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  • 1.
    Bragde, Hanna
    et al.
    Ryhov County Hospital, Sweden.
    Jansson, Ulf
    Ryhov County Hospital, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Soederman, Jan
    Ryhov County Hospital, Sweden.
    Potential blood-based markers of celiac disease2014In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 14, no 176Article in journal (Refereed)
    Abstract [en]

    Background: Blood-based diagnostics has the potential to simplify the process of diagnosing celiac disease (CD). Although high levels of autoantibodies against tissue transglutaminase (anti-TG2) are strongly indicative of active CD, several other scenarios involve a need for additional blood-based CD markers. Methods: We investigated the levels of messenger RNA (mRNA) in whole blood (n = 49) and protein in plasma (n = 22) from cases with active CD (n = 20), with confirmed CD and normalized histology (n = 15), and without a CD diagnosis (n = 14). Group differences were analyzed using Kruskal-Wallis one-way analysis of variance by ranks. We also investigated correlations between levels of potential markers, histopathology according to the modified Marsh scale, and CD risk gradient based on HLA type, using Spearman rank correlation. The relation between HLA-DQ2 gene dose effect and the expression levels of selected blood-based markers was investigated using the Mann-Whitney U test. Finally, the diagnostic performance of anti-TG2, potential blood-based CD markers, and logistic regression models of combined markers was evaluated using receiver operating characteristic (ROC) curve analysis. Results: CXCL11 protein levels and TNFRSF9 and TNFSF13B mRNA levels were identified as potential CD markers. These are all affected by or involved in the regulation of the NF-kappa B complex. CXCL11 protein levels and IL21 and IL15 mRNA levels were correlated with histopathology according to the modified Marsh scale, as were the established CD markers. HLA genotype risk and HLA-DQ2 gene dose effect did not show any significant relations with either the potential CD markers or the established CD markers. ROC curve analysis revealed a slight, non-significant increase in the area under the curve for the combined use of anti-TG2 and different constellations of potential blood-based CD markers compared to anti-TG2 alone. Conclusions: The CD markers identified in this study further emphasize the significance of components related to NF-kappa B regulation in relation to CD. However, the relevance of CXCL11, TNFSF13B, TNFRSF9, and other NF-kappa B interacting proteins recognized by pathway analysis, needs to be further investigated in relation to diagnosis and monitoring of CD.

  • 2.
    Bragde, Hanna
    et al.
    Division of Medical Diagnostics, Ryhov County Hospital, Sweden.
    Jansson, Ulf
    Department of Pediatrics, Ryhov County Hospital, Sweden.
    Jarlsfelt, Ingvar
    Division of Medical Diagnostics, Ryhov County Hospital, Sweden.
    Söderman, Jan
    Division of Medical Diagnostics, Ryhov County Hospital, Sweden.
    Gene Expression Profiling of Duodenal Biopsies Discriminates Celiac Disease Mucosa From Normal Mucosa2011In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 69, no 6, p. 530-537Article in journal (Refereed)
    Abstract [en]

    Celiac disease (CD) is identified by histopathologic changes in the small intestine which normalize during a gluten-free diet. The histopathologic assessment of duodenal biopsies is usually routine but can be difficult. This study investigated gene expression profiling as a diagnostic tool. A total of 109 genes were selected to reflect alterations in crypt-villi architecture, inflammatory response, and intestinal permeability and were examined for differential expression in normal mucosa compared with CD mucosa in pediatric patients. Biopsies were classified using discriminant analysis of gene expression. Fifty genes were differentially expressed, of which eight (APOC3, CYP3A4, OCLN, MAD2L1, MKI67, CXCL11, IL17A, and CTLA4) discriminated normal mucosa from CD mucosa without classification errors using leave-one-out cross-validation (n = 39) and identified the degree of mucosal damage. Validation using an independent set of biopsies (n = 27) resulted in four discrepant cases. Biopsies from two of these cases showed a patchy distribution of lesions, indicating that discriminant analysis based on single biopsies failed to identify CD mucosa. In the other two cases, serology support class according to discriminant analysis and histologic specimens were judged suboptimal but assessable. Gene expression profiling shows promise as a diagnostic tool and for follow-up of CD, but further evaluation is needed.

  • 3.
    Gustafsson Bragde, Hanna
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Laboratory Medicine, Region Jönköping County.
    Biomarkers of Inflammation and Intestinal Mucosa Pathology in Celiac Disease2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy triggered by gluten. The only currently available treatment is complying with a lifelong gluten-free diet, which should not be commenced before a CD diagnosis has been established by diagnostic test results (including histopathologic assessment of small intestinal biopsies and CD-specific antibody levels). This makes diagnostic swiftness and accuracy important. In cases with low CD-specific antibody levels and/or low-grade intestinal injuries the diagnosis can be difficult to establish. The main objective of this thesis was to complement and improve CD diagnostics by identifying and implementing new biomarkers, mainly based on gene expression, in small intestinal biopsies and blood. In paper I, genes were selected to reflect villous height, crypt elongation, immune response, and epithelial integrity. The results showed that a subset of those genes could discriminate active CD mucosa from mucosa without CD-related changes and grade the intestinal injury. In paper III, an unbiased investigation of gene expression in CD mucosa was performed using transcriptome analysis. Active CD and non-CD mucosa showed differential expression in a subset of genes, and some were differentially expressed in CD mucosa before histopathologic assessment could confirm intestinal alterations compatible with a CD diagnosis. Gene set analysis revealed that there are many biological processes affected in CD mucosa, including those associated with immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation.

    In parallel, gene expression was investigated in stabilised whole blood. Blood is a more accessible sampling material than intestinal biopsies, and stabilised blood is suitable for routine diagnostics since transcript levels are preserved at sampling. In paper II, expressions from a selection of genes were quantified in stabilised whole blood (RNA) and/or plasma (protein). Three genes with differential expression in CD were identified. Compared to the CD-specific autoantibodies against tissue transglutaminase (anti-TG2) alone, the addition of the information from the new potential markers resulted in a nonsignificant contribution to the diagnostic capacity of anti-TG2. An unbiased investigation using transcriptome analysis (paper IV) showed that gene level expression differences in stabilised whole blood were small between CD and non-CD. However, expression differences on a gene set level could potentially be used in CD diagnostics. CD-associated biological processes suggested by the results included a pro-inflammatory response, negative regulation of viral replication, proliferation, differentiation, cell migration, cell survival, translation, and haemostasis.

    Expression analysis using real-time polymerase chain reaction (PCR) is easy to perform, with instrumentation available at most clinical laboratories. Although select solitary biomarkers could be very useful in the diagnosis of CD, basing gene expression profiles on pathway information instead of single genes might also disclose disease heterogeneity between patients and add stability to a diagnostic method based on gene expressions. In conclusion, the results of this work demonstrate that analysing the expression of a few small intestinal genes can complement CD diagnostics. The application of gene expression analysis in cases with minor small intestine histopathological changes shows promising results, but needs further investigations. Additionally, gene expressions in other inflammatory diseases of the small intestine need to be investigated and compared with CD to complete the picture. Moreover, the findings from this work give clues about the biological contexts in which CD resides, and the potential of gene expression in blood at a gene set level is of interest for further investigations.

    List of papers
    1. Gene Expression Profiling of Duodenal Biopsies Discriminates Celiac Disease Mucosa From Normal Mucosa
    Open this publication in new window or tab >>Gene Expression Profiling of Duodenal Biopsies Discriminates Celiac Disease Mucosa From Normal Mucosa
    2011 (English)In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 69, no 6, p. 530-537Article in journal (Refereed) Published
    Abstract [en]

    Celiac disease (CD) is identified by histopathologic changes in the small intestine which normalize during a gluten-free diet. The histopathologic assessment of duodenal biopsies is usually routine but can be difficult. This study investigated gene expression profiling as a diagnostic tool. A total of 109 genes were selected to reflect alterations in crypt-villi architecture, inflammatory response, and intestinal permeability and were examined for differential expression in normal mucosa compared with CD mucosa in pediatric patients. Biopsies were classified using discriminant analysis of gene expression. Fifty genes were differentially expressed, of which eight (APOC3, CYP3A4, OCLN, MAD2L1, MKI67, CXCL11, IL17A, and CTLA4) discriminated normal mucosa from CD mucosa without classification errors using leave-one-out cross-validation (n = 39) and identified the degree of mucosal damage. Validation using an independent set of biopsies (n = 27) resulted in four discrepant cases. Biopsies from two of these cases showed a patchy distribution of lesions, indicating that discriminant analysis based on single biopsies failed to identify CD mucosa. In the other two cases, serology support class according to discriminant analysis and histologic specimens were judged suboptimal but assessable. Gene expression profiling shows promise as a diagnostic tool and for follow-up of CD, but further evaluation is needed.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2011
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:liu:diva-156089 (URN)10.1203/PDR.0b013e318217ecec (DOI)000290831700011 ()21378598 (PubMedID)2-s2.0-79955855027 (Scopus ID)
    Available from: 2019-04-03 Created: 2019-04-03 Last updated: 2019-07-01Bibliographically approved
    2. Potential blood-based markers of celiac disease
    Open this publication in new window or tab >>Potential blood-based markers of celiac disease
    Show others...
    2014 (English)In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 14, no 176Article in journal (Refereed) Published
    Abstract [en]

    Background: Blood-based diagnostics has the potential to simplify the process of diagnosing celiac disease (CD). Although high levels of autoantibodies against tissue transglutaminase (anti-TG2) are strongly indicative of active CD, several other scenarios involve a need for additional blood-based CD markers. Methods: We investigated the levels of messenger RNA (mRNA) in whole blood (n = 49) and protein in plasma (n = 22) from cases with active CD (n = 20), with confirmed CD and normalized histology (n = 15), and without a CD diagnosis (n = 14). Group differences were analyzed using Kruskal-Wallis one-way analysis of variance by ranks. We also investigated correlations between levels of potential markers, histopathology according to the modified Marsh scale, and CD risk gradient based on HLA type, using Spearman rank correlation. The relation between HLA-DQ2 gene dose effect and the expression levels of selected blood-based markers was investigated using the Mann-Whitney U test. Finally, the diagnostic performance of anti-TG2, potential blood-based CD markers, and logistic regression models of combined markers was evaluated using receiver operating characteristic (ROC) curve analysis. Results: CXCL11 protein levels and TNFRSF9 and TNFSF13B mRNA levels were identified as potential CD markers. These are all affected by or involved in the regulation of the NF-kappa B complex. CXCL11 protein levels and IL21 and IL15 mRNA levels were correlated with histopathology according to the modified Marsh scale, as were the established CD markers. HLA genotype risk and HLA-DQ2 gene dose effect did not show any significant relations with either the potential CD markers or the established CD markers. ROC curve analysis revealed a slight, non-significant increase in the area under the curve for the combined use of anti-TG2 and different constellations of potential blood-based CD markers compared to anti-TG2 alone. Conclusions: The CD markers identified in this study further emphasize the significance of components related to NF-kappa B regulation in relation to CD. However, the relevance of CXCL11, TNFSF13B, TNFRSF9, and other NF-kappa B interacting proteins recognized by pathway analysis, needs to be further investigated in relation to diagnosis and monitoring of CD.

    Place, publisher, year, edition, pages
    BioMed Central, 2014
    Keywords
    Celiac disease; Molecular diagnostics; Blood-based biological markers
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-112037 (URN)10.1186/1471-230X-14-176 (DOI)000342782900001 ()25298177 (PubMedID)
    Note

    Funding Agencies|Futurum - the Academy for Healthcare; Jonkoping County Council; Medical Research Council of Southeast Sweden

    Available from: 2014-11-17 Created: 2014-11-13 Last updated: 2019-04-03
    3. Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies
    Open this publication in new window or tab >>Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies
    Show others...
    2018 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 75, no 23, p. 4385-4401Article in journal (Refereed) Published
    Abstract [en]

    Establishing a celiac disease (CD) diagnosis can be difficult, such as when CD-specific antibody levels are just above cutoff or when small intestinal biopsies show low-grade injuries. To investigate the biological pathways involved in CD and select potential biomarkers to aid in CD diagnosis, RNA sequencing of duodenal biopsies from subjects with either confirmed Active CD (n=20) or without any signs of CD (n=20) was performed. Gene enrichment and pathway analysis highlighted contexts, such as immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation. Twenty-nine potential CD biomarkers were selected based on differential expression and biological context. The biomarkers were validated by real-time polymerase chain reaction of eight RNA sequencing study subjects, and further investigated using an independent study group (n=43) consisting of subjects not affected by CD, with a clear diagnosis of CD on either a gluten-containing or a gluten-free diet, or with low-grade intestinal injury. Selected biomarkers were able to classify subjects with clear CD/non-CD status, and a subset of the biomarkers (CXCL10, GBP5, IFI27, IFNG, and UBD) showed differential expression in biopsies from subjects with no or low-grade intestinal injury that received a CD diagnosis based on biopsies taken at a later time point. A large number of pathways are involved in CD pathogenesis, and gene expression is affected in CD mucosa already in low-grade intestinal injuries. RNA sequencing of low-grade intestinal injuries might discover pathways and biomarkers involved in early stages of CD pathogenesis.

    Place, publisher, year, edition, pages
    SPRINGER BASEL AG, 2018
    Keywords
    RNA-seq; RNA sequencing; Molecular biomarkers; Gene expression profiling; Gene ontology enrichment analysis
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-152799 (URN)10.1007/s00018-018-2898-5 (DOI)000449307300008 ()30097691 (PubMedID)
    Note

    Funding Agencies|Futurum-the Academy for Health and Care, Region Jonkoping County; Medical Research Council of Southeast Sweden; National Genomics Infrastructure - Swedish Research Council

    Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2019-04-10
  • 4.
    Soderman, Jan
    et al.
    Ryhov County Hospital, Sweden .
    Noren, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Ryhov County Hospital, Sweden.
    Christiansson, Malin
    Ryhov County Hospital, Sweden .
    Bragde, Hanna
    Ryhov County Hospital, Sweden .
    Thiebaut, Raphaele
    University of Paris Diderot, France University of Paris Diderot Sorbonne Paris Cite, France .
    Hugot, Jean-Pierre
    University of Paris Diderot, France University of Paris Diderot Sorbonne Paris Cite, France Hop Robert Debre, France .
    Tysk, Curt
    Örebro University, Sweden Örebro Uni, Sweden .
    OMorain, Colm A.
    Adelaide and Meath Hospital, Ireland Trinity Coll Dublin, Ireland .
    Gassull, Miquel
    Health Science Research Institute, Spain .
    Finkel, Yigael
    Sachs Childrens Hospital, Sweden .
    Colombel, Jean-Frederic
    Hop Calmette, France Icahn School Medical Mt Sinai, NY 10029 USA .
    Lemann, Marc
    Hop St Louis, France .
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Analysis of single nucleotide polymorphisms in the region of CLDN2-MORC4 in relation to inflammatory bowel disease2013In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 19, no 30, p. 4935-4943Article in journal (Refereed)
    Abstract [en]

    AIM: To investigate a possible genetic influence of claudin (CLDN) 1, CLDN2 and CLDN4 in the etiology of inflammatory bowel disease. METHODS: Allelic association between genetic regions of CLDN1, CLDN2 or CLDN4 and patients with inflammatory bowel disease, Crohns disease (CD) or ulcerative colitis were investigated using both a case-control study approach (one case randomly selected from each of 191 Swedish inflammatory bowel disease families and 333 controls) and a family-based study (463 non-Swedish European inflammatory bowel disease-families). A nonsynonymous coding single nucleotide polymorphism in MORC4, located on the same linkage block as CLDN2, was investigated for association, as were two novel CLDN2 single nucleotide polymorphism markers, identified by resequencing. RESULTS: A single nucleotide polymorphism marker (rs12014762) located in the genetic region of CLDN2 was significantly associated to CD (case-control allelic OR = 1.98, 95% CI: 1.17-3.35, P = 0.007). MORC4 was present on the same linkage block as this CD marker. Using the case-control approach, a significant association (case control allelic OR = 1.61, 95% CI: 1.08-2.41, P = 0.018) was found between CD and a nonsynonymous coding single nucleotide polymorphism (rs6622126) in MORC4. The association between the CLDN2 marker and CD was not replicated in the family-based study. Ulcerative colitis was not associated to any of the single nucleotide polymorphism markers. CONCLUSION: These findings suggest that a variant of the CLDN2-MORC4 region predisposes to CD in a Swedish population.

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