Article

A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature

Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
Nature (Impact Factor: 41.46). 09/2010; 467(7314):460-4. DOI: 10.1038/nature09386
Source: PubMed

ABSTRACT

Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 × 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.

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    • "The example dataset included in R2GUESS originates from a larger study (Heinig et al. 2010) from which we selected the Hopx genes, as inPetretto et al. (2010). For each gene, we investigated the ability of R2GUESS to identify a parsimonious set of predictors that explains the joint variability of gene expression in four tissues (adrenal gland, fat, heart, and kidney). "

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    • "The helicase enzyme IFIH1 (also known as MDA5 or melanoma differentiation-associated protein-5) triggers the secretion of interferons in response to viral infection. The interferon-regulating factor 7-(IRF7-) driven inflammatory network (IDIN) genes also contribute to the risk of T1D [69]. Different non-MHC candidate gene products related to T1D involving the cytokine pathways are IL "
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    • "In addition to IFIH1 other innate immune system genes in the IRF7 - driven network may also be associated with the risk of diabetes [ Heinig et al . , 2010 ] . There was no ethical permission to carry out genetic analyses in these blood donors , and further studies in bigger study series are needed to find out if the IFIH1 / IRF7 polymorphisms regulate immune responses to CBV1 strains . In any case , CBV1 up - regulated genes in this IRF7 - driven inflam - matory network in different indiv"
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