title: Genetic variation in GPBAR1 predisposes to quantitative changes in colonic transit and bile acid excretion.
abstract: The pathobiology of irritable bowel syndrome (IBS) is multifaceted. We aimed to identify candidate genes predisposing to quantitative traits in IBS. In 30 healthy volunteers, 30 IBS-constipation, and 64 IBS-diarrhea patients, we measured bowel symptoms, bile acid (BA) synthesis (serum 7α-hydroxy-4-cholesten-3-one and FGF19), fecal BA and fat, colonic transit (CT by scintigraphy), and intestinal permeability (IP by 2-sugar excretion). We assessed associations of candidate genes controlling BA metabolism (KLB rs17618244 and FGFR4 rs351855), BA receptor (GPBAR1 rs11554825), serotonin (5-HT) reuptake (SLC6A4 through rs4795541 which encodes for the 44-bp insert in 5HTTLPR), or immune activation (TNFSF15 rs4263839) with three primary quantitative traits of interest: colonic transit, BA synthesis, and fecal BA excretion. There were significant associations between fecal BA and CT at 48 h (r = 0.43; P < 0.001) and IP (r = 0.23; P = 0.015). GPBAR1 genotype was associated with CT48 (P = 0.003) and total fecal BA [P = 0.030, false detection rate (FDR) P = 0.033]. Faster CT48 observed with both CC and TT GPBAR1 genotypes was due to significant interaction with G allele of KLB, which increases BA synthesis and excretion. Other univariate associations (P < 0.05, without FDR correction) observed between GPBAR1 and symptom phenotype and gas sensation ratings support the role of GPBAR1 receptor. Associations between SLC6A4 and stool consistency, ease of passage, postprandial colonic tone, and total fecal BA excretion provide data in support of future hypothesis-testing studies. Genetic control of GPBAR1 receptor predisposing to pathobiological mechanisms in IBS provides evidence from humans in support of the importance of GPBAR1 to colonic motor and secretory functions demonstrated in animal studies.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota; camilleri.michael@mayo.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota;
authors.forename: Andrea
authors.initials: A
authors.lastname: Shin
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota;
authors.forename: Irene
authors.initials: I
authors.lastname: Busciglio
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota;
authors.forename: Paula
authors.initials: P
authors.lastname: Carlson
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota;
authors.forename: Andres
authors.initials: A
authors.lastname: Acosta
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota;
authors.forename: Adil E
authors.initials: AE
authors.lastname: Bharucha
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota;
authors.forename: Duane
authors.initials: D
authors.lastname: Burton
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota;
authors.forename: Jesse
authors.initials: J
authors.lastname: Lamsam
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota; and.
authors.forename: Alan
authors.initials: A
authors.lastname: Lueke
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota; and.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Donato
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D001692:Biological Transport; D016022:Case-Control Studies; D002783:Cholestenones / Q000097:blood; D003106:Colon / Q000378:metabolism* / Q000503:physiopathology; D003248:Constipation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003967:Diarrhea / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005243:Feces / Q000737:chemistry; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood; D005966:Glucuronidase / Q000235:genetics; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000090265:Klotho Proteins; D008055:Lipids / Q000032:analysis; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics
chemical_list: D001647:Bile Acids and Salts; D002783:Cholestenones; C117476:FGF19 protein, human; C473772:GPBAR1 protein, human; D008055:Lipids; D043562:Receptors, G-Protein-Coupled; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; C002656:7 alpha-hydroxy-4-cholesten-3-one; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: bile acid; immune; serotonin; transit