title: Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome.
abstract: OBJECTIVE
  The complex genetic aetiology underlying irritable bowel syndrome (IBS) needs to be assessed in large-scale genetic studies. Two independent IBS cohorts were genotyped to assess whether genetic variability in immune, neuronal and barrier integrity genes is associated with IBS.
  
  
  METHODS
  384 single nucleotide polymorphisms (SNPs) covering 270 genes were genotyped in an exploratory cohort (935 IBS patients, 639 controls). 33 SNPs with Puncorrected<0.05 were validated in an independent set of 497 patients and 887 controls. Genotype distributions of single SNPs were assessed using an additive genetic model in IBS and clinical subtypes, IBS-C and IBS-D, both in individual and combined cohorts. Trait anxiety (N=614 patients, 533 controls), lifetime depression (N=654 patients, 533 controls) and mRNA expression in rectal biopsies (N=22 patients, 29 controls) were correlated with SNP genotypes.
  
  
  RESULTS
  Two SNPs associated independently in the exploratory and validation cohort: rs17837965-CDC42 with IBS-C (ORexploratory=1.59 (1.05 to 1.76); ORvalidation=1.76 (1.03 to 3.01)) and rs2349775-NXPH1 with IBS-D (ORexploratory=1.28 (1.06 to 1.56); ORvalidation=1.42 (1.08 to 1.88)). When combining both cohorts, the association of rs2349775 withstood post hoc correction for multiple testing in the IBS-D subgroup. Additionally, three SNPs in immune-related genes (rs1464510-LPP, rs1881457-IL13, rs2104286-IL2RA), one SNP in a neuronal gene (rs2349775-NXPH1) and two SNPs in epithelial genes (rs245051-SLC26A2, rs17837965-CDC42) were weakly associated with total-IBS (Puncorrected<0.05). At the functional level, rs1881457 increased IL13 mRNA levels, whereas anxiety and depression scores did not correlate with rs2349775-NXPH1.
  
  
  CONCLUSIONS
  Rs2349775 (NXPH1) and rs17837965 (CDC42) were associated with IBS-D and IBS-C, respectively, in two independent cohorts. Further studies are warranted to validate our findings and to determine the mechanisms underlying IBS pathophysiology.
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium.
authors.forename: Mira M
authors.initials: MM
authors.lastname: Wouters
authors.affiliation: Vesalius Research Center, VIB, Leuven University, Leuven, Belgium Laboratory for Translational Genetics, Department of Oncology, Leuven University, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cleynen
authors.affiliation: Department of Medicine, University of Manchester, Manchester, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Whorwell
authors.affiliation: Centre for Family Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Agréus
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aldona
authors.initials: A
authors.lastname: Dlugosz
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter Thelin
authors.initials: PT
authors.lastname: Schmidt
authors.affiliation: Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Halfvarson
authors.affiliation: Department of Internal Medicine, Gothenburg University, Gothenburg, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Simrén
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, Umeå University, Umeå, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Karling
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium.
authors.forename: Sander
authors.initials: S
authors.lastname: Van Wanrooy
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Mondelaers
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium.
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Greger
authors.initials: G
authors.lastname: Lindberg
authors.affiliation: Queen's Medical Centre, Nottingham, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Spiller
authors.affiliation: Academic DPU, GlaxoSmithKline, Research Triangle Par, North Carolina, USA.
authors.forename: George
authors.initials: G
authors.lastname: Dukes
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Boeckxstaens
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D003248:Constipation / Q000235:genetics*; D003967:Diarrhea / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D060005:Genotyping Techniques; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020764:cdc42 GTP-Binding Protein / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D006023:Glycoproteins; D009479:Neuropeptides; C112162:neurexophilin; D020764:cdc42 GTP-Binding Protein
keywords: GENETIC POLYMORPHISMS; IMMUNE RESPONSE