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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.

SUBMITTER: Lee A 

PROVIDER: S-EPMC4277413 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

IDO1 and IDO2 non-synonymous gene variants: correlation with crohn's disease risk and clinical phenotype.

Lee Alexander A   Kanuri Navya N   Zhang Yuanhao Y   Sayuk Gregory S GS   Li Ellen E   Ciorba Matthew A MA  

PloS one 20141226 12


<h4>Background</h4>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 a  ...[more]

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