Global research team links new genes to diabetes

Analysis identifies potential new therapeutic targets, suggests possible ties to prostate cancer

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BETHESDA, Md.—An international research collaboration recently reported it has identified several new genetic variants involved in type 2 diabetes, paving the way for development of potential new therapeutic targets.

Scientists involved with the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium discovered six "previously unknown loci with robust evidence for association" that increase diabetes risk—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, which affects more than 200 million people worldwide.

The research team also reached a second important conclusion—that the new variant most strongly associated with type 2 diabetes may also be tied to prostate to cancer.

The unprecedented findings were published March 30 in Nature Genetics by DIAGRAM, based at Oxford University, the University of Michigan, Massachusetts General Hospital and Harvard Medical School. DIAGRAM researchers combined data from three previously published genome-wide association studies in an effort to boost the statistical power of their searches. The three studies were the Diabetes Genetics Initiative (DGI), the Finland-United States Investigation of NIDDM Genetics (FUSION) and the Wellcome Trust Case Control Consortium (WTCCC).

Based on this pooling, 10,128 people and more than 2.2 million gene variants were available for analysis. Those links that were statistically significant at this stage were then investigated further using the pooled results from 10 other studies analyzing 57,000 additional people.

In that final stage, six of the gene variants were reliably linked to diabetes. The researchers were also able to show that the associations they felt were important had a similar pattern of association in separate populations.

The strongest evidence for an association was with a variant in a non-coding region of a gene called JAZF1. The researchers say that another variant in this same gene has been associated with prostate cancer. Overall, people who had this particular variant were 1.1 times (95 percent CI 1.07 to 1.13) more likely to have type 2 diabetes, according to the report.

"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," says Dr. Eleftheria Zeggini of Oxford University, one of the study's lead authors.

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.

"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," says study co-author Dr. Francis S. Collins, director of the NHGRI. "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."

The researchers say that further sequencing and mapping is needed to identify exactly where these gene variants are, although the report gives some indication of which genes they are near. Once found, these DNA changes must then be tested in the laboratory in cellular and animal models, which may give insights into the biology 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," adds another senior author, Dr. David Altshuler of Massachusetts General Hospital.
In addition to studying the biology of the SNPs, DIAGRAM says it may join forces with additional groups in the future to conduct an even larger scale meta-analysis.

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