Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα
- Caroline Swan1,
- Nathalie P Duroudier1,
- Eugene Campbell2,
- Abed Zaitoun3,
- Margaret Hastings4,
- George E Dukes5,
- Joanne Cox5,
- Fiona M Kelly5,
- Jonathan Wilde5,
- Mark G Lennon5,
- Keith R Neal6,
- Peter J Whorwell4,
- Ian P Hall1,
- Robin C Spiller2
- 1Division of Therapeutics and Molecular Medicine, University of Nottingham, Nottingham, UK
- 2NIHR Biomedical Research Unit, Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
- 3Department of Histopathology, Nottingham University Hospitals, Nottingham, UK
- 4Department of Gastroenterology, University of South Manchester, Wythenshawe Hospital, Manchester UK
- 5GSK Research and Development Ltd, GlaxoSmithKline, Harlow, UK
- 6Department of Public Health Medicine and Epidemiology, University of Nottingham, Nottingham, UK
- Correspondence to Professor Robin C Spiller, NIHR Biomedical Research Unit, Nottingham Digestive Diseases Centre, University of Nottingham, University Hospital Nottingham, Queens Medical Centre, E Floor West Block, NG7 2UH, UK;
Contributors Conception, design and overall supervision of study: RS, GD, PW and IH. Collection of samples: EC and MH. Experimental design, analysis of samples and genotyping data: CS and ND supervised by IH. Affymetrix array and Taqman analysis: JW, FMK and JIW, Write up: All authors.
- Revised 31 March 2012
- Accepted 2 April 2012
- Published Online First 8 June 2012
Objectives The postinfectious irritable bowel syndrome (PI-IBS) suggests that impaired resolution of inflammation could cause IBS symptoms. The authors hypothesised that polymorphisms in genes whose expression were altered by gastroenteritis might be linked to IBS with diarrhoea (IBS-D) which closely resembles PI-IBS.
Design Part 1: 25 healthy volunteers (HVs), 21 patients 6 months after Campylobacter jejuni infection, 37 IBS-D and 19 IBS with constipation (IBS-C) underwent rectal biopsy for gene expression analysis and peripheral blood mononuclear cell cytokine production assessment. Part 2: Polymorphisms in genes whose expression was altered in Part 1 were assessed in 179 HV, 179 IBS-D, 122 IBS-C and 41 PI-IBS.
Results Part 1: Mucosal expression of seven genes was altered in IBS: CCL11, CCL13, Calpain 8 and TNFSF15 increased while NR1D1, GPR161 and GABRE decreased with similar patterns after infection with C jejuni. Part 2: The authors assessed 21 known single nucleotide polymorphisms (SNPs) in these seven genes and one SNP in each of the TNFα and IL-10 genes. Three out of five TNFSF15 SNPs (rs6478108, rs6478109 and rs7848647) showed reduced minor allele frequency (MAF) (0.28, 0.27 and 0.27) in subjects with IBS-D compared with HV (0.38, 0.36 and 0.37; p=0.007, 0.015 and 0.007, respectively) confirming others recent findings. The authors also replicated the previously reported association of the TNFα SNP rs1800629 with PI-IBS which showed an increase in the MAF at 0.30 versus 0.19 for HV (p=0.04).
Conclusion IBS-D and PI-IBS patients are associated with TNFSF15 and TNFα genetic polymorphisms which also predispose to Crohn's disease suggesting possible common underlying pathogenesis.
- Inflammatory bowel syndrome
- coeliac disease
- functional bowel disorder
- diverticular disease
- gastrointestinal motility
CS and ND contributed equally to the manuscript.
Funding Educational grant from GlaxoSmithKline, grant number: GRGC Ref No: 00474.
Competing interests The study was an investigator-initiated study funded by GlaxoSmithKline who supported the project both financially and by performing the array analyses and confirmatory PCR analyses on the rectal biopsies. All subjects received this information prior to study entry. The genetic analyses and write up was performed by the investigators independent of the funder. The Nottingham Biomedical Research Unit is supported by a grant from the National Institute for Health Research. No other conflicts of interest.
Ethics approval Approval provided by theNottingham NHS Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We have uploaded the Affymatrix data to a public access database GEO, accession number (GSE36701) which will be available to all from October 2012.