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Researchers Uncover Common Variant Linked to Diabetes in Greenlanders

NEW YORK (GenomeWeb) – A common variant among Greenlanders is associated with insulin resistance and type 2 diabetes, researchers led by the University of Copenhagen's Torben Hansen reported in Nature today.

Through association mapping of T2D-related traits in some 2,700 people in Greenland, Hansen and his colleagues homed in on a variant within the TBC1D4 gene that's linked with the condition. This nonsense variant, they reported, leads to a prematurely terminated version of the long TBC1D4 isoform and is associated with higher levels of circulating glucose and insulin levels after glucose tolerance testing.

"[I]n homozygous carriers [this variant] causes insulin resistance in skeletal muscle and confers a high risk of a subtype of T2D that is characterized by a deterioration of postprandial glucose homeostasis," Hansen and his colleagues said in their paper.

Type 2 diabetes affects some 347 million people worldwide, according to the World Health Organization. And Greenland, which has a small and isolated founder population of some 57,000 people, has seen a "dramatic increase" in T2D in the last quarter century, the researchers added.

Studying such a founder population, they said, could increase the statistical power to uncover associations between genes and disease.

To search for variants linked to glucose homeostasis, the researchers genotyped 2,733 people participating in the Inuit Health in Transition study using the Illumina Metabochip, a custom iSelect array that includes more than 196,700 SNPs, and analyzed the results using a linear mixed model, to take into account both admixture and relatedness.

In this cohort of participants without previously known T2D, the researchers linked a minor allele of rs7330796 to higher plasma levels of glucose and serum levels of insulin, an association they replicated in a separate Greenland cohort of 1,401 people.

By sequencing the exomes of nine trios, Hansen and his colleagues narrowed in on four coding SNPs in the vicinity of rs7330796. A nonsense polymorphism — p.Arg684Ter — in TBC1D4 was associated with plasma glucose levels in the discovery cohort.

Further conditional analyses such as those looking at the interactions of rs7330796 and p.Arg684Ter on plasma glucose and serum insulin levels, the researchers said, indicated that p.Arg684Ter is the causal variant.

The effect of the variant on plasma glucose levels also suggested, the researchers said, that the variant mainly has an effect in homozygous carriers, indicating a recessive inheritance pattern.

In the discovery cohort, homozygous carriers of p.Arg684Ter had higher plasma glucose levels than all other individuals and had a strong association with T2D risk. Homozygous carriers also had decreased peripheral insulin sensitivity and lower fasting plasma glucose and serum insulin levels.

"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," Hansen and his colleagues said.

Further, the effect of the p.Arg684Ter allele on plasma glucose and T2D risk is larger than others previously found through genome-wide association studies, they said.

TBC1D4, the researchers noted, mediates insulin-stimulated Akt-induced glucose uptake, through Rab-mediated regulation of GLUT4 mobilization. Knockout mice lacking the TBC1D4 gene have decreased basal plasma glucose levels, are resistant to insulin-stimulated glucose uptake in both muscle and adipose tissue, and have lower GLUT4 levels.

Additionally, the p.Arg684Ter variant is predicted to affect only the long TBC1D4 isoform, which is typically expressed in skeletal tissue. The variant appears to cause early termination in exon 11, the researchers said.

In three people — one with no copy of the p.Arg684Ter variant, one with one copy, and one with two copies — the researchers noted that levels of the long TBC1D4 isoform decreased as the number p.Arg684Ter variants increased, as did the levels of GLUT4 proteins. The short TBC1D4 isoform was expressed at low levels regardless of the presence of the variant.

"Our data indicate that disruption of the full-length TBC1D4 protein in skeletal muscle results in severely decreased insulin-stimulated glucose uptake, leading to postprandial hyperglycemia, impaired glucose tolerance, and T2D," they said.

In the discovery cohort, the researchers calculated the p.Arg684Ter variant to have a minor allele frequency of 17 percent, and estimated it to have MAF of 23 percent and 0 percent, respectively, in the Inuit and European populations that are ancestral to modern Greenlanders.

As the researchers noted, the variant can be found in other populations, so it "is not unique to the Greenlandic population but is probably common only among Greenlanders and other related populations."

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