Diabetes in Population Isolates: Lessons from Greenland

Abstract

Type 2 diabetes (T2D) is an increasing health problem worldwide with particularly high occurrence in specific subpopulations and ancestry groups. The high prevalence of T2D is caused both by changes in lifestyle and genetic predisposition. A large number of studies have sought to identify the genetic determinants of T2D in large, open populations such as Europeans and Asians. However, studies of T2D in population isolates are gaining attention as they provide several advantages over open populations in genetic disease studies, including increased linkage disequilibrium, homogeneous environmental exposure, and increased allele frequency. We recently performed a study in the small, historically isolated Greenlandic population, in which the prevalence of T2D has increased to more than 10%. In this study, we identified a common nonsense variant in TBC1D4, which has a population-wide impact on glucose-stimulated plasma glucose, serum insulin levels, and T2D. The variant defines a specific subtype of non-autoimmune diabetes characterized by decreased post-prandial glucose uptake and muscular insulin resistance. These and other recent findings in population isolates illustrate the value of performing medical genetic studies in genetically isolated populations. In this review, we describe some of the advantages of performing genetic studies of T2D and related cardio-metabolic traits in a population isolate like the Greenlandic, and we discuss potentials and perspectives for future research into T2D in this population.

Figure 1. The effect of the TBC1D4 p.Arg684Ter variant on 2-h plasma glucose in Greenlanders compared to the effect of reported variants in Europeans

The figure shows the effects of the reported variants on 2-h plasma glucose [19, 36] in mmol/l as a function of minor allele frequency (as a function of risk genotype frequency, assuming a recessive model). The effect sizes are reported on a log-scale. The TBC1D4 variant is plotted assuming both an additive and a recessive model.

Figure 2. Fasting and 2-h plasma glucose levels in p.Arg684Ter allele carriers with T2D

Homozygous TBC1D4 p.Arg684Ter variant carriers are shown in blue; homozygous p.Arg684Ter variant non-carriers and heterozygotes are shown in white. Data are from the 172 individuals with screen-detected T2D from the IHIT cohort for whom genotype information for this specific variant was available. T2D was diagnosed according to WHO 1999 criteria [7] based on fasting and 2-h plasma glucose values.

Figure 3. The effect of variants reported to associate with glycemic traits in Europeans and Greenlandic Inuit

The effects were estimated for the ancestral population using AsaMap [47]. Only variants associated with the trait in an additive model (p < 0.01, for joint analysis of Greenlandic IHIT and B99 (n = 3693 and n = 3437) and Danish Inter99 (n = 6116 and n = 5774)) for fasting and 2-h plasma glucose respectively were included in the plot. No assumptions of similar effects of the rare allele in the two populations were made in this test, and therefore opposite effects in the two populations can still provide a statistical significant association. The effect sizes are given in standard deviation (SD) for the reported risk allele, following a rank-based inverse normal transformation. The risk allele frequency (RAF) is shown for Europeans, Greenlandic Inuit, and the admixed Greenlandic population. The variants included in the plot are: SLC30A8 rs11558471 (A/G), DGKB rs2191349 (T/G), GCKR rs780094 (C/T), ADCY5 rs11708067 (A/G), CDKN2B rs10811661 (T/C), GCK rs4607517 (G/A), G6PC2 rs560887 (G/A), MTNR1B rs10830963 (C/G) and TCF7L2 rs7903146 (C/T). In parentheses are the major/minor alleles mapped on the plus strand with the risk allele in bold face.