Irritable bowel syndrome-diarrhea: characterization of genotype by exome sequencing, and phenotypes of bile acid synthesis and colonic transit

Am J Physiol Gastrointest Liver Physiol. 2014 Jan 1;306(1):G13-26. doi: 10.1152/ajpgi.00294.2013. Epub 2013 Nov 7.

Abstract

The study objectives were: to mine the complete exome to identify putative rare single nucleotide variants (SNVs) associated with irritable bowel syndrome (IBS)-diarrhea (IBS-D) phenotype, to assess genes that regulate bile acids in IBS-D, and to explore univariate associations of SNVs with symptom phenotype and quantitative traits in an independent IBS cohort. Using principal components analysis, we identified two groups of IBS-D (n = 16) with increased fecal bile acids: rapid colonic transit or high bile acids synthesis. DNA was sequenced in depth, analyzing SNVs in bile acid genes (ASBT, FXR, OSTα/β, FGF19, FGFR4, KLB, SHP, CYP7A1, LRH-1, and FABP6). Exome findings were compared with those of 50 similar ethnicity controls. We assessed univariate associations of each SNV with quantitative traits and a principal components analysis and associations between SNVs in KLB and FGFR4 and symptom phenotype in 405 IBS, 228 controls and colonic transit in 70 IBS-D, 71 IBS-constipation. Mining the complete exome did not reveal significant associations with IBS-D over controls. There were 54 SNVs in 10 of 11 bile acid-regulating genes, with no SNVs in FGF19; 15 nonsynonymous SNVs were identified in similar proportions of IBS-D and controls. Variations in KLB (rs1015450, downstream) and FGFR4 [rs434434 (intronic), rs1966265, and rs351855 (nonsynonymous)] were associated with colonic transit (rs1966265; P = 0.043), fecal bile acids (rs1015450; P = 0.064), and principal components analysis groups (all 3 FGFR4 SNVs; P < 0.05). In the 633-person cohort, FGFR4 rs434434 was associated with symptom phenotype (P = 0.027) and rs1966265 with 24-h colonic transit (P = 0.066). Thus exome sequencing identified additional variants in KLB and FGFR4 associated with bile acids or colonic transit in IBS-D.

Keywords: klotho B; risk factor; susceptibility; symptom.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Bile Acids and Salts* / biosynthesis
  • Bile Acids and Salts* / genetics
  • Bile Acids and Salts* / metabolism
  • Biological Transport / genetics
  • Diarrhea / etiology
  • Diarrhea / genetics*
  • Diarrhea / physiopathology
  • Exome
  • Feces / chemistry
  • Female
  • Gastrointestinal Transit / genetics*
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Irritable Bowel Syndrome / complications
  • Irritable Bowel Syndrome / genetics*
  • Irritable Bowel Syndrome / physiopathology
  • Klotho Proteins
  • Male
  • Membrane Proteins / genetics*
  • Molecular Sequence Data
  • Receptor, Fibroblast Growth Factor, Type 4 / genetics*
  • Sequence Analysis, DNA

Substances

  • Bile Acids and Salts
  • KLB protein, human
  • Membrane Proteins
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 4
  • Klotho Proteins