Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Charlton 8-110, 200 First Street S.W., Rochester, MN 55905, USA.
Dig Dis Sci. 2012 May;57(5):1222-6. doi: 10.1007/s10620-012-2035-5. Epub 2012 Jan 21.
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.
背景：Klothoβ（KLB）和成纤维细胞生长因子受体 4（FGFR4）的蛋白产物影响成纤维细胞生长因子 19 对肝胆汁酸（BA）合成的反馈抑制。KLB 和 FGFR4 的变体影响腹泻为主的肠易激综合征（IBS-D）的结肠传输（CT）。 目的：本研究旨在检验以下假设：BA 螯合剂考来维仑在 IBS-D 患者中对 CT 的减缓作用受 KLB 和 FGFR4 基因变异的影响。 方法：我们研究了 KLB 和 FGFR4 编码变异（SNP）对 24 名女性 IBS-D 患者接受 BA 鳌合剂考来维仑 1.875g bid 与安慰剂（PLA）治疗 14 天后闪烁扫描 CT 结肠传输的药物遗传学效应。 结果：FGFR4 rs351855 和 KLB rs497501 与考来维仑对升结肠（AC）排空时间一半（t(1/2)，P=0.046 和 P=0.085）和 24 小时总体 CT（几何中心，GC24：P=0.073 和 P=0.042）的不同影响相关，rs351855 GA/AA（而非 GG）和 rs497501 CA/AA（而非 CC）基因型的传输速度较慢。 结论：FGFR4 rs351855 和 KLB rs4975017 SNP 可能确定对考来维仑有良好反应的 IBS-D 患者亚组。
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