Clinical—Alimentary TractA Klothoβ Variant Mediates Protein Stability and Associates With Colon Transit in Irritable Bowel Syndrome With Diarrhea
Section snippets
Subjects
Our study assessed a total of 717 subjects: 435 patients with a functional gastrointestinal disorder (Rome II criteria positive consisting of 177 patients with IBS-C, 174 with IBS-D, 84 with alternating-type IBS) and 282 healthy volunteers. Of these, 239 participants had undergone scintigraphic colonic transit measurement. Baseline characteristics of the full cohort of 714 participants and the subset of 238 participants with colonic transit and genotyping information are shown in Table 1. The
Hardy–Weinberg Equilibrium for Candidate SNPs
Table 2 lists the 15 SNPs analyzed, P values for Hardy–Weinberg equilibrium, and predicted MAFs and observed MAFs separately for the healthy participants (n = 279) within the entire cohort of 714 subjects (with genotype data) and the healthy participants (n = 55) within the subset of 238 subjects with colonic transit measurements.
In the healthy participants, FGFR4 rs376618 was the only SNP of the 15 candidate SNPs to differ significantly from Hardy–Weinberg equilibrium, both in the full cohort
Discussion
In this study, we show that a functional gene variant mediating stability of KLB, a protein regulating BA synthesis, associates with colonic transit in IBS-D. This association is modulated by 2 independent genetic variants in FGFR4, whose protein product directly interacts with KLB.34 This study links common polymorphisms in human genes regulating BA synthesis to colonic transit at 24 hours, a well-characterized intermediate phenotype, in IBS-D. These data support the hypothesis that genetic
References (41)
The functional gastrointestinal disorders and the Rome III process
Gastroenterology
(2006)- et al.
Genetic approaches to functional gastrointestinal disorders
Gastroenterology
(2010) - et al.
Results of the glucose-lowering effect of WelChol study (GLOWS): a randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes
Clin Ther
(2007) Bile acids: regulation of synthesis
J Lipid Res
(2009)- et al.
A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis
Clin Gastroenterol Hepatol
(2009) - et al.
Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein
Mech Dev
(2000) - et al.
Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis
Dev Cell
(2002) - et al.
Redundant pathways for negative feedback regulation of bile acid production
Dev Cell
(2002) - et al.
Is there an association between GNbeta3-C825T genotype and lower functional gastrointestinal disorders?
Gastroenterology
(2006) - et al.
Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21
J Biol Chem
(2007)
Liver-specific activities of FGF19 require Klotho beta
J Biol Chem
Genetics and irritable bowel syndrome: from genomics to intermediate phenotype and pharmacogenetics
Dig Dis Sci
Bile acid malabsorption in patients with chronic diarrhoea
Scand J Gastroenterol
Systematic evaluation of the causes of chronic watery diarrhea with functional characteristics
Am J Gastroenterol
Absence of histopathological changes of ileum and colon in functional chronic diarrhea associated with bile acid malabsorption, assessed by SeHCAT test: a prospective study
Am J Gastroenterol
Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome
Aliment Pharmacol Ther
Bile acid malabsorption in patients with chronic diarrhoea: clinical value of SeHCAT test
Scand J Gastroenterol
Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on intestinal transit and bowel function
Clin Gastroenterol Hepatol
Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2)
J Clin Invest
Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset idiopathic bile acid malabsorption
Scand J Gastroenterol
Cited by (72)
Intestinal epithelial β Klotho is a critical protective factor in alcohol-induced intestinal barrier dysfunction and liver injury
2022, eBioMedicineCitation Excerpt :Brain KLB knockout mice exhibit an increase in alcohol preference.17 In the gut, the decreased KLB expression caused by gene variation is associated with increased intestinal permeability in patients with irritable bowel syndrome with diarrhea,12 suggesting that the downregulated KLB may play a role in alcohol-induced intestinal epithelial dysfunction and liver injury. From apical-to-basal, the paracellular space between intestinal epithelial cells is sealed with tight junction (TJ, zonula occludens), adherens junction (zonula adherens), and desmosomes.18
β-Klotho gene variation is associated with liver damage in children with NAFLD
2020, Journal of HepatologyCitation Excerpt :These previous data suggested that the decrease of hepatic Klotho protein in pediatric NAFLD could be ascribable to the beta isoform (KLB), which is the main form in the liver.25–28 Recently, two functional genetic variants modulating the activity of the KLB/FGFR4 pathway, namely rs17618244 G>A KLB and rs1966265 G>A FGFR4, encoding for the R728Q and V10I aminoacidic substitutions have been associated with accelerated transit in irritable bowel syndrome,29 supporting a possible functional impact on the regulation of the gut-liver axis via modulation of FGF19 signaling.30 Therefore, the aim of this study was to examine the impact of the rs17618244 G>A KLB and rs1966265 G>A FGFR4 variants on liver damage severity in pediatric patients with NAFLD.
Irritable bowel syndrome
2019, Clinical and Basic Neurogastroenterology and MotilityBile acids and FXR in functional gastrointestinal disorders
2018, Digestive and Liver DiseaseCitation Excerpt :It has been shown that hydrophobic BAs augmented small intestinal permeability either through nicotinic cholinergic mechanisms or changes within the small intestinal brush border membrane (changes in fragility and fluidity of the membrane) and caused higher influx of fluid and electrolytes to the intestinal lumen that contributed to the loose stool consistency. Genetic variations in the regulation of endogenous BA synthesis play a role in the etiology of IBS-D. Two genes, klotho B and FGFR4, were identified to modulate BA pool and contribute to worsening of symptoms in patients with accelerated colonic transit and IBS-D patients [80]. More specifically, differences in protein stability were detected between two alleles within klotho B (rs17618244) which provide a biologically plausible mechanism by which the single nucleotide polymorphisms may affect intestinal motility [80].
Conflicts of interest The authors disclose no conflicts.
Funding Dr Camilleri's research in irritable bowel syndrome is supported by National Institutes of Health grants R01-DK079866 and 1RC1-DK086182.