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Nov 29, 2012

Understanding Genetic Risk for Diabetes

  • Researchers have demonstrated how a genetic variant associated with type 1 diabetes and other autoimmune diseases influences susceptibility to autoimmunity. There has been debate over whether a mutation in the gene PTPN22 causes a gain of function or a loss of function. Now, scientists at Joslin Diabetes Center, in collaboration with a team at the University of Würzburg, have shown that the mutation indeed promotes a gain of function that leads to type 1 diabetes.

    PTPN22 plays a role in lymphocyte function. A PTPN22 variant has already been implicated as a risk factor for type 1 diabetes and several other autoimmune disorders. The gene is involved in the formation of a key protein known as lymphoid tyrosine phosphatase (LYP), which helps control the activity of T and B cells in the immune system. The PTPN22 mutation generates a variation of LYP with a different molecular structure.

    Most studies of the PTPN22 disease variant have suggested that this variant is a gain-of-function genetic mutation that enhances LYP activity and lessens the activity of T and B cells, which increases susceptibility to autoimmunity. “When immune cells are less reactive during the maturation phase of their development, the cells can evade mechanisms that help protect against autoimmunity,” says study lead author Stephan Kissler, Ph.D., of Joslin’s Section of Immunobiology. However, one study that analyzed data from humans and genetically modified mice suggested that the LYP variant associated with type 1 diabetes is a loss-of-function mutation that reduces LYP activity.

    To help resolve the conflicting data, Joslin scientists conducted studies with a mouse model developed by Dr. Kissler’s graduate student and co-author, Peilin Zheng, Ph.D. Using a technology that combines RNA interference with lentiviral transgenesis, the scientists can manipulate gene activity in the most widely used mouse model for type 1 diabetes, the nonobese diabetic mouse (NOD). In this study, the researchers were able to turn off and on the PTPN22 gene in the NOD mouse.

    When PTPN22 was turned off in mice, mimicking a loss-of-function mutation, the researchers observed an increase in regulatory T cells and a decreased risk of autoimmune diabetes. Thus, the PTPN22 knockdown actually conferred protection from disease. “This is the first study conducted on the diabetic mouse model that supports the LYP gain-of-function hypothesis,” says Dr. Kissler. “Our work should help to resolve the controversy.”

    By providing additional data that suggests the potential therapeutic value of PTPN22 manipulation, the study may further the development of new therapeutic options that inhibit LYP to reduce or prevent autoimmunity. “Our goal is to treat autoimmunity. Inhibiting LYP in patients may increase regulatory immune cells and could confer protection against autoimmunity, but it remains to be tested if our promising findings in this mouse model are reflected in humans,” says Dr. Kissler.

    The study appeared yesterday (online ahead of print) in the journal Diabetes. The paper is titled “PTPN22 Silencing in the NOD Model Indicates the Type 1 Diabetes-Associated Allele Is Not a Loss-of-Function Variant”.


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