Pharmacogenetics of the Effects of Colesevelam on Colonic Transit in Irritable Bowel Syndrome with Diarrhea
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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).
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.
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.
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.
FGFR4 rs351855 and KLB rs4975017 SNPs may identify a subset of IBS-D patients with beneficial response to colesevelam.
KeywordsBile acid Klothoβ FGFR4
We thank Mary Lempke, Pharm. D., research pharmacist, and Cindy Stanislav, secretary, for assistance. This work is funded by grant RO1-DK092179 from the National Institutes of Health to Dr. Camilleri and by Mayo Clinic CTSA grant (RR24150).
Conflict of interest
The authors have no conflicts of interest to disclose.
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