583 GpBAR1 Genotype Predicts Bowel Function and Pathophysiology in Diarrhea-Predominant Irritable Bowel Syndrome

Abstract

Background: Genetic predisposition in irritable bowel syndrome (IBS) is supported by prior association studies (Camilleri et al AJP 302:G1075-G1084, 2012). To date, no single genetic predisposition has been convincingly associated with symptoms and relevant quantitative traits in IBS. Aim: To identify candidate genes predisposing to symptoms, colonic transit, bile acid disturbances, and epithelial permeability in IBS.Methods:We assessed associations of variations in candidate genes controlling bile acid (BA) metabolism (KLB and FGFR4), BA receptor GPBAR1 (or TGR5), serotonin reuptake (5HTTLPR) or immune activation (TNFSF15) with bowel function, BA synthesis and total fecal BA, colonic transit (CT) and intestinal permeability (IP) in 30 healthy volunteers (HV), 30 patients with IBS-C (constipation) and 64 with IBS-D (diarrhea) (by Rome III criteria). Colonic tone and sensation were also measured by barostat in 48 IBS-D patients. Primary endpoints assessed in all participants were: fasting serum C4 (screen for hepatic BA synthesis rate), total fecal BA and fat excretion (per 48h on 100g fat diet), overall CT by scintigraphy (geometric center, GC) at 24h and 48h, intestinal and colonic permeability by urine mannitol excretion at 0-2h and 8-24h following 2-sugar ingestion test. Candidate genotype analysis of blood DNA was conducted using PCR-based methods: rs4795541 (5HTTLPR); rs351855 (FGFR4); rs17618244 (KLB); rs11554825 (GPBAR1); rs4263839 (TNFSF15). Bowel functions, C4, total and individual fecal BA, CT, colonic sensation, and IP were compared in IBS-C, IBS-D and HV. We used Spearman correlation to explore relationships of total fecal BA with CT and IP. The univariate associations of each genotype were assessed in the total set of participants by the KruskalWallis test (2 degrees of freedom general genetic model). Results: There were expected differences in IBS-C, IBS-D and HV groups in number of BMs, stool consistency and ease of passage, CT (GC48h), IP, fecal fat, serum FGF19 and C4, and total fecal BA (table). There were significant associations between total fecal BA and CT GC48 (r=0.43; p<0.001) and IP (r=0.23; p=0.015). There were significant (p<0.05) univariate associations between: a) GPBAR1 and symptom phenotype, gas sensation ratings, total fecal BA excretion, and CT GC48h. There were weaker associations of GPBAR1 variation with BM frequency and gas sensation threshold (both p<0.1); b) 5HTTLPR and stool consistency and ease of passage, postprandial colonic tone, and total fecal BA excretion; c) FGFR4 and IBS symptom phenotype, postprandial colonic tone, pain sensation threshold and serum FGF19 (p=0.06). Variations in TNFSF15 and KLB were not associated with any traits. Conclusion: Genetic control of 5HT reuptake and GPBAR1 receptor predisposes to symptoms and key pathophysiological mechanisms in IBS. Support: NIH DK92179