Irritable bowel syndrome (IBS) is a common condition with high impact on quality of life, health care costs, and incidence of abdominal or pelvic surgery. Two pathophysiological mechanisms in IBS are heightened visceral sensitivity and/or abnormal motor function. We have previously shown that the adrenergic nervous system is involved in modulating gastrointestinal functions in healthy humans and in IBS. Specifically, in the previous cycle of this grant, we demonstrated that clonidine, an alpha2-adrenergic agonist, relaxes the colon, reduces sensations of gas and pain during distention, without impacting on the normal rate of transit through the entire gut, or inhibiting the effect of meal ingestion on colonic motility. Secondly, we demonstrated that clonidine, 0.1 mg b.i.d., improved bowel dysfunction and provided satisfactory relief of IBS in a subgroup of patients. Subgroups with high vs. no response to clonidine in IBS patients suggest a role for adrenergic genotypes in determining the response in patients. In preliminary studies in Caucasian patients with diarrhea-predominant IBS, we have identified an alpha2c adrenoreceptor NciI polymorphism (located in the region coding for the third intracellular loop of the receptor) with a higher allele frequency (0.33) than in ethnic controls (0.04). Accurate, thorough phenotypic characterization of patients with IBS and their responses to clonidine are essential for pharmacogenomic studies. Our overall objective is to characterize in IBS patients the relationship between the phenotypic response to elonidine and genetic variations in noradrenergic and alpha2-adrenergic control using a candidate gene analysis approach. We hypothesize that: 1) physiological studies of whole gut transit, gastric volume and response to feeding, rectal sensory and motor functions, and cerebral and peripheral sympathetic function will characterize the phenotype of different symptom-based subgroups of IBS patients; 2) patients with sympathetic adrenergic dysfunction are more sensitive to the effects of 0.1mg and 0.15 mg clonidine on physiological measurements of gut function; and 3) polymorphisms of the alpha2A-and alpha2c adrenoreceptor genes or mutations in norepinephrine transporter (NET) protein influence the physiological (motor and sensory) responses to clonidine.
Our first aim i s to characterize whole gut transit, rectal sensory and motor functions, gastric volumes, postprandial abdominal symptoms and central and peripheral adrenergic functions in 120 patients with IBS and 40 controls. Secondly, we aim to study the effects of acute administration of 0.1 or 0.15 mg clonidine (p.o.) on the same gastrointestinal functions in IBS patients and controls.
Our third aim i s to assess the relationship between the responses of physiological sensory and motor gut parameters to clonidine and polymorphisms of the alpha2A-and alpha2c-adrenergic receptors on chromosomes 2 and 10 and mutations in the gone encoding the NET protein.
A fourth aim will assess the feasibility of recruiting African- American IBS patients from other medical centers to obtain preliminary data on symptom phenotype and adrenergic genotype in these patients and their community controls. The significance of this project is that it will provide novel, comprehensive information on the symptom and physiological phenotype of different subgroups of IBS, and characterize the pharmacogenetic mechanisms determining the response to clonidine through studies of candidate genes that control ?2-adrenoreceptor function and norepinephrine transport in IBS.
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