Association of TNFSF15 polymorphism with irritable bowel syndrome
- Marco Zucchelli1,
- Michael Camilleri2,
- Anna Nixon Andreasson3,4,
- Francesca Bresso5,
- Aldona Dlugosz5,
- Jonas Halfvarson6,
- Leif Törkvist7,
- Peter T Schmidt5,
- Pontus Karling8,
- Bodil Ohlsson9,
- Richard H Duerr10,11,
- Magnus Simren12,
- Greger Lindberg5,
- Lars Agreus3,
- Paula Carlson2,
- Alan R Zinsmeister2,
- Mauro D'Amato1
- 1Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- 2Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA
- 3Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- 4Stress Research Institute, Stockholm University, Stockholm, Sweden
- 5Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- 6Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden
- 7Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- 8Department of Medicine, Umeå University, Umeå, Sweden
- 9Department of Clinical Sciences, Skånes University Hospital, Malmoe, Sweden
- 10Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- 11Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- 12Department of Internal Medicine, Gothenburg University, Gothenburg, Sweden
- Correspondence to Mauro D'Amato, Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovag 7–9, 14183, Stockholm, Sweden;
- Revised 20 April 2011
- Accepted 28 April 2011
- Published Online First 2 June 2011
Background Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder, affecting more than 10% of the general population worldwide. Although a genetic component is suspected, unambiguous susceptibility genes have so far not been identified. This study tested the hypothesis that genes contributing to epithelial barrier integrity, control of mucosal immune responses and interactions with bacteria in the gut are associated with IBS.
Methods Single nucleotide polymorphisms (SNPs) corresponding to top signals of association with Crohn's disease at 30 known susceptibility loci were tested for their effect on IBS risk in 1992 individuals from two independent case–control cohorts from Sweden and the USA. Association tests included a conservative Bonferroni correction for multiple comparisons, and were also performed on specific subgroups of patients characterised by constipation (IBS-C), diarrhoea (IBS-D) or alternating constipation and diarrhoea (IBS-A).
Results The Crohn's disease risk allele rs4263839 G in the TNFSF15 gene was significantly associated with an increased risk of both IBS (p=2.2×10−5; OR 1.37) and more pronouncedly, IBS-C (p=8.7×10−7; OR 1.79) in the entire sample. Similar associations and risk effects of the same magnitude were observed in the two cohorts analysed separately. A correlation between rs4263839 genotype and TNFSF15 mRNA expression was detected both in peripheral blood and in rectal mucosal biopsies from healthy individuals (combined p=0.0033).
Conclusions TNFSF15 is a susceptibility gene for IBS and IBS constipation. As TL1A, the protein encoded by TNFSF15, contributes to the modulation of inflammatory responses, the results support a role of immune activation in IBS.
The first two authors contributed equally to this work.
Funding Supported by grants from the Swedish Research Council and the Prof Nanna Svartz Fond to MD. MC's research in IBS is supported by NIH grants R01-DK079866 and 1RC1-DK086182.
Competing interests None.
Patient consent Obtained.
Ethics approval The study was approved by the responsible local ethics committees at Swedish clinics and the Mayo Clinic Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.