Mining for protective mutations

An international collaboration discovers mutations in a gene that can reduce diabetes risk and offer a potential drug target

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CAMBRIDGE, Mass.—Diabetes stands as one of the most prevalent medical burdens worldwide, and with obesity and old age as primary risk factors, the issue is only expected to get worse. In the face of this challenge, a good deal of focus is on options for mitigating one’s chances of developing diabetes through better diet and exercise.
But an international team headed by scientists from Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard are taking another tack in the search for prevention options: protective genetic mutations. A recent study by this team uncovered mutations of a gene that reduce a person’s risk of developing type 2 diabetes, even if that person has existing risk factors.
The gene in question is SLC30A8, and in a genetic analysis of 150,000 patients, the researchers discovered some presented with rare mutations that reduced their risk of type 2 diabetes by 65 percent. SLC30A8 encodes ZnT8, a protein that has been previously shown to play a role in transporting zinc to the insulin-secreting beta cells found in the pancreas, and a common variant in that gene has been known to influence diabetes risk. Members of co-senior author David Altshuler’s team showed in the lab that the protective mutations disrupt the normal function of ZnT8, though how reducing the protein’s functions offers protective advantages isn’t yet known. Altshuler is deputy director and chief academic officer at the Broad Institute and a Harvard Medical School professor at Massachusetts General Hospital.
This study is the offspring of a research partnership struck in 2009 between the Broad Institute, MGH, Pfizer Inc. and Lund University Diabetes Centre in Sweden. The partnership sought to identify mutations that reduce the risk of type 2 diabetes, focusing on people with severe risk factors, such as age and obesity, who had never developed diabetes and presented with normal blood sugar levels. Focusing on genes that had previously been identified as playing a role in type 2 diabetes, they used next-generation sequencing to analyze the subjects’ genomes for rare mutations.
What they discovered was a mutation that seemed to abolish function of the SLC30A8 gene, one that is enriched in non-diabetic individuals in Sweden and Finland (and extremely rare outside of Finland). A few years later, the results were shared with deCODE genetics, who proceeded to discover a second mutation in an Icelandic population that also seemed to negate function of SLC30A8, reducing risk for developing type 2 diabetes and lowering blood sugar in non-diabetics.
“This approach has a number of important benefits. Looking at mutations in humans is a more direct strategy for understanding a disease than working with lab animals or cells, because proteins don’t always work the same way in humans as in animals,” says first author Jason Flannick, a research fellow in Altshuler's lab at the Broad Institute and at Massachusetts General Hospital. “‘Loss of function’ mutations are particularly valuable because they tell us how to manipulate a protein in humans to achieve a desired therapeutic effect (protection from disease). For instance, SLC30A8 was identified several years ago as a potential drug target, but nobody knew whether drugs should increase or decrease its activity – in fact, many scientists thought that you would want to activate it. Our work turns that hypothesis on its head, because it shows that humans with less SLC30A8 activity are protected from type 2 diabetes.”
In order to determine whether those protective mutations were exclusive to the two found in the Finnish and Icelandic populations, the Broad Institute—as part of the National Institutes of Health-funded T2D-GENES Project, chaired by Mike Boehnke at the University of Michigan—sequenced 13,000 samples from multiple ethnicities. The T2D-GENES Project also joined the collaboration and found an additional 10 mutations in the same gene that also demonstrated a protective effect. Their results confirmed that inheriting a single copy of a defective version of SLC30A8 resulted in a 65-percent reduction in the risk of developing diabetes.
Flannick explains that there are several mutations related to this gene, many of which have yet to be identified or catalogued. One common mutation of SLC30A8 is rather like a dark twin of the beneficial mutation discovered in this study: it is present in some 35 percent of the population and increases disease risk by altering the activity of the protein SLC30A8 encodes.
“Our work was the first example of mutations in SLC30A8 that have protective effects,” he notes. “The 12 we identified all truncate the protein, and thus have the largest predicted effects to date on the protein. While we were able to show that the average reduction in risk of these mutations was 65 percent, we don’t have enough data—even with 150,000 samples—to conclude whether all have the same effect or whether the magnitude varies.”
This approach is not without restrictions, however, as Flannick notes that “it doesn’t tell us how reducing SLC30A8 activity protects against diabetes; it’s important to do future lab or genetic work to understand this.” In addition, validating their discovery required several thousands patients and massive amount of genetic and clinical data, all for just a single gene. In the future, he says, “To find more genes like it, we need new solutions to encourage and enable this kind of sharing at a very large scale.”
Moving forward, Flannick says they need to understand how these loss of function mutations can reduce diabetes risk, by studying either individuals with the mutations or the effects of said mutations in the lab. Should that work solidify SLC30A8’s potential as a drug target, further work will be required to determine the best way of inhibiting its activity.
“This work underscores that human genetics is not just a tool for understanding biology: it can also powerfully inform drug discovery by addressing one of the most challenging and important questions — knowing which targets to go after,” said Altshuler.
Major funding for this research came from Pfizer Inc., the National Institutes of Health, the Doris Duke Charitable Foundation and other organizations. The study, “Loss-of-function mutations in SLC30A8 protect against type 2 diabetes,” was published in Nature Genetics.

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