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Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome
  1. Mira M Wouters1,
  2. Diether Lambrechts2,3,
  3. Michael Knapp4,
  4. Isabelle Cleynen1,
  5. Peter Whorwell5,
  6. Lars Agréus6,
  7. Aldona Dlugosz7,
  8. Peter Thelin Schmidt7,
  9. Jonas Halfvarson8,
  10. Magnus Simrén9,
  11. Bodil Ohlsson10,
  12. Pontus Karling11,
  13. Sander Van Wanrooy1,
  14. Stéphanie Mondelaers1,
  15. Severine Vermeire1,
  16. Greger Lindberg12,
  17. Robin Spiller13,
  18. George Dukes14,
  19. Mauro D'Amato15,
  20. Guy Boeckxstaens1
  1. 1Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium
  2. 2Vesalius Research Center, VIB, Leuven University, Leuven, Belgium
  3. 3Laboratory for Translational Genetics, Department of Oncology, Leuven University, Leuven, Belgium
  4. 4Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
  5. 5Department of Medicine, University of Manchester, Manchester, UK
  6. 6Centre for Family Medicine, Karolinska Institutet, Stockholm, Sweden
  7. 7Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  8. 8Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden
  9. 9Department of Internal Medicine, Gothenburg University, Gothenburg, Sweden
  10. 10Department of Clinical Sciences, Skånes University Hospital, Malmoe, Sweden
  11. 11Department of Medicine, Umeå University, Umeå, Sweden
  12. 12Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  13. 13Queen's Medical Centre, Nottingham, UK
  14. 14Academic DPU, GlaxoSmithKline, Research Triangle Par, North Carolina, USA
  15. 15Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
  1. Correspondence to Dr Mira Wouters, Translational Research Center for Gastrointestinal Disorders, Leuven University, Herestraat 49 bus 701, Leuven 3000, Belgium; mira.wouters{at}


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.

Design 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.


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