Rare Mutation Protects Against Diabetes, May Be Drug Target

March 05, 2014

A newly identified, rare genetic mutation present in only 0.4% of people appears to reduce the risk for type 2 diabetes by about 65%.

The findings are published online in Nature Genetics by a consortium of international researchers, led by Jason Flannick, PhD, of Massachusetts General Hospital, Boston.

This is "the second example of a relatively rare variant in the genome that protects against type 2 diabetes, with relatively large effect," one of the corresponding authors, Kári Stefánsson, MD, from deCOde Genetics, Reykjavík, Iceland, told Medscape Medical News. "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."

This therefore points to a relatively "clean" target for drug development, said Dr. Stefánsson. "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. But no treatment will be available based on this for [at least] the next 5 to 10 years."

Asked to comment, Eric Topol, MD, of Scripps Translational Research Institute, La Jolla, California, said: "This is a very important finding — protection from type 2 diabetes, via very rare variants in a zinc-transporter gene (ZnT8)." And he agrees that it has major implications for drug discovery: "It paves the way for a whole new path for drug development and is indeed being used by at least 2 companies (Amgen [which owns deCODE Genetics] and Pfizer)."

Nevertheless, the consortium of scientists led by Dr. Flannick cautions that "substantial work is required to understand how reduced ZnT8 activity lowers type 2 diabetes risk."

Mutation Has No Impact on Weight, Affects Insulin

Dr. Flannick and colleagues 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.

Dr. Topol said 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 in the chain 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.

Earlier Finding of Cyclin D2 Association With Diabetes

Dr. Stefánsson also described the findings of the previous paper that identified the first rare mutation that appears protective against type 2 diabetes, in a gene called cyclin D2 (Nat Genet. 2014;46:294–298), he explained.

"That one is somewhat interesting because in addition to halving the risk of type 2 diabetes, it increases body mass, which is counterintuitive; it sort of speaks against the 'thrifty-gene' hypothesis." Carriers were, on average, 2.7-kg heavier and 1.2-cm taller than individuals who did not have this mutation, "so it's not a subtle impact on body size," he explained.

However, the likelihood of developing a drug based on these findings is much lower than in the case of the zinc-transporter gene, he said. "Cyclin D2 is involved with cell-cycle control, and we are concerned that we might predispose to proliferative disorders, like cancer, so we are somewhat skeptical of this as a drug target."

Dr. Stefánsson is chair and president of deCODE Genetics. Disclosures for the coauthors are listed online. Dr. Topol is editor-in-chief of Medscape Medical News.

Nat Genet. Published online March 2, 2014. Abstract


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