Interleukin-6 (IL-6) is a molecule that plays a role in the regulation of inflammatory responses, and may therefore play an important role in the T1D autoimmune disease process. IL-6 binds to its receptor on the surface of cells and sends signals inside the cells. This IL-6 receptor is also known to be released into the circulation. Genetic variation in the IL-6 receptor gene is associated with an increased risk of several human diseases with an inflammatory component, including coronary heart disease, rheumatoid arthritis, and asthma. A common variation in the composition of this gene has been suggested to affect the circulatory concentrations of IL-6 receptors. In this study, the authors describe a genetic association of this genetic variant of IL-6 receptors to T1D and provide evidence that this variant exerts its effect by regulating the balance between circulating and membrane-bound IL-6 receptors. These data show for the first time that this variant directly controls the surface levels of IL-6 receptor on individual immune cells and that these differences in receptor levels translate into a functional impairment in IL-6 signaling. These findings may have implications for clinical trials targeting inflammatory mechanisms involving IL-6 signaling and may provide tools for identifying patients with specific potential benefit from therapeutic intervention in the IL-6 signaling pathway.
Ramifications for Individuals with T1D:
These findings may have implications for clinical trials targeting inflammatory mechanisms involving IL-6 signaling and may provide tools for identifying patients with specific potenital benefit from therapeutic intervention in the IL-6 receptor signaling pathway.
This work was partly funded by JDRF.
Investigators and Institutions:
Ricardo C. Ferreira., Daniel F. Freitag, Antony J. Cutler, Joanna M. M. Howson, Daniel B. Rainbow, Deborah J. Smyth, Stephen Kaptoge, Pamela Clarke, Charlotte Boreham, Richard M. Coulson, Marcin L. Pekalski, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S. Rich, Adam S. Butterworth, Anders Malarstig, John Danesh, John A. Todd with the following Institutions: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
Ferreira RC, Freitag DF, and others. Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases. PLoS Genet 2013 Apr;9(4): e1003444. doi:10.1371/journal.pgen.1003444.