Potential Proteomic Biomarkers Associated To Mucosal Healing In Crohn’s Disease
MEUWIS, Marie-Alice ; Baiwir, Dominique ; Mazzucchelli, Gabriel et al
Poster (2014, October 06)
Introduction and objectives: In Crohn's disease (CD), there is a discrepancy between clinical activity of the disease (symptoms) and intestinal healing. However absence of tissue healing is associated ... [more ▼]
Introduction and objectives: In Crohn's disease (CD), there is a discrepancy between clinical activity of the disease (symptoms) and intestinal healing. However absence of tissue healing is associated with the risk of relapse and tissue damage progression. Endoscopy is costly and invasive. Hence biomarkers correlating with intestinal healing could improve disease management. We aimed to identify potential biomarkers associated to CD mucosal healing by a shotgun proteomics label free study. Methods: We used the STORI clinical trial cohort (n=103) aiming at identifying markers associated to relapse prediction after Infliximab treatment withdrawals. We used serum samples of patients in clinical remission, grouped according to the degree of intestinal healing seen at endoscopy. We performed depletion of the 20 most abundant plasma proteins on each serum pools and ran a proteomics label free differential analysis using 2D-nanoUPLC-MSE HDMS Synapt G1 for data acquisition and Protein Lynks Global Server vs 2.4 for data analysis (Waters, Corp., Milford, USA). Results and Discussion: We obtained potential biomarkers and designed a multiplexed -selected reaction monitoring (SRM) method for validation of these candidates in each individual patient. The method may also be tested in an independent set of IBD patients with and without mucosal healing. Conclusions: This research strategy and results of SRM validation of potential biomarkers associated to mucosal healing in this cohort of CD patients as well as the tests done on other CD patients, may provide new opportunities for CD follow-up tests development. [less ▲]Detailed reference viewed: 87 (11 ULg)
Overlap syndrome consisting of PSC-AIH with concomitant presence of a membranous glomerulonephritis and ulcerative colitis
; BOVY, Christophe ; COIMBRA MARQUES, Carla et al
in World Journal of Gastroenterology (2014), 20(16), 4811-4816
Abstract The association of primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) is known as an overlap syndrome (OS). OS can also be described in the setting of concomitant presence of AIH ... [more ▼]
Abstract The association of primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) is known as an overlap syndrome (OS). OS can also be described in the setting of concomitant presence of AIH and PSC. These diseases can in some cases be associated with ulcerative colitis. In this case report we describe, to our knowledge, the first case in the literature of a young Caucasian male suffering from ulcerative colitis and an overlap syndrome consisting of an association between PSC-AIH, with the concomitant presence of a membranous glomerulonephritis. [less ▲]Detailed reference viewed: 27 (3 ULg)
Identifying Inflammatory Bowel Disease causative genes through trans-eQTLs mapping within GWAS loci
Docampo Martínez, Elisa ; Theatre, Emilie ; Dmitrieva, Joelia Borisnova et al
Poster (2014, April 24)
Lifetime prevalence of inflammatory bowel disease (IBD) is reaching an alarming rate of >1/400 in industrialized societies. Improved understanding of disease pathogenesis is essential to develop more ... [more ▼]
Lifetime prevalence of inflammatory bowel disease (IBD) is reaching an alarming rate of >1/400 in industrialized societies. Improved understanding of disease pathogenesis is essential to develop more effective preventive, diagnostic and therapeutic measures. Genome-wide association studies (GWAS) have identified ~ 160 risk loci contributing to inherited predisposition to IBD, leading to the identification of new perturbed pathways and potential drug targets. Nevertheless, causative genes and variants remain unknown for the vast majority of risk loci. GWAS loci are likely to be regulatory and therefore alter expression levels of other genes. We hypothesize that if an IBD associated SNP is an expression quantitative loci (eQTL)-the " disease-association pattern " (DAP) should mirror the " eQTL association pattern " (EAP) of the causative gene if looking in the right target tissue(s). With this premise, our project aims to detect causative genes implicated in IBD's susceptibility through the evaluation of trans-eQTLs within GWAS loci. To this purpose, nine blood cell types and ileal, colonic and rectal biopsies have been collected for 330 healthy individuals of Northern European descent. All individuals have been genotyped with the OmniExpress Illumina array interrogating > 700K genetic variants. Transcriptome analysis has been conducted for all individuals and all cell/tissue types using Illumina HT12 arrays interrogating > 47,000 transcripts. Genotype and transcriptome data have undergone rigorous quality control. Transcriptome data have been pretreated variance stabilizing transformation, QQ normalization and correction for random and fixed effects in each cell type. Only expression probes mapped against Refseq have been considered. Genomic positions have been recovered and probes mapping to more than one genomic position (taking into account splice junctions with Tophat software) with a 96% identity have been discarded. Trans-eQTL mapping will be conducted on a SNP-by-SNP basis using linear regression (additive model) with PLINK software. In order to circumvent genome wide multiple testing penalty, we will test for a given SNP in the genome, any evidence for an excess of low p-values when testing its effect on the expression of genes located on other chromosomes or far away on the same chromosome. Confirmation of putative multigene transregulators will afterwards be performed by RNAseq experiments. We will then quantify the resemblance between DAP in the 160 GWAS-identified risk loci (raw data from IIBDGC plus imputed data) and " multigene trans-EAP " with Spearman's rank correlation. We will also evaluate the biological relevance of this list by performing a network analysis after adding the identified trans targets to the list of previously identified positional candidate genes (mapping to GWAS-identified IBD risk loci). Finally, as a the ultimate proof of causality, the selected genes will be resequenced in 3,000 IBD cases and 3,000 controls, using 600 DNA pools of 10 individuals with Illumina Truseq Amplicon. With this strategy, we expect to detect new causative variants that may constitute new drug targets for IBD. Latest results will be presented. [less ▲]Detailed reference viewed: 28 (2 ULg)
Combined use of GWAS and eQTL information to identify genes controlling platelet biology
Gori, Ann-Stephan ; LECUT, Christelle ; Theatre, Emilie et al
Poster (2014, April 24)
Genome Wide Association Studies (GWAS) have identified at least 68 loci involved in megakaryopoiesis and platelet formation. As for all GWAS, identified risk loci span hundreds of kilobases encompassing ... [more ▼]
Genome Wide Association Studies (GWAS) have identified at least 68 loci involved in megakaryopoiesis and platelet formation. As for all GWAS, identified risk loci span hundreds of kilobases encompassing multiple genes, such that causative variants and genes remain largely unknown. To aid in the identification of causative genes underlying GWAS hits for platelet function (as well as other phenotypes including common complex diseases), we have generated a dataset (" CEDAR ") comprising genome-wide SNP and transcriptome data on nine primary cell types, including platelets, for 330 healthy Caucasian individuals. In addition, we have measured platelet counts and volume, as well as platelet reactivity to ADP, collagen and thrombin-related peptide for all these individuals. After extensive quality control, the ensuing data set has been used to identify (i) QTL influencing platelet count, volume and reactivity, and (ii) cis-and transacting eQTL operating in platelets. To aid in the identification of genes underlying platelet biology, we are applying a recently developed method to search for correlations between association patterns with platelet phenotypes and eQTL association patterns. Such findings would strongly incriminate the corresponding genes (affected by the eQTL) as being causally involved in determining the cognate platelet phenotype. Latest results will be presented. [less ▲]Detailed reference viewed: 41 (4 ULg)
Utilisation optimale des inhibiteurs de la pompe à protons dans le cadre des soins primaires
Tack, Jacques ; LOUIS, Edouard ; et al
in Revue Médicale de Liège (2014), 69(3), 139-145Detailed reference viewed: 25 (1 ULg)
Comparison of two FFPE preparation methods using label-free shotgun proteomics: Application to tissues of diverticulitis patients.
QUESADA CALVO, Florence ; Bertrand, Virginie ; Longuespée, Rémi et al
in Journal of proteomics (2014), 112C
Formalin-fixed paraffin-embedded (FFPE) specimens of patients are useful sources of materials for clinical research and have recently gained interest for use in the discovery of clinical proteomic ... [more ▼]
Formalin-fixed paraffin-embedded (FFPE) specimens of patients are useful sources of materials for clinical research and have recently gained interest for use in the discovery of clinical proteomic biomarkers. However, the critical step in this field is the ability to obtain an efficient and repeatable extraction using the limited quantities of material available for research in hospital biobanks. This work describes the evaluation of the peptide/protein extraction using FFPE sections treated by the following two methods before shotgun proteomic analysis: a commercial solution (FFPE-FASP) (filter aided sample preparation) and an antigen retrieval-derived protocol (On Slice AR). Their efficiencies and repeatabilities are compared using data-independent differential quantitative label-free analysis. FFPE-FASP was shown to be globally better both qualitatively and quantitatively than On Slice AR. FFPE-FASP was tested on several samples, and differential analysis was used to compare the tissues of diverticulitis patients (healthy and inflammatory tissues). In this differential proteomic analysis using retrospective clinical FFPE material, FFPE-FASP was reproducible and provided a high number of confident protein identifications, highlighting potential protein biomarkers. BIOLOGICAL SIGNIFICANCE: In clinical proteomics, FFPE is an important resource for retrospective analysis and for the discovery of biomarkers. The challenge for FFPE shotgun proteomic analysis is preparation by an efficient and reproducible protocol, which includes protein extraction and digestion. In this study, we analyzed two different methods and evaluated their repeatabilities and efficiencies. We illustrated the reproducibility of the most efficient method, FFPE-FASP, by a pilot study on diverticulitis tissue and on FFPE samples amount accessible in hospital biobanks. These data showed that FFPE is suitable for use in clinical proteomics, especially when the FFPE-FASP method is combined with label-free shotgun proteomics as described in the workflow presented in this work. [less ▲]Detailed reference viewed: 75 (23 ULg)
FDG PET/CT in Crohn's disease : correlation of quantitative FDG PET/CT parameters with clinical and endoscopic surrogate markers of disease activity
; ; et al
in European Journal of Nuclear Medicine and Molecular Imaging (2014), 41Detailed reference viewed: 18 (0 ULg)
Diagnostic differentiel d'une diarrhee chronique.
in Revue medicale de Liege (2014), 69(1), 51-6
Chronic diarrhoea is a frequent clinical presentation in our population. It may correspond to many gastrointestinal or systemic pathologies. Most frequent causes are irritable bowel syndrome, functional ... [more ▼]
Chronic diarrhoea is a frequent clinical presentation in our population. It may correspond to many gastrointestinal or systemic pathologies. Most frequent causes are irritable bowel syndrome, functional intestinal disorders or lactose intolerance, but organic diseases have also to be searched. Focused patient questioning and some specific aspects of clinical examination play a key-role in diagnosis orientation and the use of complementary explorations. The present paper proposes a structured diagnostic procedure aiming at an optimal use of complementary explorations. [less ▲]Detailed reference viewed: 34 (5 ULg)
Can we predict the high-risk patient?
; Louis, Edouard
in Digestive diseases (Basel, Switzerland) (2014), 32(4), 328-36
BACKGROUND: While therapeutic strategies able to change the natural history of inflammatory bowel diseases (IBD) are being developed, factors predicting aggressive disease are needed to be able to choose ... [more ▼]
BACKGROUND: While therapeutic strategies able to change the natural history of inflammatory bowel diseases (IBD) are being developed, factors predicting aggressive disease are needed to be able to choose the appropriate therapeutic strategy for the individual patient based on the risk/benefit ratio. The aim of this review is to focus on the tools assisting the clinician in routine practice regarding the prediction of disease evolution. METHODS: A literature review was performed, which was mainly based on PubMed search, using the following terms: Crohn's disease, ulcerative colitis, inflammatory bowel disease, genetics, serology, biomarkers, endoscopy, C-reactive protein, faecal calprotectin, disease evolution and complications. RESULTS: For the prediction of disease evolution, clinical characteristics, particularly disease location and behaviour, are probably currently the most useful. In addition, a series of biomarkers, including genetic, serological and inflammatory markers, as well as characteristics of endoscopic lesions may have an added value. CONCLUSIONS: Simple clinical, biological and endoscopic tools may help the clinician in predicting disease evolution in IBD. However, these tools are still insufficient, and prospective evaluation of new genetic and biological markers are needed. [less ▲]Detailed reference viewed: 19 (0 ULg)
Assessment of the Influence of Inflammation and FCGR3A Genotype on Infliximab Pharmacokinetics and Time to Relapse in Patients with Crohn's Disease.
; ; et al
in Clinical pharmacokinetics (2014)
BACKGROUND AND OBJECTIVES: Infliximab is a monoclonal anti-tumor necrosis factor-alpha (anti-TNFalpha) antibody that profoundly modified the treatment of Crohn's disease (CD). The polymorphism of Fc ... [more ▼]
BACKGROUND AND OBJECTIVES: Infliximab is a monoclonal anti-tumor necrosis factor-alpha (anti-TNFalpha) antibody that profoundly modified the treatment of Crohn's disease (CD). The polymorphism of Fc fragment of IgG, low affinity IIIa, receptor (CD16a) [FCGR3A] influences the biological response to infliximab in patients with CD. Our aim was to study its influence on infliximab pharmacokinetics and risk of relapse after infliximab discontinuation. METHODS: In 111 CD patients in remission, infliximab was discontinued and its concentrations were measured for 30 months or until relapse. Infliximab pharmacokinetics were described using monocompartmental population modeling. RESULTS: The elimination rate of infliximab increased with C-reactive protein (CRP) [p = 0.00018] and was 16 % higher in FCGR3A-158V/V patients than in F carriers (p = 0.0028). Risk of relapse was higher in patients with baseline CRP >/=5 mg/L than in those with a lower value (p = 0.0000029). In addition, there was a first-order interaction between CRP and the FCGR3A genotype; in patients with high CRP, risk of relapse was higher for V/V patients than for F carriers (hazard ratio 4.80 and 2.84 for V/V and F carriers, respectively; p = 0.013). CONCLUSION: Both increased inflammation and FCGR3A-158V/V genotype are associated with increased infliximab elimination and risk of relapse after infliximab discontinuation in patients with CD. [less ▲]Detailed reference viewed: 9 (2 ULg)
Depth of remission in Crohn's disease patients seen in a referral centre : associated factors and impact on disease outcome.
; ; et al
in Acta gastro-enterologica Belgica (2014), 77(1), 41-6
INTRODUCTION: Our goals were to assess the prevalence of biological and tissue remission in routine practice in Crohn's disease, and to evaluate the correlation between biological or tissue remission and ... [more ▼]
INTRODUCTION: Our goals were to assess the prevalence of biological and tissue remission in routine practice in Crohn's disease, and to evaluate the correlation between biological or tissue remission and clinical or demographic characteristics as well as their impact on disease outcome. METHODS: We performed a retrospective monocenter study. Biological remission was defined by a CRP < 5 mg/I. Tissue remission was defined by the absence of ulcer at endoscopy and/or absence of signs of acute inflammation at MRI. Association with demographic, clinical and laboratory markers was studied by logistic regression models and rates of relapses, hospitalizations and surgeries were compared using the logrank test. RESULTS: Among the 263 patients included, 147 were in clinical remission; 102/147 (69%) were in biological remission. Fifty-six patients also had morphological evaluation: 37 (66%) were in tissue remission. Biological remission was associated with older age, higher hemoglobin and lower BMI. Tissue remission was associated with older age, lower platelets count, absence of previous surgery, and the use of immunosuppressant. Time-to-relapse was significantly longer in patients with biological remission and in patients with tissue remission as compared to patients without biological or tissue remission. CONCLUSIONS: Among the patients in clinical remission seen as outpatients, two thirds were either in biological and/or tissue remission. Biological and/or tissue remission was associated with a better outcome than clinical remission alone. [less ▲]Detailed reference viewed: 13 (1 ULg)
Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease.
; ; Louis, Edouard et al
in Inflammatory bowel diseases (2014), 20(6), 978-86
BACKGROUND: Crohn's disease (CD)-associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors ... [more ▼]
BACKGROUND: Crohn's disease (CD)-associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors of clinical relapse after infliximab discontinuation (STORI Study) was investigated to determine the impact of dysbiosis in CD relapse. METHODS: Fecal samples from 33 patients with CD in this cohort were collected at baseline, 2 months, 6 months, and at the end of the follow-up period (19 relapsers and 14 nonrelapsers). Healthy volunteers subjects (n = 29) were used as a control group. The fecal microbiota composition was assessed using quantitative PCR, and comparisons between the patient groups were made at different time points using the Wilcoxon test. The analysis of the time-to-relapse was performed according to the baseline median level of each bacterial signal. RESULTS: Dysbiosis was observed in patients with CD compared with healthy subjects, and it was characterized by low mean counts of Firmicutes (Clostridium coccoides [P = 0.0003], C. leptum [P < 0.0001], and Faecalibacterium prausnitzii [P = 0.003]). Lower rates of Firmicutes were seen in relapsers compared with nonrelapsers. Moreover, a low rate of F. prausnitzii (P = 0.014) and a low rate of Bacteroides (P = 0.030) predicted relapse independently from high C reactive protein level (P = 0.0001). CONCLUSIONS: In this work, we report that CD-associated dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal. A deficit in some bacterial groups or species, such as F. prausnitzii, may represent a predictive factor for relapse. Restoring normobiosis in CD could be a new goal for optimal CD management. [less ▲]Detailed reference viewed: 13 (0 ULg)
Use of azathioprine in IBD: modern aspects of an old drug.
Louis, Edouard ; ;
in Gut (2014), 63(11), 1695-9Detailed reference viewed: 15 (3 ULg)
Data dependent versus Data independent acquisition applied to samples with different protein dynamic range
Smargiasso, Nicolas ; Mazzucchelli, Gabriel ; Baiwir, Dominique et al
Poster (2014)Detailed reference viewed: 56 (1 ULg)
El sindrome tirogastrico autoinmune : sus efectos sobre los micronutrientes y la tumorigenesis gastrica
VALDES SOCIN, Hernan Gonzalo ; LUTTERI, Laurence ; Cavalier, Etienne et al
in Revista Argentina de Endocrinologia y Metabolismo (2014), 51Detailed reference viewed: 60 (5 ULg)
Hypercalcémie réfractaire et sécrétion ectopique de calcitonine dans un cancer neuroendocrine du pancréas : Effets hypocalcémiants du Cinacalcet
VALDES SOCIN, Hernan Gonzalo ; LOLY, Jean-Philippe ; BETEA, Daniela et al
in Annales d'Endocrinologie (2013, October), 74Detailed reference viewed: 61 (10 ULg)
Thrombose portale étendue chez un patient sous anti-vitamine K
LEDOUBLE, Vinciane ; BECK, Emmanuel ; PETERS, Pierre et al
in Revue Médicale de Liège (2013), (68(7-8)), 382-6Detailed reference viewed: 70 (10 ULg)
Is it ever appropriate to stop anti-tumor necrosis factor in a stable patient?
in Rubin, David, T.; Friedman, Sonia; Farraye, Francis A. (Eds.) Curbside Consultation in IBD: 49 Clinical Questions, Second Edition (2013)Detailed reference viewed: 6 (0 ULg)
Optimal use of proton pump inhibitors for treating acid peptic diseases in primary care.
Tack, Jacques ; Louis, Edouard ; et al
in Acta gastro-enterologica Belgica (2013), 76(4), 393-402
Heartburn, reflux and epigastric pain are frequently encountered symptoms in primary care medicine. Acid peptic diseases such as peptic ulcer and gastrointestinal reflux disease have a high prevalence ... [more ▼]
Heartburn, reflux and epigastric pain are frequently encountered symptoms in primary care medicine. Acid peptic diseases such as peptic ulcer and gastrointestinal reflux disease have a high prevalence, can have important impact on patient quality of life and represent a considerable health care cost. Proton pump inhibitors (PPIs) are the most potent pharmacological inhibitors of gastric acid secretion currently available and are the mainstay medical therapy for acid peptic diseases. This review summarizes current evidence on treatment of acid-peptic diseases with proton pump inhibitors and provides primary care clinicians with best practice guidelines for optimal use of these drugs. [less ▲]Detailed reference viewed: 13 (2 ULg)
Profile of pediatric Crohn's disease in Belgium.
; Mahachie John, Jestinah ; et al
in Journal of Crohn's & colitis (2013), 7(11), 588-98
AIM: A Belgian registry for pediatric Crohn's disease, BELCRO, was created. This first report aims at describing disease presentation and phenotype and determining associations between variables at ... [more ▼]
AIM: A Belgian registry for pediatric Crohn's disease, BELCRO, was created. This first report aims at describing disease presentation and phenotype and determining associations between variables at diagnosis and registration in the database. METHODS: Through a collaborative network, children with previously established Crohn's disease and newly diagnosed children and adolescents (under 18 y of age) were recruited over a 2 year period. Data were collected by 23 centers and entered in a database. Statistical association tests analyzed relationships between variables of interest at diagnosis. RESULTS: Two hundred fifty-five patients were included. Median age at diagnosis was 12.5 y (range: 1.6-18 y); median duration of symptoms prior to diagnosis was 3 m (range: 1-12 m). Neonatal history and previous medical history did not influence disease onset nor disease behavior. Fifty three % of these patients presented with a BMI z-score < -1. CRP was an independent predictor of disease severity. Steroids were widely used as initial treatment in moderate to severe and extensive disease. Over time, immunomodulators and biological were prescribed more frequently, reflecting a lower prescription rate for steroids and 5-ASA. A positive family history was the sole significant determinant for earlier use of immunosuppression. CONCLUSION: In Belgium, the median age of children presenting with Crohn's disease is 12.5 y. Faltering growth, extensive disease and upper GI involvement are frequent. CRP is an independent predictive factor of disease activity. A positive family history appears to be the main determinant for initial treatment choice. [less ▲]Detailed reference viewed: 63 (24 ULg)