Expression profiling of human genetic and protein interaction networks in type 1 diabetes.
Proteins contributing to a complex disease are often members of the same functional pathways. Elucidation of such pathways may provide increased knowledge about functional mechanisms underlying disease. By combining genetic interactions in Type 1 Diabetes (T1D) with protein interaction data we have previously identified sets of genes, likely to represent distinct cellular pathways involved in T1D risk. Here we evaluate the candidate genes involved in these putative interaction networks not only at the single gene level, but also in the context of the networks of which they form an integral part. mRNA expression levels for each gene were evaluated and profiling was performed by measuring and comparing constitutive expression in human islets versus cytokine-stimulated expression levels, and for lymphocytes by comparing expression levels among controls and T1D individuals. We identified differential regulation of several genes. In one of the networks four out of nine genes showed significant down regulation in human pancreatic islets after cytokine exposure supporting our prediction that the interaction network as a whole is a risk factor. In addition, we measured the enrichment of T1D associated SNPs in each of the four interaction networks to evaluate evidence of significant association at network level. This method provided additional support, in an independent data set, that two of the interaction networks could be involved in T1D and highlights the following processes as risk factors: oxidative stress, regulation of transcription and apoptosis. To understand biological systems, integration of genetic and functional information is necessary, and the current study has used this approach to improve understanding of T1D and the underlying biological mechanisms.
Bergholdt
Regine
R
Hagedorn Research Institute and Steno Diabetes Center, Gentofte, Denmark. rber@hagedorn.dk
Brorsson
Caroline
C
Lage
Kasper
K
Nielsen
Jens Høiriis
JH
Brunak
Søren
S
Pociot
Flemming
F
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D055815:Young Adult
D011506:Proteins