title: Pharmacogenetics of the effects of colesevelam on colonic transit in irritable bowel syndrome with diarrhea.
abstract: BACKGROUND
  Protein products of klothoβ (KLB) and fibroblast growth factor receptor 4 (FGFR4) impact fibroblast growth factor 19-mediated feedback inhibition of hepatic bile acid (BA) synthesis. Variants of KLB and FGFR4 influence colonic transit (CT) in diarrhea-predominant irritable bowel syndrome (IBS-D).
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that colesevelam's slowing effects on CT in IBS-D patients is influenced by genetic variants in KLB and FGFR4.
  
  
  METHODS
  We examined pharmacogenetic effects of KLB and FGFR4 coding variants (SNPs) on scintigraphic CT response to the BA sequestrant, colesevelam 1.875 g b.i.d. versus placebo (PLA) for 14 days in 24 female IBS-D patients.
  
  
  RESULTS
  FGFR4 rs351855 and KLB rs497501 were associated with differential colesevelam effects on ascending colon (AC) half-emptying time (t(1/2), P = 0.046 and P = 0.085 respectively) and on overall CT at 24 h (geometric center, GC24: P = 0.073 and P = 0.042, respectively), with slower transit for rs351855 GA/AA (but not for GG) and rs497501 CA/AA (but not CC) genotypes.
  
  
  CONCLUSIONS
  FGFR4 rs351855 and KLB rs4975017 SNPs may identify a subset of IBS-D patients with beneficial response to colesevelam.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Charlton 8-110, 200 First Street S.W., Rochester, MN 55905, USA.
authors.forename: Banny S
authors.initials: BS
authors.lastname: Wong
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Carlson
authors.forename: Suwebatu
authors.initials: S
authors.lastname: Odunsi-Shiyanbade
authors.forename: Sanna
authors.initials: S
authors.lastname: McKinzie
authors.forename: Irene
authors.initials: I
authors.lastname: Busciglio
authors.forename: Duane
authors.initials: D
authors.lastname: Burton
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D000328:Adult; D000499:Allylamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000235:genetics; D001711:Biotransformation; D000069472:Colesevelam Hydrochloride; D003106:Colon / Q000378:metabolism / Q000503:physiopathology; D003967:Diarrhea / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005772:Gastrointestinal Transit / Q000235:genetics*; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*
chemical_list: D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; C117476:FGF19 protein, human; C538995:KLB protein, human; D008565:Membrane Proteins; D000499:Allylamine; D005346:Fibroblast Growth Factors; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000090265:Klotho Proteins; D000069472:Colesevelam Hydrochloride