In the most comprehensive look at genetic risk factors for type 2 diabetes to date, researchers from USC, the University of Michigan, the National Human Genome Research Institute, the University of North Carolina and Finland’s National Health Institute have identified at least four new genetic variants associated with increased risk of diabetes and confirmed the existence of another six.

The findings are posted in the current online edition of the journal Science.

“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.”

These findings distinguish at least 10 genetic variants confidently associated with increased susceptibility to type 2 diabetes, a disease that 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 in U.S. adults of blindness, kidney failure and amputations not related to trauma.

“These genetic risk factors will make it more likely that we can predict who is at risk for the disease,” said Richard Bergman, the chair of the department of physiology and biophysics at the Keck School of Medicine of USC. “We know type 2 takes a long time to develop and if we can identify those at risk of the disease, we may be able to prevent or delay the risk of disease in these people.”

Researchers used a relatively new, comprehensive strategy known as a genome-wide association study by using two groups of participants: a large group of people with the disease being studied and a large group of otherwise similar people without the disease. Utilizing DNA purified from blood or cells, researchers quickly surveyed each participant’s complete set of DNA, or genome, for strategically selected markers of genetic variation.

In the latest work, researchers began by scanning the genomes of more than 2,300 Finnish people who took part in the Finland-United States Investigation of NIDDM Genetics (FUSION) and Finrisk 2002 studies. 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 results with results from genome scans of 3,000 Swedish and Finnish participants in the Diabetes Genetics Initiative and 5,000 British participants in the Wellcome Trust Case Control Consortium.

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.

“This is a very exciting time for the genetics of type 2 diabetes. There are real signals in the genome for the disease. Many are unexpected or unexplained and each one accounts for only a small risk,” said Tom Buchanan, professor of medicine at USC. “However, together they account for a lot of risk. Our challenge now, a challenge that the USC Diabetes Group has already begun to undertake in human studies, is to figure out how the risk genes work and how they work together with environmental factors to cause diabetes. The FUSION results are a big step for genetics, but an even bigger opportunity for understanding one of the most common and most rapidly increasing diseases of the developed world.”

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’ 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.

Bergman, Buchanan and Richard Watanabe, associate professor of preventive medicine at USC, were instrumental in helping decipher some of these results.

“We were able to provide the important physiologic and clinical feedback necessary to guide the hunt for the genes,” Watanabe said. “In addition, compared to the other centers, USC's contribution was unique in that it was multi-dimensional. We provided support in terms of performing assays, providing the biologic perspective, and performing data analysis and interpretation. It speaks to the diverse talent and expertise in diabetes research that exists at USC.”

The researchers emphasized that their predictions of disease risk need to be interpreted with caution because the diabetes group in their sample was “enriched” with people who had affected siblings and because the healthy group excluded people who had impaired glucose tolerance or impaired fasting glucose.

The study was led by Michael Boehnke of the University of Michigan’s School of Public Health, Ann Arbor; Francis Collins of the National Human Genome Research Institute; Richard Bergman of USC; Karen Mohlke of the University of North Carolina, Chapel Hill; and Jaakko Tuomilehto of the University of Helsinki, South Ostrobothnia Central Hospital 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.