Diabetes Dateline
Fall 2007

Researchers Identify New Genetic Risk Factors for Type 2 Diabetes

In the most comprehensive look at genetic risk factors for type 2 diabetes to date, a U.S.-Finnish team, along with two consortia—the Diabetes Genetics Initiative at the Broad Institute and the Wellcome Trust Case Control Consortium/U.K. Type 2 Diabetes Genetics Consortium—has identified at least four new genetic variants associated with increased diabetes risk and confirmed the existence of another six. The groups’ findings boost the number of genetic variants linked to increased susceptibility to type 2 diabetes to at least 10.

The U.S.-Finnish team received major support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Human Genome Research Institute’s (NHGRI) Division of Intramural Research, both part of the National Institutes of Health (NIH). The laboratory analysis of genetic variants in the first stage of the study was conducted by the Center for Inherited Disease Research with funding from the NIH and Johns Hopkins University.

“It has been a formidable challenge to identify the complex genetic factors involved in common diseases, such as type 2 diabetes,” said NHGRI Director Francis Collins, M.D., Ph.D. “Now, thanks to the tools and technologies generated by the sequencing of the human genome and subsequent mapping of common human genetic variations, we finally are making significant progress.”

In addition to lifestyle factors like obesity, poor diet, and lack of exercise, doctors have long known that heredity is a significant risk factor for developing type 2 diabetes—people who have a parent or sibling with type 2 diabetes face a 3.5 times greater risk of developing the disease than people with no family history. However, researchers have only just begun to zero in on particular genetic variants that increase or decrease disease susceptibility.

To make their discoveries, researchers used a relatively new, comprehensive strategy known as a genome-wide association study. For this kind of study, researchers use 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. Using DNA purified from blood cells, researchers quickly survey each participant’s complete set of DNA, or genome, for strategically selected markers of genetic variation.

If certain genetic variations are found more frequently in people with the disease compared with healthy people, the variations are said to be associated with the disease. The associated genetic variations can serve as a strong pointer to the region of the genome where the genetic risk factor resides. However, the first variants detected may not themselves directly influence disease susceptibility, and the actual causative variant may lie nearby. This means researchers often need to take additional steps, such as sequencing every DNA base pair in that particular region of the genome, to identify the exact genetic variant that affects disease risk.

Major Effort

The genomes of more than 32,000 people were tested for the study, making it one of the largest genome-wide association efforts conducted to date.

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, or beta, cells.

• CDKN2A and CDKN2B. The proteins produced by these genes inhibit the activity of cyclin-dependent protein kinases, including one that has been shown to influence the growth of beta cells in mice.

• chromosome 11. One 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.

Genetic variants associated with diabetes that were confidently confirmed by the new research are TCF7L2, SLC30A8, HHEX, PPARG, and KCNJ11.

“These genetic findings are exciting news for diabetes research,” said NIDDK Director Griffin P. Rodgers, M.D. “While more work remains to be done, the newly identified genetic variants may point us in the direction of valuable new drug targets for the prevention or treatment of type 2 diabetes.”

Visit www.diabetes.niddk.nih.gov/dm/pubs/overview for more information about diabetes and www.genome.gov/20019523 for more information about genome-wide association studies.

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NIH Publication No. 08–4562
October 2007