Co-senior author David Altshuler, deputy director and chief academic officer at the Broad Institute and a Harvard Medical School professor at Massachusetts General Hospital, said the findings focus the search for developing novel therapeutic strategies for type 2 diabetes.
If a drug could be developed that mimics the protective effect of these mutations, it could open up new ways of preventing type 2 diabetes, Altshuler said.
Altshuler and colleagues studied the genome of aging, overweight people who had normal blood sugar levels.
The initial analysis revealed a mutation in the gene SLC30A8 that stopped it from functioning -- a discovery the research team found surprising. Previous studies in mice showed mutations in this gene increased the risk of type 2 diabetes.
The researchers said the further genetic analysis of 150,000 patients showed rare mutations in the gene SLC30A8 reduced the risk of type 2 diabetes by 65 percent. The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility.
The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes.
As part of the T2D-GENES Project, Mike Boehnke at the University of Michigan and the Broad Institute of the Massachusetts Institute of Technology and Harvard performed sequencing of 13,000 samples drawn from multiple ethnicities.
The researchers found 10 more mutations in the same gene, that again saw a protective effect. Combining all the results confirmed that inheriting one copy of a defective version of SLC30A8 led to a 65 percent reduction in risk of diabetes.
"Through this partnership, we have been able to identify genetic mutations related to loss of gene function, which are protective against type 2 diabetes," said Tim Rolph, vice president and chief scientific officer of cardiovascular, metabolic & endocrine disease research at Pfizer Inc. "Such genetic associations provide important new insights into the pathogenesis of diabetes, potentially leading to the discovery of drug targets, which may result in a novel medicine."
The findings were published in the journal Nature Genetics.