TY - JOUR
T1 - IDO1 and IDO2 non-synonymous gene variants
T2 - Correlation with Crohn's disease risk and clinical phenotype
AU - Lee, Alexander
AU - Kanuri, Navya
AU - Zhang, Yuanhao
AU - Sayuk, Gregory S.
AU - Li, Ellen
AU - Ciorba, Matthew A.
N1 - Publisher Copyright:
© 2014, Public Library of Science. All rights reserved.
PY - 2014/12/26
Y1 - 2014/12/26
N2 - 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 overexpressed 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.
AB - 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 overexpressed 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.
UR - http://www.scopus.com/inward/record.url?scp=84919935141&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0115848
DO - 10.1371/journal.pone.0115848
M3 - Article
C2 - 25541686
AN - SCOPUS:84919935141
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 12
M1 - e115848
ER -