September 16, 2014

VIENNA — New research has identified a mutation in a gene, which appears to be carried only by Inuit people in Greenland, that dramatically increases the risk for type 2 diabetes by up to 50% when two copies of the variant are inherited.

The mutation in the gene, TBC1D4, confers "around a 40-fold higher effect size than what has been shown previously with other genes," Niels Grarup, MD, PhD, of the University of Copenhagen, Denmark, told a press briefing here at the European Association for the Study of Diabetes 2014 Meeting.

The observed effect size is "several times larger than any previous findings in large-scale genomewide association studies of these traits," say he and his colleagues, who published their research earlier this summer, led by Ida Moltke, PhD, of the University of Chicago (Nature. 2014;512:190-193).

Torben Hansen, from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, who was also involved in the work, told the press briefing the gene likely explains 10% to 15% of cases of type 2 diabetes in Greenland.

Asked to comment on the work, Leif C. Groop, MD, PhD, director of the Diabetes Center, Lund University, told Medscape Medical News this work reinforces "the need to study isolated populations, looking for rare variants."

And although he said there are seemingly no immediate clinical applications of the research "and we don't understand what this really means, it may be able to tell us about the causes of type 2 diabetes and what has happened in the course of evolution."

"Seeing is a prerequisite for understanding," said Dr. Groop, who will be the chair of the session in which the work is presented here tomorrow.

Dr. Grarup said they have looked for the mutation but failed to find it in any other ethnic group. However, what they learn from studying its effects in the Inuit may lead to important information that can be applied across the board, he said. For example, the team are now studying how the rise in postprandial glucose that results from this defect affects cardiovascular risk.

Logistics of the Study Challenging

Dr. Niels Grarup

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes prevalence during the past 25 years, Dr. Grarup explained.

"Greenland is a large country [with an area larger than Western Europe] with a small population," he noted, and in contrast to what is seen in many countries, type 2 diabetes rates "are higher in rural areas than in the urban areas, with obesity involving central fat [around the abdomen] prevalent among the Inuit," he noted.

Motivated by this, the researchers performed association mapping of type 2 diabetes–related quantitative traits in up to 2575 Greenlandic individuals without known diabetes, from the Inuit Health in Transition (IHIT) cohort.

This was a huge logistical task and was possible only because so many Greenlanders volunteered to participate; the investigation team had to access many of the individuals by boat.

Dr. Grarup noted that while there has been much mixing of the population in Greenland, with individuals migrating from Scandinavia, the mutation they discovered — a nonsense variant in the gene TBC1D4 with an allele frequency of 17% — was present only in predominantly pure Inuit individuals.

Over Age 40, 60% of Homozygous Individuals Have Diabetes

Those with 2 copies of the mutated gene (homozygous carriers) had markedly higher concentrations of plasma glucose and serum insulin 2 hours after an oral glucose load compared with individuals with other genotypes (both noncarriers and heterozygous carriers).

The homozygous carriers also had marginally lower concentrations of fasting plasma glucose and fasting serum insulin, and their type 2 diabetes risk was markedly increased (odds ratio [OR], 10.3).

"At the age of 40 to 60 years, more than 60% of the homozygous carriers of this mutation have type 2 diabetes," Dr. Grarup noted, and over the age of 60, more than 80% have diabetes.

The researchers were also able to show that the mutation does not appear to affect insulin secretion from the pancreas; rather, it disrupts insulin's action in the peripheral tissues, leading to a distinct type 2 diabetes subtype.

Gene May Have Been Advantageous in Evolutionary Terms

Dr. Hansen explained to journalists that the mutation may have originally conferred a protective effect. Because Inuit populations have traditionally survived on a fat and protein diet only, consuming whatever they can from the sea, "for the Inuit it may not have been a disadvantage to have prolonged hyperglycemia after eating," he noted.

But how this genetic mutation may affect Inuit now, who although primarily still residing in rural areas are being exposed to more and more Western dietary products, is unknown, he said.

However, Dr. Grarup said that many Inuit still live in the traditional way, as sealers and hunters in small isolated communities. But life is changing, and so it will be important to examine the effects as changes in communities occur.

"If this mutation has been driven to high frequency because it's advantageous when you have a diet composed of protein and fat, and now you are living on a diet that has a lot of carbohydrates, this mutation may actually be very harmful for these individuals," he said.

"It's complicated; the culture is rapidly changing, so it will always be just a glimpse in time," he told Medscape Medical News. And "the recruitment of these individuals was done 10 to 15 years ago, so things might have changed again."

European Association for the Study of Diabetes 2014 Meeting; September 17, 2014; Vienna, Austria. Abstract 103

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