A klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea

Banny S. Wong, Michael Camilleri, Paula J. Carlson, Maria E. Guicciardi, Duane Burton, Sanna McKinzie, Archana S. Rao, Alan R. Zinsmeister, Gregory J. Gores

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

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 Klothoβ (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 nonsynonymous SNPs of fibroblast growth factor receptor 4 (FGFR4) revealed that rs1966265 (Val10Ile) and rs351855 (Gly388Arg) modulate rs1768244's association with 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.

Original languageEnglish (US)
Pages (from-to)1934-1942
Number of pages9
JournalGastroenterology
Volume140
Issue number7
DOIs
StatePublished - Jun 2011

Keywords

  • Bile acid
  • FGF19
  • FGFR4
  • KLB

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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