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 infuence colonic transit (CT) in diarrheapredominant 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 infuenced 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. © 2012 Springer Science+Business Media, LLC.