title: Association of TNFSF15 polymorphism with irritable bowel syndrome.
abstract: BACKGROUND
  Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder, affecting more than 10% of the general population worldwide. Although a genetic component is suspected, unambiguous susceptibility genes have so far not been identified. This study tested the hypothesis that genes contributing to epithelial barrier integrity, control of mucosal immune responses and interactions with bacteria in the gut are associated with IBS.
  
  
  METHODS
  Single nucleotide polymorphisms (SNPs) corresponding to top signals of association with Crohn's disease at 30 known susceptibility loci were tested for their effect on IBS risk in 1992 individuals from two independent case-control cohorts from Sweden and the USA. Association tests included a conservative Bonferroni correction for multiple comparisons, and were also performed on specific subgroups of patients characterised by constipation (IBS-C), diarrhoea (IBS-D) or alternating constipation and diarrhoea (IBS-A).
  
  
  RESULTS
  The Crohn's disease risk allele rs4263839 G in the TNFSF15 gene was significantly associated with an increased risk of both IBS (p=2.2×10(-5); OR 1.37) and more pronouncedly, IBS-C (p=8.7×10(-7); OR 1.79) in the entire sample. Similar associations and risk effects of the same magnitude were observed in the two cohorts analysed separately. A correlation between rs4263839 genotype and TNFSF15 mRNA expression was detected both in peripheral blood and in rectal mucosal biopsies from healthy individuals (combined p=0.0033).
  
  
  CONCLUSIONS
  TNFSF15 is a susceptibility gene for IBS and IBS constipation. As TL1A, the protein encoded by TNFSF15, contributes to the modulation of inflammatory responses, the results support a role of immune activation in IBS.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Zucchelli
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.|Stress Research Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Anna Nixon
authors.initials: AN
authors.lastname: Andreasson
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bresso
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aldona
authors.initials: A
authors.lastname: Dlugosz
authors.affiliation: Department of Internal Medicine,Örebro University Hospital,Örebro, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Halfvarson
authors.affiliation: Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Törkvist
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Schmidt
authors.affiliation: Department of Medicine, Umeå University, Umeå, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Karling
authors.affiliation: Department of Clinical Sciences, Skånes University Hospital, Malmoe, Sweden.
authors.forename: Bodil
authors.initials: B
authors.lastname: Ohlsson
authors.affiliation: Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.affiliation: Department of Internal Medicine, Gothenburg University, Gothenburg, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Simren
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Greger
authors.initials: G
authors.lastname: Lindberg
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Agreus
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Carlson
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
mesh_terms: D000328:Adult; D000483:Alleles; D003248:Constipation / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics*
chemical_list: C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15