Scientists from Cambridge University have discovered four rare mutations of a gene associated with type 1 diabetes (T1D) that reduce the risk of developing the disease. Their findings, published today in the journal Science Express, suggest a link between T1D and the enterovirus (a common virus that enters via the gastrointestinal tract but is often non-symptomatic).
Everyone carries the IFIH1 gene, which plays a role in the body's antiviral responses. Importantly, it is also located in the region of the human genome associated with T1D, an autoimmune disorder which results in the body attacking its own insulin-producing pancreatic cells. The IFIH1 gene codes for a protein that recognizes the presence of viruses in the cell and controls immune activation. It is within this gene that scientists have identified four gene variants that protect against T1D.
Enteroviruses are well known to be associated with T1D: enterovirus infections are more common among newly diagnosed T1D patients and pre-diabetic subjects than in the general population and often precede the appearance of biological markers for pre-diabetes. However, no one knows if these infections are a cause of type 1 diabetes.
The study by Nejentsev et al., which was conducted at the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, establishes that the IFIH1 protein is involved in T1D, highlighting a molecular pathway by which enterovirus infections may contribute to the development of the disease. The four rare variants they identified, which are predicted to reduce function of the IFIH1 protein, consistently decrease the risk of T1D, 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.
Professor John Todd, senior author on the study, said: "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."
In the past three years genome-wide association studies have been a major success, revealing dozens of regions in the human genome that harbour genes which predispose individuals to various diseases, such as diabetes or cancers. Nevertheless, as disease-associated regions may contain several genes with different functions, scientists rarely know which gene or gene variant (mutations of the gene) in these regions cause the disease.
In order to overcome this limitation, the scientists searched for variants that had obvious biological effects, e.g. those affecting gene expression or protein function. They hypothesized that if a gene harbors several such variants, then it is likely to be causative. Most of such variants are rare in the population and are not tested in genome-wide association studies. Nevertheless, they could be discovered by sequencing (examining the sequence of the pairs of nucleotides which make up a gene).
The researchers studied 10 candidate genes associated with T1D. Using a novel technique (high throughput sequencing of DNA pools) in collaboration with 454 Life Sciences, a Roche company, they examined the DNA of 480 T1D patients and 480 healthy controls. This approach allowed them to not only discover several rare variants associated with T1D, 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 T1D patients, controls or family members and proved that four rare variants or versions that reside in the gene IFIH1 reduce the risk of developing T1D.
The study demonstrates that re-sequencing genes associated with diseases can help pinpoint the specific gene or genes that lead to the disease.
"Finding several new rare disease variants with clear biological functions was crucial. Not only has this proved that IFIH1 is involved in type 1 diabetes, it also gave us clues to understand the mechanism" said Dr. Sergey Nejentsev, Royal Society Research Fellow at the Department of Medicine, the first author of the study. He added: "This experiment shows the way to identify causative genes contributing to various common diseases."
Genevieve Maul | EurekAlert!
Further reports about: > DNA > Diabetes > Enteroviruses > Genetic > IFIH1 > IFIH1 gene > Science TV > T1D > biological markers > enterovirus infections > gastrointestinal tract > gene variant > human genome > immune activation > insulin-producing pancreatic cells > pre-diabetes > rare genetic mutations > type 1 diabetes > viral infection
MicroRNA helps cancer evade immune system
19.09.2017 | Salk Institute
Ruby: Jacobs University scientists are collaborating in the development of a new type of chocolate
18.09.2017 | Jacobs University Bremen gGmbH
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...
Scientists from the MPI for Chemical Energy Conversion report in the first issue of the new journal JOULE.
Cell Press has just released the first issue of Joule, a new journal dedicated to sustainable energy research. In this issue James Birrell, Olaf Rüdiger,...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
19.09.2017 | Event News
19.09.2017 | Physics and Astronomy
19.09.2017 | Power and Electrical Engineering