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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031369-25
Application #
8322139
Study Section
Behavioral Medicine, Interventions and Outcomes Study Section (BMIO)
Program Officer
Hamilton, Frank A
Project Start
1993-07-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
25
Fiscal Year
2012
Total Cost
$636,259
Indirect Cost
$202,403
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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
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
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
Markland, Alayne D; Palsson, Olafur; Goode, Patricia S et al. (2013) Association of low dietary intake of fiber and liquids with constipation: evidence from the National Health and Nutrition Examination Survey. Am J Gastroenterol 108:796-803
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
van Tilburg, Miranda A L; Palsson, Olafur S; Whitehead, William E (2013) Which psychological factors exacerbate irritable bowel syndrome? Development of a comprehensive model. J Psychosom Res 74:486-92
Robinson, Barbara L; Matthews, Catherine A; Palsson, Olafur S et al. (2013) Obstetric sphincter injury interacts with diarrhea and urgency to increase the risk of fecal incontinence in women with irritable bowel syndrome. Female Pelvic Med Reconstr Surg 19:40-5
Palsson, Olafur S; Whitehead, William E (2013) Psychological treatments in functional gastrointestinal disorders: a primer for the gastroenterologist. Clin Gastroenterol Hepatol 11:208-16; quiz e22-3
Nyrop, Kirsten A; Grover, Madhusudan; Palsson, Olafur S et al. (2012) Likelihood of nursing home referral for fecally incontinent elderly patients is influenced by physician views on nursing home care and outpatient management of fecal incontinence. J Am Med Dir Assoc 13:350-4
Palsson, Olafur S; Baggish, Jeffrey S; Turner, Marsha J et al. (2012) IBS patients show frequent fluctuations between loose/watery and hard/lumpy stools: implications for treatment. Am J Gastroenterol 107:286-95

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