A natural mutation of a gene that helps regulate the reactivity of the immune system is a major contributor to type 1diabetes, Medical College of Georgia researchers have found.
The newly discovered gene, SUMO-4, controls the activity of NFκB, 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," said 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," said 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," said 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, said Dr. She, Georgia Research Alliance Eminent Scholar in Genomic Medicine. 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.
"You guess the function, you guess the disease possibilities, then you guess which genes might be involved in the pathogenesis," Dr. She said. "As a community, we have guessed right a few times, including identification of HLA. But this is the first time we have used a systematic approach to find the gene and it’s the first gene in which we know how it contributes to the disease."
For example, HLA is a regulator of immunity that has been known for 30 years, but researchers still don’t know exactly how it causes diabetes. The MCG team has found that SUMO-4 encodes a protein that modifies the activity of NFκB. It was already known that NFκB regulates the production of certain cytokines and that cytokines have a role in type 1 diabetes as well as other autoimmune diseases. What wasn’t known was the cause of the excessive cytokine production seen in those diseases. Now they know that SUMO-4 regulates the activity of NFκB, which in turn regulates whether cytokine production is on autopilot, shut down or revved up.
The SUMO-4 mutation they found overrides the systems that put cytokine production on autopilot or shut it down. Instead, it enables cytokine production not only to increase but directs the increased immune response at the insulin-producing beta cells of the pancreas.
Dr. She credits many for the findings but especially Dr. Wang for his diligence in working through this more systematic – but still extremely tedious – approach to identifying not only the gene but how it causes disease.
"This is the reason scientists stay in science," Dr. She said. "These are the days you look for, days when you can make a difference, not just for science, but for humanity, for patients, for people who have diabetes and, perhaps even more, for people who are going to develop diabetes." He noted that none of the work would be possible without the contributions of study families. "We are trying to improve their lives, but without them, we cannot do anything."
The studies were funded by National Institute of Child Health and Development and the Juvenile Diabetes Research Foundation. Collaborators included researchers at the University of Florida; Endocrinologia, Instituto Clinica Medica II, University of Rome; the University of Southern California School of Medicine, Los Angeles; Cedars-Sinai Medical Center and the University of California, Los Angeles; Hanyang University Hospital in Korea; Facultad de Medicina, Universidad Complutense in Madrid; HLA Laboratory, Beijing Red Cross Blood Center, China; and Unite de Recherches de 1’INSERM U580, Centre de l’Association Claude Bernard, France.
Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D, Zheng W, Purohit S, Podolsky RH, Muir A, Wang J, Dong Z, Brusko T, Atkinson M, Pozzilli P, Zeidler A, Raffel LJ, Jacob CO, Park Y, Serrano-Rios M, Larrad MT, Zhang Z, Garchon HJ, Bach JF, Rotter JI, She JX, Wang CY.
A functional variant of SUMO4, a new IkappaBalpha modifier, is associated with type 1 diabetes.
Nat Genet. 2004 Jul 11
Medical College of Georgia
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