title: Irritable bowel syndrome-diarrhea: characterization of genotype by exome sequencing, and phenotypes of bile acid synthesis and colonic transit.
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.
authors.affiliation: Mayo Clinic, Charlton 8-110, 200 First St. S.W., Rochester, MN 55905. camilleri.michael@mayo.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.forename: Eric W
authors.initials: EW
authors.lastname: Klee
authors.forename: Andrea
authors.initials: A
authors.lastname: Shin
authors.forename: Paula
authors.initials: P
authors.lastname: Carlson
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Grover
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D000328:Adult; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000235:genetics; D003967:Diarrhea / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D059472:Exome; D005243:Feces / Q000737:chemistry; D005260:Female; D005772:Gastrointestinal Transit / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D001647:Bile Acids and Salts; C538995:KLB protein, human; D008565:Membrane Proteins; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000090265:Klotho Proteins
keywords: klotho B; risk factor; susceptibility; symptom