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Researchers Identify 12 Genomic Regions Associated with Type 2 Diabetes Predisposition

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Originally published July 6.

In a meta-analysis of eight genome-wide association studies of type 2 diabetes involving more than 8,000 diabetes patients and nearly 39,000 controls of European descent, researchers from numerous institutions worked together to link DNA variants in 12 regions on the genome with increased risk of type 2 diabetes.

The study, which also followed up on "previously unidentified meta-analysis signals" in more than 34,000 cases and nearly 60,000 controls, was published online on June 27 in Nature Genetics.

The 12 genomic regions implicated in the study included "the second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A)," the study authors reported in the paper. "The identified loci affect both beta-cell function and insulin action, and, overall, type 2 diabetes association signals show evidence of enrichment for genes involved in cell cycle regulation."

The research was led by Benjamin Voight of the Broad Institute of Harvard and Massachusetts Institute of Technology, and included scientists from numerous US and European academic institutions.

The findings reported in the study add to previously published work by the researchers that linked approximately 25 common variants to type 2 diabetes predisposition through genome-wide association studies. Currently, known variants conferring susceptibility to type 2 diabetes account for less than 10 percent of the overall genetic risk thought to be related to disease predisposition.

"What our study suggests is that many of these variants are associated with changes in glucose levels long before people get diabetes," said study co-leader Michael Boehnke, professor of biostatistics at University of Michigan's School of Public Health, in a statement.

The researchers' aim was to home in on study participants' genetic predisposition to type 2 diabetes. Specifically, researchers were looking for variants in genome regions linked to elevated glucose levels in those who had not yet developed diabetes. Elevated blood glucose levels have shown to be a major predictor of diabetes.

"One surprising finding was that the regions with diabetes variants also seemed to be associated with nonrelated diseases," the University of Michigan said in a statement announcing the study's publication. In order to investigate whether regions linked to type 2 diabetes could also be linked to other ailments and traits, researchers analyzed a database containing a list of all the genome-wide association studies conducted to date.

According to Boehnke, researchers identified an "overlap or predisposition of not just related but also apparently unrelated traits," suggesting "there could be master regulators in the genome that play a role in many different aspects of physiology and health."

In the Nature Genetics paper, the researchers emphasize the importance of "obtaining complete descriptions of causal genetic variation (of all types and frequencies) at the loci uncovered by this and other GWA studies," since such loci are likely to represent "hotspots at which the overall contribution to T2D predisposition and biology may be considerably greater than that estimated using the discovered common variants alone."

In order to validate these preliminary findings, researchers will widen their search of regional genome associations through sequencing. By expanding the power of the study, "there are likely to be many additional common variant signals of similar effect that could be detected by further expansion of the GWA meta-analysis approach," the researchers wrote in Nature Genetics.

Currently, a three-study international team co-led by the Michigan group is sequencing 2,650 individuals with and without diabetes. The researchers hope to have insight into the variants present in individuals with and without diabetes in the next 18 months.

The study received funding from the American Diabetes Association and other non-profits; from industry, including The Foundation of Bristol-Myers Squibb, Lilly, Novartis, Novo Nordisk, Roche; from various government entities, among them the National Human Genome Research Institute and the National Institute of Diabetes, Digestive and Kidney Diseases; as well as from various academic institutions.

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