LONDON—Scientists from Cambridge University have discovered four rare mutations of a gene associated with type 1 diabetes that reduce the risk of developing the disease. Their findings, published March 5 in the journal Science Express, suggest a link between type 1 diabetes, also known as juvenile-onset diabetes, and the enterovirus, a common virus that enters via the gastrointestinal tract but is often non-symptomatic.
The study, which was conducted at the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, establishes a connection between the IFIH1 gene, which plays a role in the body's antiviral responses, and type 1 diabetes, highlighting a molecular pathway by which enterovirus infections may contribute to the development of the disease. The study builds on previous genome-wide association studies that revealed dozens of regions in the human genome that harbor genes which predispose individuals to various diseases, such as diabetes or cancers. However, those studies were limited in that scientists rarely know which gene or gene variant in these regions cause the disease.
In order to overcome this limitation, the scientists searched for variants that had obvious biological effects, hypothesizing that if a gene harbors several such variants, then it is likely to be causative. Most of these variants are rare in the population and are not tested in genome-wide association studies, but could be discovered by sequencing.
The researchers studied 10 candidate genes associated with type 1 diabetes. Using a novel high-throughput sequencing method developed in collaboration with 454 Life Sciences, a Roche company, they examined the DNA of 480 type 1 diabetes patients and 480 healthy controls. This approach allowed them to not only discover several rare variants associated with type 1 diabetes, but also to accurately measure their frequency in the pools of patients and controls.
The researchers then genotyped approximately 30,000 individuals who were either type 1 diabetes patients, controls or family members and proved that four rare variants or versions that reside in the gene IFIH1 reduce the risk of developing type 1 diabetes.
The four rare variants they identified, which are predicted to reduce function of the IFIH1 protein, consistently decrease the risk of type 1 diabetes, rather than predispose to it. This suggests a model where normal immune activation caused by enterovirus infection and mediated by IFIH1 protein stimulates autoimmunity that eventually leads to T1D, says Dr. John Todd, senior author on the study.
"We have been able to pinpoint one particular gene among a long list of candidates," Todd says. "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."
The findings and new scientific method will ultimately provide the knowledge to develop better strategies to detect, treat and prevent T1D and other genetic-based diseases in the future, Todd says.
"These new results pinpoint the IFIH1-MDA5 gene as being causal and actively participating in type 1 diabetes development, and indicate a route to identifying more genes specifically acting in the disease, from currently a very large list of possible candidate genes," Todd says. "While these results only accounts a very small piece of the whole picture, it is an important principal finding."
The study, which was conducted at the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, establishes a connection between the IFIH1 gene, which plays a role in the body's antiviral responses, and type 1 diabetes, highlighting a molecular pathway by which enterovirus infections may contribute to the development of the disease. The study builds on previous genome-wide association studies that revealed dozens of regions in the human genome that harbor genes which predispose individuals to various diseases, such as diabetes or cancers. However, those studies were limited in that scientists rarely know which gene or gene variant in these regions cause the disease.
In order to overcome this limitation, the scientists searched for variants that had obvious biological effects, hypothesizing that if a gene harbors several such variants, then it is likely to be causative. Most of these variants are rare in the population and are not tested in genome-wide association studies, but could be discovered by sequencing.
The researchers studied 10 candidate genes associated with type 1 diabetes. Using a novel high-throughput sequencing method developed in collaboration with 454 Life Sciences, a Roche company, they examined the DNA of 480 type 1 diabetes patients and 480 healthy controls. This approach allowed them to not only discover several rare variants associated with type 1 diabetes, but also to accurately measure their frequency in the pools of patients and controls.
The researchers then genotyped approximately 30,000 individuals who were either type 1 diabetes patients, controls or family members and proved that four rare variants or versions that reside in the gene IFIH1 reduce the risk of developing type 1 diabetes.
The four rare variants they identified, which are predicted to reduce function of the IFIH1 protein, consistently decrease the risk of type 1 diabetes, rather than predispose to it. This suggests a model where normal immune activation caused by enterovirus infection and mediated by IFIH1 protein stimulates autoimmunity that eventually leads to T1D, says Dr. John Todd, senior author on the study.
"We have been able to pinpoint one particular gene among a long list of candidates," Todd says. "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."
The findings and new scientific method will ultimately provide the knowledge to develop better strategies to detect, treat and prevent T1D and other genetic-based diseases in the future, Todd says.
"These new results pinpoint the IFIH1-MDA5 gene as being causal and actively participating in type 1 diabetes development, and indicate a route to identifying more genes specifically acting in the disease, from currently a very large list of possible candidate genes," Todd says. "While these results only accounts a very small piece of the whole picture, it is an important principal finding."
