at a movement disorder clinic. parkin analysis included sequencing and dosage analysis of all 12 exons.Only one of 19 cases had compound parkin mutations, but contrary to our postulate, the affected relative with late-onset parkinsonism did not have a parkin mutation. In effect, none of the anticipation cases could be attributed to parkin. In contrast, 21% of early-onset parkinsonism patients without anticipation had parkin mutations.Anticipation is not linked to parkin, and may signify a distinct disease entity.
| S-EPMC551608 | biostudies-literature
Project description:Fistulas still represent one of the most important complications in patients with Crohn's disease (CD). At least one third of CD patients suffer from fistulas during their disease course and amongst them longstanding remission of complex fistulas occurs only in about one third. So far, fistula pathogenesis is only partially understood. From a histopathological view, a fistula is a tube covered by flat epithelial cells. Current research suggests that the driving force for fistula development is epithelial-to-mesenchymal transition (EMT). Around the fistula, high levels of tumor necrosis factor (TNF), IL-13, and TGF? can be detected and recent studies indicated an involvement of the intestinal microbiota. Fistula diagnosis requires clinical and surgical assessment, radiologic investigations, e.g., magnet resonance imaging and endoscopy. Routine medical treatment of fistulas includes antibiotics, immunosuppressives, and anti-TNF antibodies. There is no well-established role for calcineurin inhibitors in fistula treatment, corticosteroids appear to be even contra-productive. A promising novel approach might be the application of adipose tissue-derived or bone marrow-derived mesenchymal stem cells that have been studied recently. Due to insufficient efficacy of medical treatment and recurrence of fistulas, surgical interventions are frequently necessary. Further research is needed to better understand fistula pathogenesis aiming to develop novel treatment option for our patients.
| S-EPMC5539341 | biostudies-literature