Genetic link between type-1 diabetes and enterovirus infection

6 March 2009

Type 1 diabetes (T1D) is a young-onset (before the age of 40) form of diabetes that affects an estimated 300,000 people in the UK alone, including 20,000 children under the age of 15. An autoimmune process causes progressive destruction of insulin-producing beta-cells in the pancreas, and a concomitant inability to control blood glucose levels. This form of diabetes, which accounts for 5-15% of all diabetes cases (see Diabetes UK website), would be fatal without multiple daily injections of insulin, in addition to careful dietary control. Susceptibility to this form of diabetes is known to have a significant genetic element, but is presumed to also involve important environmental factors.

Researchers at the University of Cambridge have identified new genetic variants associated with a reduced risk of developing T1D. The genome-wide association study (GWA) published in Science identifies four variants in the IFIH1 (MDA5) gene, which encodes an enzyme involved in the induction of immune responses to the RNA of picornaviruses [Nejentsev S et al. (2009) Science DOI: 10.1126/science.1167728 (Epub ahead of print)]. The IFIH1 protein detects the presence of viral RNA in the cellular cytoplasm and triggers activation of key signaling pathways to induce an interferon-beta mediated antiviral immune response. The variants associated with reduced risk of T1D are suggested to reduce the normal functionality of the IFIH1 protein.

The authors note that infection with enteroviruses (a picornavirus sub-group of small RNA genome viruses) is more common among newly diagnosed T1D patients and pre-diabetic subjects than in the general population, and speculate that normal IFIH1-mediated immune activation caused by enterovirus infection may stimulate the autoimmune response against pancreatic beta cells. IFIH1 mutations that disrupt this mechanism may therefore confer a protective effect against the disease. Senior author Professor John Todd commented: "We have been able to pin-point one particular gene among a long list of candidates. Now we and others can begin to study the biology of IFIH1 in the context of type 1 diabetes knowing that it is part of the cause of the disease" (see press release).

Another recent study to be published in Diabetologia supports the proposed link between T1D and enterovirus infection. It reports the detection of enteroviruses in pancreatic tissue from about 60% of 72 paediatric patients with T1D, but very few of the samples of tissue from 50 children without the disease (see press release). This research also found that 40% of adults with type 2 diabetesshowed signs of enteroviral infection of their pancreatic beta cells, compared with only 13 percent of non-diabetic (control) adults of the same age. The authors propose that vaccination against enteroviral infection in childhood could reduce the incidence of both common forms of diabetes.

Comment: This latest research provides a prime example of how genetic and environmental factors may interact to cause disease, as well as a demonstration of how highly-powered GWAs can provide vital insight into the genetic basis of disease, and of pathological mechanisms, opening up prospects for improved prevention and development of novel therapeutics. The proposal that anti-enteroviral vaccines might be important prevention is perhaps somewhat premature, however, since there are approaching 100 different strains of enterovirus, and it is not yet known which may be associated with diabetes.

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