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

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 140; no. 7; pp. 1934 - 1942
• Main Authors: Wong, Banny S., Camilleri, Michael, Carlson, Paula J., Guicciardi, Maria E., Burton, Duane, McKinzie, Sanna, Rao, Archana S., Zinsmeister, Alan R., Gores, Gregory J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2011
• Subjects: Adult; Bile acid; Bile Acids and Salts - metabolism; Case-Control Studies; Colon - metabolism; Colon - physiopathology; Diarrhea - genetics; Diarrhea - metabolism; Diarrhea - physiopathology; Female; FGF19; FGFR4; Gastroenterology and Hepatology; Gastrointestinal Motility - genetics; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; HEK293 Cells; Humans; Irritable Bowel Syndrome - genetics; Irritable Bowel Syndrome - metabolism; Irritable Bowel Syndrome - physiopathology; Kinetics; KLB; Klotho Proteins; Liver - metabolism; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Middle Aged; Minnesota; Models, Genetic; Models, Statistical; Phenotype; Polymorphism, Single Nucleotide; Protein Stability; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Transfection; Minnesota; KLB; FGF; FGFR; BAM; IBS-D; IBS-C; MAF; SNP; t; Bile acid; FGF19; CYP; IBS; FGFR4; GC; BA; single nucleotide polymorphism; diarrhea-predominant irritable bowel syndrome; fibroblast growth factor; geometric center; bile acid malabsorption; irritable bowel syndrome; cytochrome P450; half-life; constipation-predominant irritable bowel syndrome; Klothoβ; minor allele frequency; fibroblast growth factor receptor
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2011.02.063

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. 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. 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. 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.