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The role of CARD9 variations in ulcerative colitis.

Projectomschrijving

Inflammatory  bowel  diseases  (IBD)  is  een  verzamelnaam  voor  een groep  aandoeningen  van  het maag-darmstelsel. Er zijn twee hoofdgroepen: Colitis Ulcerosa (CU) en de ziekte van Crohn (CD). De genetische achtergrond van CD is uitgebreid bestudeerd. Er zijn meer dan 30 genen bekend die een rol spelen bij de ontwikkeling van CD. Voor CU zijn er echter pas enkele genen bekend. Het  CARD9- is één van de mogelijk betrokken genen.  Het doel van dit project is meer te weten te komen over de biologische  functie  van  het  CARD9-gen  en  de  klinische  gevolgen  onderzoeken  van  mutaties in het CARD9-gen.  

Producten

Titel: Genetic association analysis of the functional c.714T>G polymorphism and mucosal expression of dectin-1 in inflammatory bowel disease.
Auteur: de Vries HS, Plantinga TS, van Krieken JH, Stienstra R, van Bodegraven AA, Festen EA, Weersma RK, Crusius JB, Linskens RK, Joosten LA, Netea MG, de Jong DJ.
Magazine: PLoS ONE
Titel: Inflammatory bowel disease and celiac disease: overlaps in the pathology and genetics, and their potential drug targets.
Auteur: Festen EA, Szperl AM, Weersma RK, Wijmenga C, Wapenaar MC.
Magazine: Endocrine Metabolic & Immune Disorders-Drug Targets
Titel: Association of DLG5 variants with gluten-sensitive enteropathy
Auteur: Festen EA, Zhernakova A, Wijmenga C, Weersma RK.
Magazine: Gut
Titel: Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP
Auteur: Zhernakova A, Festen EAM, Franke L, Trynka G, van Diemen CC, Monsuur AJ, Bevova M, Nijmeijer RM, van 't Slot R, Heijmans R, Boezen HM, van Heel DA, van Bodegraven AA, Stokkers PC, Wijmenga C, Crusius JB, Weersma RK
Magazine: American Journal of Human Genetics
Titel: A meta-analysis of genome wide association scans identifies TAGAP and PUS10 as shared risk loci for Crohn's disease and celiac disease. IN PRESS
Auteur: Festen EAM, Goyette P, Green T, Beauchamp C, Boucher G, Trynka G, Dubois PC, Lagac C, Stokkers PCF, Hommes DW, Barisani D, Palmieri O, Annese V, van Heel DA, Weersma RK, Daly MJ, Wijmenga C, Rioux JD
Magazine: PLoS Genetics
Titel: Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease.
Auteur: Fransen K, Visschedijk MC, van Sommeren S, Fu JY, Franke L, Festen EA, Stokkers PC, van Bodegraven AA, Crusius JB, Hommes DW, Zanen P, de Jong DJ, Wijmenga C, van Diemen CC, Weersma RK.
Magazine: Human Molecular Genetics
Titel: Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis.
Auteur: Festen EA, Goyette P, Scott R, Annese V, Zhernakova A, Lian J, Lefèbvre C, Brant SR, Cho JH, Silverberg MS, Taylor KD, de Jong DJ, Stokkers PC, Mcgovern D, Palmieri O, Achkar JP, Xavier RJ, Daly MJ, Duerr RH, Wijmenga C, Weersma RK, Rioux JD.
Magazine: Gut
Titel: Association of FcgR2a, but not FcgR3a, with inflammatory bowel diseases across three Caucasian populations.
Auteur: Weersma RK, Crusius JB, Roberts RL, Koeleman BP, Palomino-Morales R, Wolfkamp S, Hollis-Moffatt JE, Festen EA, Meisneris S, Heijmans R, Noble CL, Gearry RB, Barclay ML, Gómez-Garcia M, Lopez-Nevot MA, Nieto A, Rodrigo L, Radstake TR, van Bodegraven AA, Wijmenga C, Merriman TR, Stokkers PC, Peña AS, Martín J, Alizadeh BZ.
Magazine: Inflammatory Bowel Diseases
Titel: Multi-ethnic studies in complex traits.
Auteur: Fu J, Festen EA, Wijmenga C
Magazine: Human Molecular Genetics
Titel: A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn's disease and celiac disease.
Auteur: Festen EA, Goyette P, Green T, Boucher G, Beauchamp C, Trynka G, Dubois PC, Lagacé C, Stokkers PC, Hommes DW, Barisani D, Palmieri O, Annese V, van Heel DA, Weersma RK, Daly MJ, Wijmenga C, Rioux JD.
Magazine: PLoS Genetics
Titel: Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort.
Auteur: Weersma RK, Stokkers PC, van Bodegraven AA, van Hogezand RA, Verspaget HW, de Jong DJ, van der Woude CJ, Oldenburg B, Linskens RK, Festen EA, van der Steege G, Hommes DW, Crusius JB, Wijmenga C, Nolte IM, Dijkstra G; Dutch Initiative on Crohn and Colitis (ICC).
Magazine: Gut
Titel: Association of Crohn's disease-associated NOD2 variants with intestinal failure requiring small bowel transplantation and clinical outcomes
Auteur: Janse M, Weersma RK, Sudan DL, Festen EA, Wijmenga C, Dijkstra G, Mercer D.
Magazine: Gut
Titel: Genetic analysis in a Dutch study sample identifies more ulcerative colitis susceptibility loci and shows their additive role in disease risk.
Auteur: Festen EA, Stokkers PC, van Diemen CC, van Bodegraven AA, Boezen HM, Crusius BJ, Hommes DW, van der Woude CJ, Balschun T, Verspaget HW, Schreiber S, de Jong DJ, Franke A, Dijkstra G, Wijmenga C, Weersma RK.
Magazine: American Journal of Gastroenterology
Titel: The genetic basis of inflammatory bowel disease unravelled by genetic association studies
Auteur: Visschedijk MC, Festen EA, Wijmenga C, Weersma RK.
Magazine: Geneeskunde en Sport
Titel: Shared genetic background of inflammatory diseases of the bowel
Auteur: E.A.M. Festen

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Samenvatting van de aanvraag

Inflammatory bowel diseases (IBD) are a group of chronic disorders of the gastrointestinal tract and comprise two main entities: ulcerative colitis (UC) and Crohn’s disease (CD). IBD is a complex multifactorial disorder affecting approximately 0.25 % of Western European populations. The genetics of CD has been studied extensively and genetic analysis has already identified more than 30 CD susceptibility genes, while work on UC has progressed less well and only a few susceptibility genes have been identified to date. We have recently identified CARD9 as a risk gene for UC (OR 1.28 95%CI 1.11-1.47)); it might be involved in the pathogenesis via regulation of the IL17 response to pathogens. The aim of this proposal is to elucidate the role of CARD9 in UC, which translates into two objectives: A. To gain fundamental knowledge on the biological function of CARD9 and its role in the pathogenesis of UC B. To determine the clinical consequences of carrying CARD9 risk variants. We propose an original strategy, focusing on the role of CARD9 and combining fundamental research with clinical research, which will allow translation of our genetic findings to clinical work. Specifically we will: 1. Identify the disease-causing variant in CARD9 by re-sequencing the gene in a large cohort of UC patients 2. Determine the tissue and cellular expression of CARD9 in normal and UC intestinal biopsies 3. Functionally characterize CARD9 using an in vivo (mouse) model system 4. Determine genotype/phenotype correlations in a large cohort of UC patients 5. Develop prediction models based on CARD9 variants in combination with known UC genetic risk variants. The basis for this project is the availability of DNA samples from a cohort of 1120 UC patients with detailed clinical information and of intestinal biopsy material from approximately 300 UC patients in this cohort. We have established a collaboration with Dr. R. Xavier, Harvard Medical School, Boston, USA, who recently made a CARD9-/- mouse. We also recently identified novel UC associated genetic risk variants by a genome-wide association scan (GWAS) on UC patients through a collaboration with Prof. S. Schreiber, Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Germany. This will enable us to create predictive models for UC susceptibility.

Onderwerpen

Kenmerken

Projectnummer:
92003533
Looptijd: 100%
Looptijd: 100 %
2009
2011
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. T.N. Wijmenga
Verantwoordelijke organisatie:
Universitair Medisch Centrum Groningen