583 GpBAR1 Genotype Predicts Bowel Function and Pathophysiology in Diarrhea- Predominant Irritable Bowel Syndrome Michael Camilleri, Andrea Shin, Irene A. Busciglio, Andres Acosta, Adil E. Bharucha, Paula Carlson, Duane D. Burton, Michael Ryks, Deborah L. Rhoten, Jesse Lamsam, Alan J. Lueke, Leslie Donato, Alan R. Zinsmeister 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 (constipa- tion) 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 Kruskal- Wallis 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 pheno- type, postprandial colonic tone, pain sensation threshold and serum FGF19 (p=0.06). Varia- tions 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 HAD=Hospital Anxiety and Depression; LCA=lithocholic acid; CDCA=chenodeoxycholic acid; DCA=deoxycholic acid; CA=cholic acid; GC units range 0-5 with 0=ileocecal valve, 5=stool; mannitol excretion in urine is cumulative in mg over 0-2 or 8-24h 584 FKBP5 Gene Is Associated With IBS Diagnosis Shad B. Smith, William Maixner, Olafur S. Palsson, Miranda A. Van Tilburg, Motoyori Kanazawa, William E. Whitehead A goal of this study was to identify new genetic markers for irritable bowel syndrome (IBS) by (a) comparing cases to controls and, (b) when candidate SNPs are identified, to test for an association with visceral pain thresholds, bowel habits, and psychological symptoms of anxiety. Methods: Over a 10-year period DNA was collected from 498 adult patients with irritable bowel syndrome (IBS) and 293 healthy controls approximately matched for gender, age, and race. Inclusion criteria for IBS required a physician diagnosis of IBS confirmed by Rome II symptom criteria, negative glucose breath test for small bowel bacterial overgrowth, and absence of structural disease that might explain abdominal pain and altered bowel habits. DNA was extracted from leukocytes and stored at -80°C until ready for analysis. A gene chip (the Algynomics Pain Research Panel version 2, based on Illumina's Infinium iSelect platform) was used to assess 555 candidate genes selected for their involvement in S-109 AGA Abstracts pathways related to pain, inflammation, and mood. Case-control association tests were performed in PLINK v1.07 using logistic regression, with adjustment for race, age, and sex. Association with quantitative traits using linear regression was also performed. Alpha was 1.53e-5 after adjustment for the number of independent tests performed. Results: The 20 strongest hits out of 4456 SNPs tested included 12 SNPs in the FKBP5 gene, 2 of which were significant after Bonferroni correction (odds ratio for minor allele = 0.53 for both; see Figure). No significant associations were found between SNPs in FKBP5 and IBS subtype or the traits of pain sensitivity, anxiety, or altered bowel habits. Conclusions: These findings suggest FKBP5 could play a role in the etiology of IBS. Association of multiple SNPs in the same gene with IBS diagnosis likely represents linkage disequilibrium. The FKBP5 gene encodes the FK506 binding protein, which previous publications suggest plays a role in immune regulation and interacts with glucocorticoid receptors contributing to post-traumatic stress disorder. Further work is needed to confirm that FKBP5 contributes to IBS and to identify the pathways through which it may act. Analyses are in progress to assess gene- environment interactions between FKBP5 and childhood exposure to psychological trauma. [Supported by R01 DK031369] Figure 1. The Q-Q plot compares the observed -log(p-values) of all tested SNPs on the ordinate with the -log(p-values) expected under the null hypothesis of no association on the abscissa. SNPs, represented by dots, that are significantly elevated above the diagonal line are statistically significant associations. 585 Architecture of Anatomical Brain Networks Differs in Irritable Bowel Syndrome Compared to Healthy Controls Jennifer S. Labus, John D. Van Horn, Carinna Torgerson, Arpana Gupta, Cody Ashe- McNalley, Cathy Liu, Bruce D. Naliboff, Kirsten Tillisch, Emeran A. Mayer Introduction. Sex and disease based changes in the architecture of large-scale anatomical brain networks have been reported. One parameter to characterize a network's structural integrity and information flow is the number of regions connected to another region (referred to as "degree"). Regions with high degree are considered essential for facilitating functional integration. Aim. We hypothesized differences in the degree of cortical (prefrontal/orbitofron- tal, insular [INS]) and subcortical (N. Accumbens [N.Acc], amygdala) regions are associated with IBS diagnosis, and its interaction with sex related differences. Methods. Using structural and diffusion tensor imaging, gray and white matter in the brain were measured in 47 healthy control subjects (HCs; 24 F) and 46 IBS (27 F). Each gray matter image was segmented and parcelled into 165 regions based on Destrieux and Harvard-Oxford atlases using Freesurfer and the UCLA Laboratory of Neuroimaging pipeline. Using TrackVis, deterministic tractography measured anatomical (white matter) connectivity between regions.Code from the Brain Connectivity Toolbox was used to calculate degree of each region for each subject. The general linear model was applied to examine the influence of sex, disease and their interaction on the degree of cortical and subcortical regions. Regions showing differences in degree were correlated with the Visceral Sensitivity Index (VSI), a treatment outcome measure of gastrointestinal specific anxiety that has excellent ability to discriminate IBS from HCs. Results. In general, male (M) IBS patients compared to F IBS and M and F HCs had a higher degree of connectivity in subcortical (bilateral amygdala, right N. Acc, subcallosal gyrus), and cortical (anterior insula, and frontal (left inferior orbital frontal gryus, and orbital sulci) regions. In IBS compared to HCs the right inferior part of the precentral sulci was connected to more regions (p=.043), with greatest differences seen between F IBS and F HCs (p=.006). In IBS but not HCs, M compared to F had greater connectivity of the R inferior frontal gyrus (p=.002). Interestingly, significant sex differences were found in HCs but not IBS in anterior and posterior midcingulate, posterior insula, and gyrus rectus. Across all subjects, higher VSI scores were associated with greater degree in the precentral sulci, (r(93)=.25, p=.02), N.Acc.(r(93)=.34, p=.001), inferior orbital frontal gyrus(r(93)=.29, p=.005), and orbital sulci (r(93)=.28, p=.007). Conclusion. Overall, altered brain gut interactions in IBS may be associated with differential organization of white matter tracts that comprise anatomical brain networks, and these organizational changes are sex related. Furthermore, degree of connectivity in reward and orbital frontal regions may provide a neurobiological substrate of self-reported gastrointestinal specific anxiety. AGA Abstracts