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Researchers Identify new Genetic Risk Factors for Type 2 Diabetes

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In the most comprehensive look at genetic risk factors for type 2 diabetes to date, a U.S.-Finnish team, working in close collaboration with two other groups, has identified at least four new genetic variants associated with increased risk of diabetes and confirmed existence of another six.

The findings of the three groups, published in the online edition of the journal Science, boost to at least 10 the number of genetic variants confidently associated with increased susceptibility to type 2 diabetes – a disease that affects more than 200 million people worldwide.

“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 National Institutes of Health (NIH) Director Elias A. Zerhouni, M.D.

“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.”

Led by Michael Boehnke, Ph.D., of the University of Michigan’s School of Public Health, Ann Arbor; Francis Collins, M.D., Ph.D., of the National Human Genome Research Institute; Richard Bergman, Ph.D., of the University of Southern California, Los Angeles; Karen Mohlke, Ph.D. of the University of North Carolina, Chapel Hill; and Jaakko Tuomilehto, M.D., Ph.D. of the University of Helsinki and National Public Health Institute in Finland; the U.S.-Finnish team received major support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and NHGRI’s Division of Intramural Research, both part of the NIH.

The laboratory analysis of genetic variants in the first stage of the study was conducted by the Center for Inherited Disease Research, using funding from NIH and The Johns Hopkins University in Baltimore.

“We thank all the Finnish citizens who participated in this study. Their generosity has created a lasting legacy that will help to reduce the terrible toll that diabetes is taking on the world’s health,” said Dr. Tuomilehto of the Diabetes Unit in Finland’s National Public Health Institute.

After identifying promising leads through this approach, the three research teams jointly replicated their findings using smaller, more focused sets of genetic markers in additional groups totaling more than 22,000 people from Finland, Poland, Sweden, the United Kingdom and the United States. All told, the genomes of 32,554 people were tested for the study, making it one of the largest genome-wide association efforts conducted to date.

Ultimately, the researchers identified four new diabetes-associated variations, as well as confirmed previous findings that associated six other genetic variants with increased diabetes risk. 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 genetic variants associated with diabetes that were confidently confirmed by the new research are: TCF7L2, SLC30A8, HHEX, PPARG, KCNJ11 and FTO.

A variant in FTO was recently associated with increased risk of obesity. The latest study found that variations in or near the FTO gene are also associated with greater risk of type 2 diabetes, which is likely related to an increased predisposition to obesity.

When the genomes of the Finnish participants were scanned for all 10 diabetes-associated genetic variants, researchers could identify individuals whose genetic profiles placed them at increased risk for type 2 diabetes – including one subset of people who faced a risk four times higher than those at the lowest genetic risk. This “could potentially have value in a personalized preventive medicine program,” the researchers wrote.