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A natural mutation of a gene that helps regulate the reactivity of the immune system is a major contributor to type 1 diabetes, Medical College of Georgia researchers have found.
The newly discovered gene, SUMO-4, controls the activity of NF?B, a molecule that in turn controls the activity of cytokines, proteins that regulate the intensity and duration of the immune response, according to research that will be published in the August print issue of Nature Genetics and online July 11.
By examining the transmission of genes from parents to children in nearly 1,000 diabetic families from around the world, the researchers found that a certain natural mutation of that SUMO-4 gene increases the risk of type 1 diabetes.
"This helps us understand how type 1 diabetes works, and we can use this improved understanding to better predict who will get the disease and design new intervention strategies for those who do," says Dr. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and a co-senior author on the study.
"The mutation we have found is going to increase the responsive capacity of the immune system to environmental triggers or stimulators; it makes it more reactive," says Dr. Cong-Yi Wang, molecular geneticist and co-senior author.
Dr. Wang and his research team found that when that mutation encounters an environmental trigger, such as a bacterial or viral infection, it throws off the usual well-balanced activity of the immune system, initiating an autoimmune response that eventually attacks the patient's own tissue.
They already are exploring the gene's potential role in other autoimmune diseases as well such as lupus, thyroid disease, arthritis and multiple sclerosis.
SUMO-4 is the fourth gene identified that contributes to type 1 diabetes, taking a place just behind HLA, another regulator of immunity, in terms of relative risk. "Many genes are involved in type 1 diabetes, but this is one of the most important ones," explains Dr. She. He leads a research team that has followed diabetic families primarily in Florida and Georgia for the past 10 years to find precisely how genes, the immune system and the environment work together to cause type 1 diabetes, a childhood disease that requires a lifetime of taking insulin. Like its lifestyle-related counterpart, type 2 diabetes, the incidence of type 1 has increased dramatically: a near 300 percent increase in the last 20 years.
This is one of the few times scientists have successfully used a systematic approach to finding a gene involved in a complex disease such as diabetes. The MCG researchers narrowed their search for diabetes-related genes by looking at those most often transmitted to children with diabetes, Dr. She says. That approach compares with traditional forward genetics-a cumbersome process they liken to looking for a needle in a haystack-which narrows the search by predicting which of some 40,000 genes might be involved in a disease based on what scientists already know about the disease and the genes.
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