Gene that makes a zinc transporter could be a new drug target….
Kári Stefánsson, MD, from deCOde Genetics, Reykjavík, Iceland, one of the corresponding authors, stated that, "This is the second example of a relatively rare variant in the genome that protects against type 2 diabetes, with relatively large effect." "The gene loses its function, and it turns out to be advantageous in the current environment, which is somewhat counterintuitive," he observed.
And importantly, the mutation is "in a gene that makes a zinc transporter, and it has been shown before that decreased zinc transport appears to protect against type 2 diabetes, so all of this makes sense," he said.
In addition, "we did look at this mutation in the context of 750 other diseases, and we did not see any influence on them, so the only thing that the mutation does is to protect against type 2 diabetes; it does not increase the risk of any other disease."
Dr. Stefánsson added that this therefore points to a relatively "clean" target for drug development. "What needs to be done now is to study the wisdom of using the protein made by this gene as a target, and I think it will become a focus of the pharmaceutical industry for the next few years," he observed. However, he stressed that any actual resulting treatment for type 2 diabetes is still many years away.
"This is another step in the direction of understanding the biology of type 2 diabetes, and understanding the biology is quintessential to the development of effective treatments.
Lead author Jason Flannick, PhD, of Massachusetts General Hospital, Boston, and the consortium of international researchers note in their paper that loss-of-function mutations that protect against a disease without any seemingly adverse effects are "among the most useful findings from human genetics."
Building on pathways identified from genomewide association studies, they began by comparing 758 people in Finland and Sweden who were at either end of the spectrum for diabetes risk: young/lean individuals and elderly/obese.
They found that a couple of the older obese people had a mutation in an islet zinc transporter gene known as ZnT8. They expanded the research to thousands more people in mainly Scandinavian countries, who were obese and lean, old and young, with diabetes and without, and found another 31 who had mutations in the ZnT8 gene and seemed protected from type 2 diabetes.
At this point, the scientists approached deCODE Genetics and screened its database of Icelandic individuals. In total, almost 150,000 subjects of Icelandic, Finnish, and Swedish heritage were sequenced. Overall, the carriers of the mutation have a 65% reduced risk for type 2 diabetes; but Icelandic individuals, who have a very homogenous ancestry, had an 80% reduced risk, Dr. Stefánsson noted.
Asked to comment, Eric Topol, MD, of Scripps Translational Research Institute, La Jolla, California, said that one lesson to be learned from this research is how many patients it takes "to find these ‘buried treasures’ of Mother Nature — this took 150,000 people, and even more would have been better," he observed.
The next step is to study those who carry the mutation in more detail, Dr. Stefánsson said. "So far, the scientists have been able to deduce that the mutation has very little effect on body mass; it appears to affect the risk of type 2 diabetes by affecting insulin secretion."
"We are calling in the carriers of this mutation and submitting them to glucose-tolerance tests, feeding them a mixed diet, and looking at levels of insulin and glucagon, and so on," he said.
Nat Genet. Published online March 2, 2014. Abstract