Irritable bowel syndrome (IBS) affects 10% of US adults and is associated with significant impairment in quality of life. Despite decades of research, there is no consensus on its pathophysiology and no consistently effective treatment. Genetic studies have yielded inconsistent findings. Our hypothesis is that this has occurred because IBS is not a unitary disorder but a group of different disorders with distinct etiologies, which require different treatments. Our previous grant supported this heterogeneity hypothesis: we tested more than 50 physiological and psychological variables in 267 IBS patients and identified 4 independent clusters: constipation- predominant (IBS-C), diarrhea-predominant (IBS-D), pain-hypersensitive (IBS-Pn), and psychologically distressed (IBS-Psy).
The aims of this proposal are to (1) identify genetic polymorphisms associated with these 4 IBS phenotypes;(2) develop, for each phenotype, an etiologic model that includes gene-environment and gene-gene interactions;and (3) test and refine these models using structural equation modeling. Associations between each IBS phenotype and genetic polymorphisms will be assessed using a Pain Panel consisting of 350 selected genes (3200 SNPs) gleaned from a systematic literature review. Associations will be considered significant only if confirmed in two independent cohorts of 225-300 IBS patients and 200-225 healthy controls. As an example of the types of models we will construct, we hypothesize for the IBS-Pn phenotype, genes regulating inflammation (e.g. MAP2K1) and genes regulating pain sensitivity more directly (e.g., GABRG2) interact to influence vulnerability to IBS-Pn, and we hypothesize that inflammatory genes may require the environmental trigger of bacterial gastroenteritis for expression while genes related to pain sensitivity may be modulated by childhood social learning through modeling and reinforcement of illness behavior. We will also test the stability of IBS phenotypes by (1) retesting 50 IBS patients with the full phenotyping protocol 6 months after initial testing and (2) surveying all subjects annually to discover changes in symptoms and diagnoses. Data acquired in this study will augment our database of IBS patients and healthy controls, which contains biological specimens (DNA, serum, some biopsies) as well as clinical and physiological data stored for future studies. This translational study entails multidisciplinary collaboration between experienced teams of pain geneticists, gastroenterologists, and psychologists.
PROJECT NARRATIVE The irritable bowel syndrome (IBS) affects 10% of the population and results in $8 billion dollars in annual health care costs, but there is no consensus on its pathophysiology or treatment. The hypothesis of our research is that IBS is not one disorder but a group of disorders with different etiologies, for which different treatments will be appropriate. Identifying these different phenotypes of IBS and the genetic markers associated with them may help to identify new targets for drug development and may help us to individualize treatment and thereby make it more successful.
|Bennet, S M P; Palsson, O; Whitehead, W E et al. (2018) Systemic cytokines are elevated in a subset of patients with irritable bowel syndrome but largely unrelated to symptom characteristics. Neurogastroenterol Motil 30:e13378|
|Aziz, Imran; Palsson, Olafur S; Törnblom, Hans et al. (2018) Epidemiology, clinical characteristics, and associations for symptom-based Rome IV functional dyspepsia in adults in the USA, Canada, and the UK: a cross-sectional population-based study. Lancet Gastroenterol Hepatol 3:252-262|
|Simrén, Magnus; Törnblom, Hans; Palsson, Olafur S et al. (2017) Management of the multiple symptoms of irritable bowel syndrome. Lancet Gastroenterol Hepatol 2:112-122|
|Simrén, M; Palsson, O S; Heymen, S et al. (2017) Fecal incontinence in irritable bowel syndrome: Prevalence and associated factors in Swedish and American patients. Neurogastroenterol Motil 29:|
|van Tilburg, Miranda A L; Levy, Rona L; Walker, Lynn S et al. (2015) Psychosocial mechanisms for the transmission of somatic symptoms from parents to children. World J Gastroenterol 21:5532-41|
|Kanazawa, M; Palsson, O S; van Tilburg, M A L et al. (2014) Motility response to colonic distention is increased in postinfectious irritable bowel syndrome (PI-IBS). Neurogastroenterol Motil 26:696-704|
|Chiarioni, Giuseppe; Kim, Sung Min; Vantini, Italo et al. (2014) Validation of the balloon evacuation test: reproducibility and agreement with findings from anorectal manometry and electromyography. Clin Gastroenterol Hepatol 12:2049-54|
|van Tilburg, Miranda A L; Zaki, Essam A; Venkatesan, Thangam et al. (2014) Irritable bowel syndrome may be associated with maternal inheritance and mitochondrial DNA control region sequence variants. Dig Dis Sci 59:1392-7|
|van Tilburg, Miranda A L; Fortunato, John E; Squires, Megan et al. (2014) Impact of eating restriction on gastrointestinal motility in adolescents with IBS. J Pediatr Gastroenterol Nutr 58:491-4|
|Chiarioni, Giuseppe; Palsson, Olafur S; Asteria, Corrado R et al. (2013) Neuromodulation for fecal incontinence: an effective surgical intervention. World J Gastroenterol 19:7048-54|
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