Pharmacogenetics of the Effects of Colesevelam on Colonic Transit in Irritable Bowel Syndrome with Diarrhea

• Published in: Digestive diseases and sciences 2012-05, Vol.57 (5), p.1222-1226
• Main Authors: Wong, Banny S., Camilleri, Michael, Carlson, Paula J., Odunsi-Shiyanbade, Suwebatu, McKinzie, Sanna, Busciglio, Irene, Burton, Duane, Zinsmeister, Alan R.
• Format: Article
• Language: English
• Subjects: Adult; Allylamine - administration & dosage; Allylamine - analogs & derivatives; Allylamine - pharmacokinetics; Amino acids; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - pharmacokinetics; Bile acids; Bile Acids and Salts - biosynthesis; Bile Acids and Salts - genetics; Biochemistry; Biotransformation; Colesevelam; Colesevelam Hydrochloride; Colon - metabolism; Colon - physiopathology; Diarrhea; Diarrhea - drug therapy; Diarrhea - etiology; Diarrhea - genetics; Diarrhea - physiopathology; Feedback, Physiological - drug effects; Female; Fibroblast growth factors; Fibroblast Growth Factors - metabolism; Gastroenterology; Gastrointestinal Transit - genetics; Hepatology; Humans; Irritable bowel syndrome; Irritable Bowel Syndrome - complications; Irritable Bowel Syndrome - drug therapy; Irritable Bowel Syndrome - genetics; Irritable Bowel Syndrome - physiopathology; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Oncology; Original Article; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Transplant Surgery
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-012-2035-5

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). Aim 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. Conclusion FGFR4 rs351855 and KLB rs4975017 SNPs may identify a subset of IBS-D patients with beneficial response to colesevelam.