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Archive - 04 - 2007
April 27, 2007 (EurekAlert) - A UK collaboration of scientists has identified three new genes that predispose individuals to develop type 2 diabetes, bringing scientists a step closer towards understanding what causes this complex disease. The study, jointly led by researchers at the University of Oxford and the Peninsula Medical School, Exeter, and forming part of the Wellcome Trust Case Control Consortium looked at over 2 billion pieces of genetic data and 6,000 people with type 2 diabetes and 8,000 controls to track down these three genes. In addition, they confirmed the link between the disease and a further two previously-identified genes. The findings, published online today in the journal Science, bring the total number of genes known to be involved in type 2 diabetes to nine, including the FTO gene reported by the same UK group two weeks ago. The FTO gene influences individual risk of type 2 diabetes through its effect on weight and obesity. Type 2 diabetes occurs as a result of a failure of the body to produce enough insulin to maintain normal levels of glucose (sugar) in the blood. This failure is usually compounded by a reduction in the capacity of the insulin released to work properly in tissues such as muscle and fat (known as insulin resistance). It is a major cause of heart disease and stroke, as well as blindness and kidney failure.There are currently around 200 million people who have type 2 diabetes worldwide, yet its underlying cause is poorly understood, limiting both treatment and prevention. Lifestyle factors, such as poor diet and lack of exercise have been known for some time to increase risk of developing the disease, but scientists are becoming increasingly aware of the role played by genetics. For each of the three genes described in the paper, the researchers have found that there are two common "versions", one of which is associated with an increased risk of developing type 2 diabetes, and the other with reduced risk. Each high-risk version increases the risk of type 2 diabetes by between 10 and 20 percent. All are common in the general population."This research helps us to understand that, for most people at least, an individuals risk of developing diabetes as they get older is influenced by a number of genes, as well as by their environment," says Professor Mark McCarthy from the University of Oxford, one of the lead authors of the paper. "Clearly, the more 'high risk' alleles a person inherits, the higher the likelihood that they will go on to develop diabetes."The exact role of the genes that have been implicated by these studies is still uncertain. However, two of them appear to be involved in the development, function and regeneration of insulin-producing beta cells, found within the pancreas. This finding is likely to help to answer a long-standing controversy in the diabetes field concerning the extent to which a reduced number of pancreatic beta-cells (as opposed to reduced function) contributes to the development of diabetes. "We now have significantly more pieces to the jigsaw that will help us understand the mechanisms behind type 2 diabetes," says Professor Andrew Hattersley of the Peninsula Medical School, also a lead author on the paper. "Each piece of new knowledge takes us a step closer towards a future with improved prevention and treatment of this very significant condition." The first important clues to the identities of these genes came from a genome-wide analysis conducted in 2,000 people with type 2 diabetes and 3,000 controls as part of the Wellcome Trust Case Control Consortium2. The Consortium is one of the biggest projects ever undertaken to identify the genetic variations that predispose people to or protect them from major diseases.Professor Peter Donnelly of the University of Oxford, who heads the consortium said: "This landmark study reveals the power of the strategy that the Wellcome Trust Case Control Consortium has adopted to study diabetes and several other common diseases. It is clear that these and other findings which the Consortium will shortly be reporting will have a major impact on our understanding of the mechanisms behind many diseases of global importance." These initial findings were then confirmed by studying a further 9,000 samples from the UK (the majority of them from the Dundee area collected by researchers from the Ninewells Hospital and Medical School. The research has been conducted in close collaboration with two other groups from the US and Scandinavia, who were undertaking similar research studies in samples from Sweden and Finland. Their results, which have also identified the same three genes, are published today alongside the UK study. In a unique collaboration, these three international groups chose to combine forces rather than compete, resulting in the largest ever collaborative study of type 2 diabetes, involving over 32,000 subjects. "The extraordinary achievements of this research project have only been made possible through the unique international collaboration," says Dr Mark Walport, Director the Wellcome Trust, which funded the UK study. "By sharing data and working together, the researchers have made significant progress in understanding the genetics underlying type 2 diabetes in a very short time." Iain Frame, Research Manager at Diabetes UK, said: "Diabetes UK welcomes these exciting findings. Its important to remember that Type 2 diabetes is a genetic condition and not just associated with lifestyle factors. This discovery will help us get closer to unravelling the genetics of the condition. If we can understand more about the genetics we can make real progress towards the prevention and treatment of Type 2 diabetes. "Diabetes UK funded the original collection of samples at the beginning of this study. It is thanks to the collaborative efforts of Diabetes UK, a number of excellent researchers and the Wellcome Trust that this discovery has been possible."
April 27, 2007 (EurekAlert) - Ten genetic variants associated with type 2 diabetes, a disease which impacts more than 170 million people worldwide, have been identified or confirmed by a U.S.-Finnish team led by scientists at the University of Michigan School of Public Health.The discoveries could lead to the development of new drugs for diabetes, permit more effective targeting of drug and behavioral therapies, and help scientists and physicians better predict who will develop diabetes, said Michael Boehnke, the Richard G. Cornell Collegiate Professor of Biostatistics at the U-M School of Public Health. Boehnke is the lead scientist on the Finland-United States Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics (FUSION) study group, which collaborated with two other groups of scientists to conduct the most comprehensive study to date of genetic risk factors for type 2 diabetes. "Until recently we knew very little about the genetic architecture of type 2 diabetes," said Boehnke, adding that diabetes has been called 'the geneticist's nightmare' because there are so many behavioral and environmental factors---in addition to genes---that are risk factors for the disease. "This is certainly not the complete genetic architecture for diabetes, but we have come a long way in better understanding the genetic basis for this disease."The groups identified at least four new genetic factors associated with increased risk of diabetes and confirmed the existence of another six. The findings of the three groups, published simultaneously today in the online edition of the journal Science, boost to at least 10 the number of genes confidently associated with increased susceptibility to type 2 diabetes. "One of the nicest aspects of this study has been the collaboration between the three groups," Scott said. "Most of these variants would have taken substantially longer to identify if each group had proceeded independently." Type 2 diabetes is characterized by high levels of blood sugar, caused by the body's inability to utilize insulin to move blood sugar into the cells for energy. Type 2 diabetes affects nearly 21 million in the United States and the incidence of the disease has skyrocketed in the last 30 years. Diabetes is a major cause of heart disease and stroke, as well as the most common cause of blindness, kidney failure and amputations in U.S. adults."By identifying these genes, we are identifying potential loci for drug action and suggesting classes of compounds that might be useful to help develop drugs to treat diabetes," Boehnke said. In the study, researchers used a relatively new strategy known as a genome-wide association study, Boehnke said. Researchers began by scanning the genomes of more than 2,300 Finnish by typing more than 300,000 strategically selected markers of genetic variation. About half of the participants had type 2 diabetes and the other half had normal blood glucose levels.To validate their findings, the researchers compared their initial findings with results from genome-wide studies of 3,000 Swedish and Finnish participants carried out by the Diabetes Genetics Initiative and 5,000 British participants done by the Wellcome Trust Case Control Consortium and UK Type 2 Diabetes Consortium. After identifying promising leads through this approach, the three research teams jointly replicated their findings by testing more focused sets of genetic markers in additional groups totaling more than 22,000 people from Finland, Sweden, Poland, the United States and the United Kingdom. All told, more than 32,000 people were tested for the study, making it one of the largest genome-wide association and follow-up efforts conducted to date."This achievement represents a major milestone in our battle against diabetes. It will accelerate efforts to understand the genetic risk factors for this disease, as well as explore how these genetic factors interact with each other and with lifestyle factors," said Elias A. Zerhouni, director of the National Institutes of Health. "Such research is opening the door to the era of personalized medicine. Our current one-size-fits-all approach will soon give way to more individualized strategies based on each person's unique genetic make-up."The newly identified diabetes-associated variations lie in or near: IGF2BP2. This gene codes for a protein called insulin-like growth factor 2 mRNA binding protein 2. Insulin-like growth factor 2 is thought to play a role in regulating insulin action.CDKAL1. This gene codes for a protein called CDK5 regulatory subunit associated protein1-like1. The protein may affect the activity of the cyclin dependent kinase 5 (CDK5) protein, which stimulates insulin production and may influence other processes in the pancreas's insulin-producing cells, known as beta cells. In addition, excessive activity of CDK5 in the pancreas may lead to the degeneration of beta cells.CDKN2A and CDKN2B. The proteins produced by these two genes inhibit the activity of cyclin-dependent protein kinases, including one that has been shown to influence the growth of beta cells in mice. Interestingly, these genes have been heavily studied for their role in cancer, but their contribution to diabetes comes as a complete surprise.Chromosome 11. One intriguing association is located in a region of chromosome 11 not known to contain any genes. Researchers speculate that the variant sequences may regulate the activity of genes located elsewhere in the genome, but more work is needed to determine the exact relationships to pathways involved in type 2 diabetes.The diabetes-associated genetic variants that were confidently confirmed by the new research are: TCF7L2, SLC30A8, HHEX, PPARG, KCNJ11 and FTO.
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