A Klothoβ Variant Mediates Protein Stability and Associates With Colon Transit in Irritable Bowel Syndrome With Diarrhea

BACKGROUND & AIMS: Bile acid (BA) malabsorption of moderate severity is reported in 32% of patients with chronic unexplained diarrhea, including diarrhea-predominant irritable bowel syndrome (IBS-D). We hypothesized that variants of genes regulating hepatic BA synthesis play a role in IBS-D. METHODS: In 435 IBS and 279 healthy subjects, we tested individual associations of 15 common single nucleotide polymorphisms (SNPs) from 7 genes critical to BA homeostasis with symptom-based subgroups using dominant genetic models. In a subset of 238 participants, we tested association with colonic transit. SNP-SNP interactions were investigated based on known protein interactions in BA homeostasis. The function of SNP rs17618244 in Klotho beta (KLB) was evaluated using a protein stability assay in HEK293 cells. RESULTS: SNP rs17618244 (Arg728Gln in KLB) is associated with colonic transit at 24 hours. G allele (Arg728) compared with A allele (Gln728) is associated with accelerated colonic transit (P=.0007) in the overall cohort; this association was restricted to IBS-D (P=.0018). Interaction tests of KLB rs17618244 with 3 non-synonymous SNPs of fibroblast growth factor receptor 4 (FGFR4) revealed that rs1966265 (Val10Ile) and rs351855 (Gly388Arg) modulate rs1768244's associationwith colonic transit in IBS-D (P=.0025 and P=.0023, respectively). KLB Arg728 significantly reduced protein stability compared with KLB Gln728, demonstrating KLB rs17618244's functional significance. No significant associations with symptom-based subgroups of IBS were detected. CONCLUSIONS: A functional KLB gene variant mediating protein stability associates with colonic transit in IBS-D. This association is modulated by 2 genetic variants in FGFR4. The FGF19-FGFR4-KLB pathway links regulation of BA synthesis to colonic transit in IBS-D.