Hot Off The Press

Highlights of our recently published results

Interleukin 7 Receptor alpha (CD127) identified as disease susceptibility gene

Allelic association in four independent family-based and case-control datasets implicates the IL7Rα gene as a significant risk factor for multiple sclerosis. The likely causal SNP, rs6897932 (T224I), located within the alternatively spliced exon 6 influences the amount of soluble and membrane bound isoforms of the protein by disrupting an exonic splicing silencer within exon 6. The change in IL7Rα isoforms ratio may impact IL-7 signaling and homeostatic regulatory circuits, enhancing pathogenic T-cell response to autoantigens (Gregory et al. Nature Genetics 2007).

First whole-genome association study completed

The International MS Genetics Consortium reports the first whole genome association-screen in patients with multiple sclerosis. The Affymetrix 500,000-SNP GeneChip was used to interrogate DNAs from 1000 individuals affected with MS and their parents. The Sequenom platform was used to examine the top hits in an independent DNA dataset consisting of 2,880 MS cases and 3,000 controls. Among the most significant non-MHC associations are polymorphisms in genes centrally involved in regulation of T cell responses, including CD25, (IL-2Rα chain) which has been recently implicated in the pathogenesis of type 1 diabetes and Graves Disease, IL-7Rα (CD127), and CD58. The results enhance significantly the MS genomics map and provide clear genetic evidence for a primary role of immune dysregulation in the pathogenesis of MS (IMSGC. New England Journal of Medicine 2007).

Transcriptional profile of mesenchymal cells and the hematopoietic stem cell niche

Microarray analysis of isolated mesenchymal stem cells finds a transcriptome enriched in transcription factors and genes downstream of the Wnt signaling pathway (e.g. Sfrp1, Dvl2, Axin1, Tcf3, Rarg, Cspg2, Efnb2). The analysis also identified a set of genes specifically involved in the maintenance of the hematopoietic niche in a quiescent state, supporting stem cell survival but preventing them from proliferate and differentiate. These findings provide novel and important insights on the mechanisms of function and regulation of mesenchymal stem cells (Pedemonte et al. BMC Genomics, 2007).

Genome-wide network analysis reveals the global properties of IFN beta treatment

We generated longitudinal transcriptional profiles in peripheral lymphocytes obtained from IFN beta-treated and untreated individuals, and used pair-wise mutual information (MI) to build networks of co-regulated genes. Interestingly, the connectivity distribution of networks generated with high MI values displayed scale-free properties, but the gene networks from individuals treated with IFN-beta revealed a tight core of immune and apoptosis-related genes associated with higher values of MI. In contrast, networks obtained from untreated individuals primarily reflected cellular housekeeping functions. The implications of this method in the creation of personalized models of response to therapy are significant (Fernald et al. Journal of Immunology 2007).