Greenlander study identifies single mutation with large diabetes risk

By Eleanor McDermid, Senior medwireNews Reporter

Researchers have used a Greenlandic cohort to identify a genetic mutation whose effect on the risk of diabetes is “several times larger” than any previously discovered.

The mutation, which is reported in Nature, predominantly affects postprandial glucose levels, with these being substantially increased in people with two copies of the mutation.

Torben Hansen (University of Copenhagen, Denmark) and co-workers chose to study the Greenlandic population because of the “dramatic increase” in the prevalence of Type 2 diabetes over recent years. And indeed 17% of the 2733 participants had at least one copy of the mutation.

The mutation is p.Arg684Ter, a nonsense polymorphism in the TBC1D4 gene, the protein product of which has an essential role in insulin-stimulated glucose uptake. The mutation specifically resulted in reduced levels of the long form of the TBC1D4 protein. According to the researchers, this means that glucose uptake should remain unaffected in tissue such as adipose tissue, the liver and the pancreatic islets, but will compromise uptake in skeletal muscle.

And glucose uptake was impaired in people with p.Arg684Ter, most markedly in those who were homozygous for the mutation. Their 2-hour glucose levels in an oral glucose tolerance test were 3.8 mmol/L higher than levels in people with one or no copies of the mutation.

Even people with just one copy had a still significant 0.43 mmol/L higher 2-hour glucose level than those without the mutation. By contrast, fasting glucose and insulin levels were slightly but significantly lower in people who were homozygous for p.Arg684Ter than in people with one or no copies.

The cohort contained 220 people with Type 2 diabetes and 1810 without. Having two copies of p.Arg684Ter was strongly associated with diabetes, at an odds ratio of 10.3. However, the association was much weaker if diabetes was defined according to glycated haemoglobin levels and excluded glucose data.

“Thus, our findings indicate that the p.Arg684Ter TBC1D4 variant confers increased risk of a subset of diabetes that features deterioration of postprandial glucose homeostasis”, say Hansen et al. “In this context, it is of interest that 2-h glucose levels appear to be a better predictor of cardiovascular disease than do fasting plasma glucose levels.”

Two copies of p.Arg684Ter were present in 15.5% of people with diabetes, compared with 1.6% of glucose-tolerant people. This indicates that the mutation accounts for more than 10% of the cases of diabetes in Greenland, says the team.

Based on previous studies, the researchers say that “the variant is not unique to the Greenlandic population but is probably common only among Greenlanders and other related populations.”

Nevertheless, they say that their study “demonstrates the strength of conducting genetic association mapping outside the traditional setting of large homogeneous populations.”

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