Any of a dozen different mutations capable of abolishing the function of one gene can reduce the risk of type 2 diabetes, even in people who have risk factors such as obesity and old age. Overall—as shown by a genetic analysis of 150,000 patients—a loss-of-function mutation in the gene reduces risk by 65%.
Loss-of-function mutations that are protective against disease are much sought after because they uncover promising drug targets. That is, drugs capable of emulating protective loss-of-function mutations could prevent untold suffering. Such mutations have already been found to offer some degree of protection against HIV and elevated cholesterol related to heart disease risk. The new result, which pertains to a gene called SLC30A8, is the first to identify loss-of-function mutations that protect against diabetes.
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. However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk—and how large an effect could be expected.
The scientists that ultimately clarified the role of debilitated versions of the SLC30A8 gene began their work in 2009. At first, the scientists included collaborators from the Broad Institute, Massachusetts General Hospital, Pfizer, and Lund University Diabetes Center in Sweden. With a focus on identifying loss-of-function mutations protective against diabetes, the scientists sequenced the exons of 115 genes near diabetes association signals identified by genome-wide association studies in 758 individuals from Finland or Sweden. To increase power, they selected individuals at the extremes of diabetes risk including 352 young and lean diabetes cases and 406 elderly and obese euglycemic controls.
The researchers identified a genetic mutation that appeared to abolish function of the SLC30A8 gene and that was enriched in nondiabetic individuals studied in Sweden and Finland. This protective effect surprised the researchers, as they explained March 2 in Nature Genetics, in an article entitled “Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.” In this article, the authors noted that studies in mice had suggested that mutations in SLC30A8 might actually have the opposite effect—increasing rather than decreasing risk of diabetes.
Motivated to reinforce their findings, the researchers were stymied at first. The particular genetic variation they had found was exceedingly rare outside of Finland. Eventually, they studied another 7,212 additional Finnish or Swedish individuals. In addition, in 2012, they shared their unpublished results with deCODE Genetics, who uncovered a second mutation in an Icelandic population that also appeared to abolish function of the gene SLC30A8. That mutation independently reduced risk for diabetes and also lowered blood sugar in nondiabetics without any evident negative consequences.
Expanding their work yet further, the investigators looked for additional protective loss-of-function SLC30A8 mutations, and they considered patient populations beyond Finland and Iceland: “As part of the Genetics of Type 2 Diabetes (Go-T2D) and Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) consortia, we sequenced SLC30A8 exons in 12,294 individuals spanning multiple ancestry groups.” Now, with the T2D-GENES project as part of the collaboration, the research team found 10 more protective mutations in the SLC30A8 gene. Altogether, the research team amassed results confirming that inheriting one copy of a faulty SLC30A8 gene reduced diabetes risk by almost two thirds.
“This remarkable collaboration involved many partners who are fully dedicated to the pursuit of therapies for type 2 diabetes,” said 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. “It’s amazing to see what can be learned when everyone works together.”
Because the protective effects of the mutations were observed in patients from multiple ethnic groups, the researchers are hopeful that a drug capable of mimicking the effects of the mutations could have broad utility around the globe. Thus far, the mutations do not appear to have any deleterious effects.
“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,” added Altshuler.
In laboratory experiments, members of Altshuler’s team showed that the protective mutations disrupt the normal function of the protein encoded by SLC30A8, known as ZnT8. The ZnT8 protein transports zinc into insulin-producing beta cells, where zinc plays a key role in the crystallization of insulin. Exactly how the reduction in ZnT8 functions plays a protective role remains unknown.