Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 Oct 1.
Published in final edited form as: Dig Dis Sci. 2012 Oct;57(10):2484–2486. doi: 10.1007/s10620-012-2370-6

New Paradigm for Studying Genetic Contributions to Irritable Bowel Syndrome

Miranda AL van Tilburg 1, William E Whitehead 1
PMCID: PMC3468322  NIHMSID: NIHMS406156  PMID: 22926498

Irritable Bowel Syndrome (IBS) is common disabling condition that is associated with an estimated $8 billion per year in direct health care costs1. In the past few decades multiple studies have been published on the etiology of IBS, and several pathophysiological factors have been found to be significantly associated with IBS diagnosis; these factors include motility disturbances, visceral hypersensitivity, psychological distress, and immune dysregulation. However, none of these factors is sufficient by itself to explain the development of IBS. Therefore, it is widely believed that IBS is not caused by a single factor but rather the interaction of various biological, psychological and social factors which interact to contribute to the etiology and maintenance of the disorder2. No single factor appears to be necessary for disease expression and none may be sufficient in isolation from the others.

Considering this complex model of the causes of IBS, it is no surprise that genetic factors in IBS generally are not expected to follow a Mendelian inheritance pattern in which the disease is caused by a single gene3-5. Rather it is thought that IBS is a complex genetic disorder with genes affecting the various etiological factors described above. It is, therefore, reasonable to expect that this complex model of IBS involving interactions between physiological vulnerabilities and psychosocial stressors will be matched at the molecular level by gene-gene and gene-environment interactions. The study by Saito and colleagues6 in this issue is significant because it demonstrates that taking these interactions into account can unmask genetic contributions to IBS etiology where simple genetic association studies failed to show an effect. This is the second study to show that a genetic polymorphism interacts with exposure to infectious gastroenteritis to contribute to the expression of post-infectious IBS; the first was the study by Villani and colleagues7 which found that polymorphisms in Toll like receptor 9, Interleukin-6 and CDH1were associated with an increased likelihood reporting persistent gastrointestinal symptoms following exposure to a water-borne outbreak of gastroenteritis. These polymorphisms were not found to be associated with IBS developing in the absence of gastroenteritis8. These two studies likely herald a turning point in the evolution of studies on the genetic contributions to IBS and other complex diseases. This paradigm shift offers the promise of more precise estimates of disease prediction, greater insights into gene function, and, by suggesting how to ameliorate the impact of genetic risk, it offers the potential of greater clinical impact.

The article by Saito and colleagues also points out the challenges in carrying out investigations of gene-environment interactions: such studies need to be hypothesis driven because the possible permutations of genetic polymorphisms and environmental exposures are nearly infinite. Several candidate gene studies have been associated with IBS3-5. These include, among others, serotonin receptor and transporter genes9-17, adrenoreceptor genes18-22, and genes in the inflammatory pathway7, 8, 23-25. In addition, multiple environmental factors have been shown to play a role in IBS such as an affluent childhood, early infant trauma (e.g., gastric suction at birth, low birth weight and sever nutritional deficits), sexual or physical abuse history, life stress, military deployment, social learning and gastroenteritis26-31. Gene studies should carefully explore the interactions of these environmental effects and polymorphisms in IBS. In identifying an a-prior hypothesis, a clear rationale is needed linking the gene's presumed function to one of the endophenotypes believed to explain the symptoms of IBS (e.g., pain hypersensitivity, stress reactivity, immune dysregulation), and an environmental exposure that is already known to be associated with this endophenotype. In the Saito study the authors focused on a possible association between 5HTTLPR and a history of abuse based on previous evidence that this polymorphism is linked to the development of psychiatric disorders in the presence of an abuse history32, but they did not find support for this gene-environment interaction in IBS. They based their second hypothesis of an interaction between GNbeta3 polymorphism and a history of gastroenteritis on previous evidence that GNbeta3 is involved in immune regulation, and their hypothesis was supported. However, there are other genetic markers more closely associated with impaired immune function in IBS such as IL1023 which might have been more logical than GNbeta3 to test for their interaction with prior gastroenteritis. The authors do not explain their preference for GNbeta3 over these other genes.

Other well-known limitations to IBS genetic association studies also apply to studies of gene-environment interactions: (1) The IBS phenotype is imprecise because it is based on symptoms ascertained by self-report and a negative medical work-up, which may lead to heterogeneity in the samples studied. (2) Validated, objective measures of environmental exposures and prospective research designs are preferable to chart reviews and retrospective self-report to protect against measurement error. With these limitations in mind, replication of findings by independent investigators will continue to be necessary to move this field forward.

Thus, for IBS multiple genes likely contribute in an additive or synergistic fashion and critical environmental exposures interact with these genetic risk factors to trigger expression of the disease phenotype only if the environmental exposure is present. So far up to 60 candidate genes have been identified in IBS33 although few have been independently replicated, and we are at an exciting cross roads where complex models including genes, endophenotypes and environmental factors may start elucidating important pathways for this enigmatic disorder. For example, the 5HTTLPR (gene) has been associated with higher rectal pain ratings34, anxiety and depression35 in IBS patients (endophenotype), and interacts with stressful life events in the expression of major depression (a possible environmental factor)36. Studies combing these factors into one model are greatly needed to unravel the mystery of IBS etiology and develop more personalized treatment models.

Acknowledgment

Supported in part by grant R01 DK031369 from NIDDK and P01 NS045685 from NINDS.

References

  • 1.Talley NJ, Gabriel SE, Harmsen WS, et al. Medical costs in community subjects with irritable bowel syndrome. Gastroenterology. 1995;109:1736–1741. doi: 10.1016/0016-5085(95)90738-6. [DOI] [PubMed] [Google Scholar]
  • 2.Drossman DA. Presidential address: Gastrointestinal illness and the biopsychosocial model. Psychosomatic Medicine. 1998;60:258–267. doi: 10.1097/00006842-199805000-00007. [DOI] [PubMed] [Google Scholar]
  • 3.Saito YA, Mitra N, Mayer EA. Genetic approaches to functional gastrointestinal disorders. Gastroenterology. 2010;138:1276–1285. doi: 10.1053/j.gastro.2010.02.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Fukudo S, Kanazawa M. Gene, environment, and brain-gut interactions in irritable bowel syndrome. J Gastroenterol Hepatol. 2011;26(Suppl 3):110–5. doi: 10.1111/j.1440-1746.2011.06631.x. [DOI] [PubMed] [Google Scholar]
  • 5.Camilleri M, Katzka DA. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1075–84. doi: 10.1152/ajpgi.00537.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Saito YA, Larson JJ, Atkinson EJ, et al. The role of 5-HTT LPR and GNbeta3 825C>T polymorphisms and gene-environment interactions in irritable bowel syndrome. Digestive Diseases and Sciences. 2012 doi: 10.1007/s10620-012-2319-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Villani AC, Lemire M, Thabane M, et al. Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis. Gastroenterology. 2010;138:1502–1513. doi: 10.1053/j.gastro.2009.12.049. [DOI] [PubMed] [Google Scholar]
  • 8.Villani AC, Saito YA, Lemire M. Validation of genetic risk factors for post-infectious irritable bowel syndrome (IBS) in patients with sporadic IBS. Gastroenterology. 2009;136:289. [Google Scholar]
  • 9.Pata C, Erdal ME, Derici E, et al. Serotonin transporter gene polymorphism in irritable bowel syndrome. Am.J.Gastroenterol. 2002;97:1780–1784. doi: 10.1111/j.1572-0241.2002.05841.x. [DOI] [PubMed] [Google Scholar]
  • 10.Camilleri M, Atanasova E, Carlson PJ, et al. Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2002;123:425–432. doi: 10.1053/gast.2002.34780. [DOI] [PubMed] [Google Scholar]
  • 11.Yeo A, Boyd P, Lumsden S, et al. Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women. GUT. 2004;53:1452–1458. doi: 10.1136/gut.2003.035451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Li Y, Nie Y, Xie J, et al. The association of serotonin transporter genetic polymorphisms and irritable bowel syndrome and its influence on tegaserod treatment in Chinese patients. Dig.Dis.Sci. 2007;52:2942–2949. doi: 10.1007/s10620-006-9679-y. [DOI] [PubMed] [Google Scholar]
  • 13.Sikander A, Rana SV, Prasad KK. Role of serotonin in gastrointestinal motility and irritable bowel syndrome. Clin Chim Acta. 2009;403:47–55. doi: 10.1016/j.cca.2009.01.028. [DOI] [PubMed] [Google Scholar]
  • 14.Niesler B, Kapeller J, Fell C, et al. 5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene and irritable bowel syndrome: effect of bowel habit and sex. Eur J Gastroenterol Hepatol. 2010;22:856–61. doi: 10.1097/MEG.0b013e32832e9d6b. [DOI] [PubMed] [Google Scholar]
  • 15.Jarrett ME, Kohen R, Cain KC, et al. Relationship of SERT polymorphisms to depressive and anxiety symptoms in irritable bowel syndrome. Biol Res Nurs. 2007;9:161–9. doi: 10.1177/1099800407307822. [DOI] [PubMed] [Google Scholar]
  • 16.Pata C, Erdal E, Yazc K, et al. Association of the -1438 G/A and 102 T/C polymorphism of the 5-Ht2A receptor gene with irritable bowel syndrome 5-Ht2A gene polymorphism in irritable bowel syndrome. J.Clin.Gastroenterol. 2004;38:561–566. doi: 10.1097/00004836-200408000-00005. [DOI] [PubMed] [Google Scholar]
  • 17.Markoutsaki T, Karantanos T, Gazouli M, et al. 5-HT2A receptor gene polymorphisms and irritable bowel syndrome. J Clin Gastroenterol. 2011;45:514–7. doi: 10.1097/MCG.0b013e318205e13b. [DOI] [PubMed] [Google Scholar]
  • 18.Kim HJ, Camilleri M, Carlson PJ, et al. Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders. GUT. 2004;53:829–837. doi: 10.1136/gut.2003.030882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Holtmann G, Siffert W, Haag S, et al. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology. 2004;126:971–979. doi: 10.1053/j.gastro.2004.01.006. [DOI] [PubMed] [Google Scholar]
  • 20.Grudell AB, Camilleri M, Carlson P, et al. An exploratory study of the association of adrenergic and serotonergic genotype and gastrointestinal motor functions. Neurogastroenterol Motil. 2008;20:213–9. doi: 10.1111/j.1365-2982.2007.01026.x. [DOI] [PubMed] [Google Scholar]
  • 21.Sikander A, Rana SV, Sharma SK, et al. Association of alpha 2A adrenergic receptor gene (ADRAlpha2A) polymorphism with irritable bowel syndrome, microscopic and ulcerative colitis. Clin Chim Acta. 2010;411:59–63. doi: 10.1016/j.cca.2009.10.003. [DOI] [PubMed] [Google Scholar]
  • 22.Onodera S, Chiba T, Sugai T, et al. A genetic association between ss3-aderenoceptor and cholinergic receptor muscarinic 3 polymorphisms in irritable bowel syndrome. Hepatogastroenterology. 2011;58:1474–8. doi: 10.5754/hge10153. [DOI] [PubMed] [Google Scholar]
  • 23.Gonsalkorale WM, Perrey C, Pravica V, et al. Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? GUT. 2003;52:91–93. doi: 10.1136/gut.52.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.van der Veek PJ, van den Berg M, de Kroon YE, et al. Role of tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome. Am.J.Gastroenterol. 2005;100:2510–2516. doi: 10.1111/j.1572-0241.2005.00257.x. [DOI] [PubMed] [Google Scholar]
  • 25.Zucchelli M, Camilleri M, Andreasson AN, et al. Association of TNFSF15 polymorphism with irritable bowel syndrome. GUT. 2011;60:1671–7. doi: 10.1136/gut.2011.241877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Chitkara DK, van Tilburg MA, Blois-Martin N, et al. Early life risk factors that contribute to irritable bowel syndrome in adults: a systematic review. Am.J Gastroenterol. 2008;103:765–774. doi: 10.1111/j.1572-0241.2007.01722.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Klooker TK, Braak B, Painter RC, et al. Exposure to severe wartime conditions in early life is associated with an increased risk of irritable bowel syndrome: a population-based cohort study. Am J Gastroenterol. 2009;104:2250–6. doi: 10.1038/ajg.2009.282. [DOI] [PubMed] [Google Scholar]
  • 28.Gray GC, Reed RJ, Kaiser KS, et al. Self-reported symptoms and medical conditions among 11,868 Gulf War-era veterans: the Seabee Health Study. Am J Epidemiol. 2002;155:1033–44. doi: 10.1093/aje/155.11.1033. [DOI] [PubMed] [Google Scholar]
  • 29.Leserman J, Drossman DA. Relationship of abuse history to functional gastrointestinal disorders and symptoms: some possible mediating mechanisms. Trauma Violence Abuse. 2007;8:331–43. doi: 10.1177/1524838007303240. [DOI] [PubMed] [Google Scholar]
  • 30.Levy RL, Langer SL, Whitehead WE. Social learning contributions to the etiology and treatment of functional abdominal pain and inflammatory bowel disease in children and adults. World J.Gastroenterol. 2007;13:2397–2403. doi: 10.3748/wjg.v13.i17.2397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Spiller R, Garsed K. Infection, inflammation, and the irritable bowel syndrome. Dig.Liver Dis. 2009;41:844–849. doi: 10.1016/j.dld.2009.07.007. [DOI] [PubMed] [Google Scholar]
  • 32.Brown GW, Harris TO. Depression and the serotonin transporter 5-HTTLPR polymorphism: a review and a hypothesis concerning gene-environment interaction. J Affect Disord. 2008;111:1–12. doi: 10.1016/j.jad.2008.04.009. [DOI] [PubMed] [Google Scholar]
  • 33.Saito YA. The role of genetics in IBS. Gastroenterol Clin North Am. 2011;40:45–67. doi: 10.1016/j.gtc.2010.12.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Camilleri M, Busciglio I, Carlson P, et al. Candidate genes and sensory functions in health and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2008;295:G219–25. doi: 10.1152/ajpgi.90202.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Mizuno T, Aoki M, Shimada Y, et al. Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety. J Psychosom Res. 2006;60:91–7. doi: 10.1016/j.jpsychores.2005.06.068. [DOI] [PubMed] [Google Scholar]
  • 36.Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–9. doi: 10.1126/science.1083968. [DOI] [PubMed] [Google Scholar]

RESOURCES