A Klothoß variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea.
Gastroenterology
; 140(7): 1934-42, 2011 Jun.
Article
en En
| MEDLINE
| ID: mdl-21396369
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 Klothoß (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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Colon
/
Síndrome del Colon Irritable
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Diarrea
/
Motilidad Gastrointestinal
/
Proteínas de la Membrana
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Adult
/
Female
/
Humans
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Male
/
Middle aged
País como asunto:
America do norte
Idioma:
En
Año:
2011
Tipo del documento:
Article