New genetic clues to diabetes

An international team that included scientists from the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), today reported it has identified six more genetic variants involved in type 2 diabetes, boosting to 16 the total number of genetic risk factors associated with increased risk of the disease.

None of the genetic variants uncovered by the new study had previously been suspected of playing a role in type 2 diabetes. Intriguingly, the new variant most strongly associated with type 2 diabetes also was recently implicated in a very different condition: prostate cancer.

The unprecedented analysis, published today in the advance online edition of Nature Genetics, combined genetic data from more than 70,000 people. The work was carried out through the collaborative efforts of more than 90 researchers at more than 40 centers in Europe and North America.

"None of the genes we have found was previously on the radar screen of diabetes researchers," said one of the paper?s senior authors, Mark McCarthy, M.D., of the University of Oxford in England. "Each of these genes, therefore, provides new clues to the processes that go wrong when diabetes develops, and each provides an opportunity for the generation of new approaches for treating or preventing this condition."

When considered individually, the genetic variants discovered to date account for only small differences in the risk of developing type 2 diabetes. But researchers say when all of the variants are analyzed together, some significant differences in risk are likely to emerge. "By combining information from the large number of genes now implicated in diabetes risk, it may be possible to use genetic tools to identify people at unusually high or low risk of diabetes. However, until we know how to use this information to prompt beneficial changes in people?s treatment or lifestyle, widespread genetic testing would be premature," said another senior author, David Altshuler, M.D., Ph.D., of Massachusetts General Hospital in Boston and the Broad Institute of Massachusetts Institute of Technology and Harvard in Cambridge, Mass.

Type 2 diabetes affects more than 200 million people worldwide, including nearly 21 million people in the United States. Previously known as adult-onset, or non-insulin dependent diabetes (NIDDM), type 2 diabetes usually appears after age 40, often in overweight, sedentary people. However, a growing number of younger people and even children are developing the disease.

Diabetes is a major cause of heart disease and stroke in U.S. adults, as well as the most common cause of blindness, kidney failure and amputations not related to trauma. Type 2 diabetes is characterized by the resistance of target tissues to respond to insulin, which controls glucose levels in the blood; and a gradual failure of insulin-secreting cells in the pancreas.

"These new variants, along with other recent genetic findings, provide a window into disease causation that may be our best hope for the next generation of therapeutics. By pinpointing particular pathways involved in diabetes risk, these discoveries can empower new approaches to understanding environmental influences and to the development of new, more precisely targeted drugs," said NHGRI Director Francis S. Collins, M.D., Ph.D., who is a co-author of the study. Dr. Collins' laboratory is a participant in the Finrisk 2002 and Finland-United States Investigation of NIDDM Genetics (FUSION), which were among the studies that contributed data to the new analysis. FUSION is funded by NHGRI?s Division of Intramural Research and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Researchers said more work is needed to understand the impact of their discovery that a genetic variant called JAZF1 appears to be involved in diabetes as well as prostate cancer. One of the study?s lead authors, Eleftheria Zeggini, Ph.D., of the University of Oxford, said, "This is now the second example of a gene which affects both type 2 diabetes and prostate cancer. We don?t yet know what the connections are, but this may have important implications for the future design of drugs for both of these conditions."

The research was conducted by the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, which brought together many groups active in the field of diabetes research. In the Nature Genetics paper, DIAGRAM researchers combined the data from three previously published genome-wide association studies in an effort to boost the statistical power of their searches — an approach that scientists refer to as meta-analysis. The strategy paid off, enabling researchers to identify six genetic variants associated with type 2 diabetes that had gone undetected in the smaller, individual studies.