Irritable Bowel Syndrome (IBS) is a gastrointestinal (GI) disorder characterized by abdominal pain and alterations in bowel pattern (e.g., diarrhea, constipation, or both) affecting 10-15% of adults and children throughout the world with annual US financial costs estimated at $6 billion dollars (adult IBS alone). IBS is challenging to patient and clinicians in that the mechanism(s) accounting for symptoms are not well understood and treatments are not consistently effective. In some individuals diet seems to play a role. Malabsorption of dietary carbohydrates (CHOs) can cause abdominal pain, flatulence, bloating, and diarrhea - symptoms which very closely mimic those of IBS. There is evidence that milder forms of congenital sucrase- isomaltase deficiency or amylase deficiency may exist in some patients with IBS resulting in sucrose or starch maldigestion. Deficiency of these or other CHO digesting enzymes could cause IBS-like symptoms in an otherwise healthy individual or exacerbate symptoms in existent IBS. Identifying the presence of enzyme deficiencies leading to CHO malabsorption would dramatically change the management of patients previously diagnosed with IBS by providing an identifiable and treatable etiology for GI symptoms in a subset of patients. Therefore, we propose the following Specific Aims: Using previously banked DNA samples from carefully phenotyped adults/children with IBS (n=805; diarrhea predominant, constipation predominant, mixed type, and unsubtyped) and healthy adult/child Controls (n=560) without GI disease all of whom completed prospective pain and stool diaries: 1) Compare the frequency of variants in the sucrase-isomaltase, maltase-glucoamylase, lactase-phlorizin hydrolase, and pancreatic amylase genes in patients with IBS versus healthy Controls. Hypothesis: Coding and regulatory sequence variants of intestinal CHO digestive enzymes are more frequent in those with IBS. 2) Determine the possible relationship between genetic variability and IBS clinical phenotype (pain frequency/severity, stooling characteristics). Hypothesis: Variants in the genes encoding sucrase- isomaltase, maltase-glucoamylase, lactase-phlorizin hydrolase, and pancreatic amylase are associated with a greater frequency of abdominal pain symptoms and increased stooling frequency in those with IBS. Results from this innovative exploratory study are likely to break new ground in identifying the pathogenesis of abdominal and bowel symptoms in adults and children with IBS. A particular strength of the proposal is the existing set of DNA samples and prospectively collected symptom data. The novel finding of patients with CHO digesting enzyme deficiency would alter dramatically the approach to diagnosis, management, and treatment as well as selection of IBS patients into clinical studies. The multidisciplinary/multisite nature of this proposal and its use of adult and pediatric patients further enhance its applicability and potential biomedical impact. This proposal fits with the goals of PA-12-139 (R21) to undertake short term preliminary clinical studies to facilitate translation into clinical practice and improve patient outcomes with IBS being a particular focus.

R21DK099643

2014-08-01

2017-07-31