TY - JOUR
T1 - Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome
AU - Wouters, Mira M.
AU - Lambrechts, Diether
AU - Knapp, Michael
AU - Cleynen, Isabelle
AU - Whorwell, Peter
AU - Agréus, Lars
AU - Dlugosz, Aldona
AU - Schmidt, Peter Thelin
AU - Halfvarson, Jonas
AU - Simrén, Magnus
AU - Ohlsson, Bodil
AU - Karling, Pontus
AU - Van Wanrooy, Sander
AU - Mondelaers, Stéphanie
AU - Vermeire, Severine
AU - Lindberg, Greger
AU - Spiller, Robin
AU - Dukes, George
AU - D'Amato, Mauro
AU - Boeckxstaens, Guy
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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); OR validation=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.
AB - 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); OR validation=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.
KW - messenger RNA
KW - protein Cdc42
UR - http://www.scopus.com/inward/record.url?scp=84902264271&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2013-304570
DO - 10.1136/gutjnl-2013-304570
M3 - Article
C2 - 24041540
AN - SCOPUS:84902264271
SN - 0017-5749
VL - 63
SP - 1103
EP - 1111
JO - Gut
JF - Gut
IS - 7
ER -
