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Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome
Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium.
Vesalius Research Center, VIB, Leuven University, Leuven, Belgium; Laboratory for Translational Genetics, Department of Oncology, Leuven University, Leuven, Belgium .
Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany .
Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium .
Vise andre og tillknytning
2014 (engelsk)Inngår i: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 63, nr 7, s. 1103-1111Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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 P-uncorrected<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 (P-uncorrected<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.

sted, utgiver, år, opplag, sider
2014. Vol. 63, nr 7, s. 1103-1111
HSV kategori
Forskningsprogram
Invärtesmedicin
Identifikatorer
URN: urn:nbn:se:oru:diva-36842DOI: 10.1136/gutjnl-2013-304570ISI: 000337917900012PubMedID: 24041540Scopus ID: 2-s2.0-84902264271OAI: oai:DiVA.org:oru-36842DiVA, id: diva2:747644
Forskningsfinansiär
Swedish Research CouncilMarianne and Marcus Wallenberg Foundation
Merknad

Funding Agencies:

Fund for Scientific Research (FWO) Flanders, Belgium G.0699.10N

Flemish government (Odysseus Program, FWO)

Swedish Medical Research Council 13409, 21691, 21692

Danone

AstraZeneca

Tilgjengelig fra: 2014-09-17 Laget: 2014-09-17 Sist oppdatert: 2018-06-09bibliografisk kontrollert

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