title: Evidence of expression variation and allelic imbalance in Crohn's disease susceptibility genes NOD2 and ATG16L1 in human dendritic cells.
abstract: Human dendritic cells (DCs) play an important role in induction and progression of Crohn's disease (CD). Accumulating evidence suggests that viral infection is required to trigger CD pathogenesis in genetically predisposed individuals. NOD2 and ATG16L1 are among the major CD susceptibility genes implicated in impaired immune response to bacterial infection. In this study, we investigated gene expression and allelic imbalance (AI) of NOD2 and ATG16L1 using common variants in human monocyte-derived DCs. Significant AI was observed in ~40% and ~70% of NOD2 and ATG16L1 heterozygotes, respectively (p<0.05). AI of NOD2 was inversely associated with its expression level (p=0.015). No correlation was detected between gene expression and AI for ATG16L1. When infected with Newcastle Disease Virus (NDV), NOD2 expression in DCs was induced about four-fold (p<0.001), whereas ATG16L1 expression was not affected (p=0.88). In addition, NDV infection tended to lower the variance in AI among DC populations for the NOD2 gene (p=0.05), but not the ATG16L1 gene (p=0.32). Findings of a simulation study, aimed to verify whether the observed variation in gene expression and AI is a result of sample-to-sample variability or experimental measurement error, suggested that NOD2 AI is likely to result from a deterministic event at a single cell level. Overall, our results present initial evidence that AI of the NOD2 and ATG16L1 genes exists in populations of human DCs. In addition, our findings suggest that viral infection may regulate NOD2 expression.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY, USA. jianzhong.hu@mssm.edu
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Hu
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
mesh_terms: D000483:Alleles; D003424:Crohn Disease / Q000235:genetics*; D003713:Dendritic Cells / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction
keywords: AI; ATG16L1; Allelic imbalance; Autophagy-related protein 16-1; CD; Crohn's disease; DCs; DMEM; Dendritic cells; Dulbecco's Modified Eagle Medium; Human dendritic cells; MOI; NDV; NOD2; Newcastle Disease Virus; Nucleotide-binding oligomerization domain-containing protein 2; multiplicity of infection