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

Michael Camilleri, Eric W. Klee, Andrea Shin, Paula Carlson, Ying Li, Madhusudan Grover, Alan R. Zinsmeister

Research output: Contribution to journalArticle

17 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)G13-G26
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number1
StatePublished - Jan 1 2014
Externally publishedYes


  • Klotho B
  • Risk factor
  • Susceptibility
  • Symptom

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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