title: IDO1 and IDO2 non-synonymous gene variants: correlation with crohn's disease risk and clinical phenotype.
abstract: BACKGROUND
  Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Genetic polymorphisms can confer CD risk and influence disease phenotype. Indoleamine 2,3 dioxygenase-1 (IDO1) is one of the most over-expressed genes in CD and mediates potent anti-inflammatory effects via tryptophan metabolism along the kynurenine pathway. We aimed to determine whether non-synonymous polymorphisms in IDO1 or IDO2 (a gene paralog) are important either as CD risk alleles or as modifiers of CD phenotype.
  
  
  METHODS
  Utilizing a prospectively collected database, clinically phenotyped CD patients (n = 734) and non-IBD controls (n = 354) were genotyped for established IDO1 and IDO2 non-synonymous single nucleotide polymorphisms (SNPs) and novel genetic variants elucidated in the literature. Allelic frequencies between CD and non-IBD controls were compared. Genotype-phenotype analysis was conducted. IDO1 enzyme activity was assessed by calculating the serum kynurenine to tryptophan ratio (K/T).
  
  
  RESULTS
  IDO1 SNPs were rare (1.7% non-IBD vs 1.1% CD; p = NS) and not linked to Crohn's disease diagnosis in this population. IDO1 SNPs did however associate with a severe clinical course, presence of perianal disease, extraintestinal manifestations and a reduced serum K/T ratio during active disease suggesting lower IDO1 function. IDO2 minor allele variants were common and one of them, rs45003083, associated with reduced risk of Crohn's disease (p = 0.025). No IDO2 SNPs associated with a particular Crohn's disease clinical phenotype.
  
  
  CONCLUSIONS
  This work highlights the functional importance of IDO enzymes in human Crohn's disease and establishes relative rates of IDO genetic variants in a US population.
authors.affiliation: Division of Gastroenterology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Navya
authors.initials: N
authors.lastname: Kanuri
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Yuanhao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States of America; Division of Gastroenterology, Veteran Affairs Medical Center, John Cochrane Division, St. Louis, Missouri, United States of America.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Sayuk
authors.affiliation: Division of Gastroenterology, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Ellen
authors.initials: E
authors.lastname: Li
authors.affiliation: Division of Gastroenterology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Ciorba
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003424:Crohn Disease / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D007737:Kynurenine / Q000097:blood; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014364:Tryptophan / Q000097:blood
chemical_list: C576710:IDO1 protein, human; C576711:IDO2 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan