Genetics of metabolic traits in Greenlanders: lessons from an isolated population

Abstract

In this review, we describe the extraordinary population of Greenland, which differs from large outbred populations of Europe and Asia, both in terms of population history and living conditions. Many years in isolation, small population size and an extreme environment have shaped the genetic composition of the Greenlandic population. The unique genetic background combined with the transition from a traditional Inuit lifestyle and diet, to a more Westernized lifestyle, has led to an increase in the prevalence of metabolic conditions like obesity, where the prevalence from 1993 to 2010 has increased from 16.4% to 19.4% among men, and from 13.0% to 25.4% among women, type 2 diabetes and cardiovascular diseases. The genetic susceptibility to metabolic conditions has been explored in Greenlanders, as well as other isolated populations, taking advantage of population-genetic properties of these populations. During the last 10 years, these studies have provided examples of loci showing evidence of positive selection, due to adaption to Arctic climate and Inuit diet, including TBC1D4 and FADS/CPT1A, and have facilitated the discovery of several loci associated with metabolic phenotypes. Most recently, the c.2433-1G>A loss-of-function variant in ADCY3 associated with obesity and type 2 diabetes was described. This locus has provided novel biological insights, as it has been shown that reduced ADCY3 function causes obesity through disrupted function in primary cilia. Future studies of isolated populations will likely provide further genetic as well as biological insights.

Molecular modelling of novel ADCY3 variant predicts a molecular target for tackling obesity

“…ADCY3 variants in association with obesity were identified in various human population studies. All reported data are presented in Table III (15,16,(31)(32)(33)(34). More specifically, ADCY3 variants (rs2033655 and rs1968482) were reported to be associated with obesity in a population of Swedish males with or without type 2 diabetes in 2008 (16).…”

Genetic study of the Arctic CPT1A variant suggests that its effect on fatty acid levels is modulated by traditional Inuit diet

“…Carriers of the rs80356779 allele (L479) might need to consume more marine foods in order to achieve the optimal levels of 20:5 omega-3 and 22:5 omega-3 compared to non-carriers. Furthermore, it is possible that other genetic variants affect the individual response to the more westernized diet, making it relevant to further investigate the role of gene×diet interactions in obesity and metabolic diseases in the Greenlandic population, as several relevant genetic variants exists [33]. For example, the intake of sugar, especially from soft drinks, is high in Greenland [12], and potential effects of sugars like high-fructose corn syrup [34] could be different in Inuit.…”

An LDLR missense variant poses high risk of familial hypercholesterolemia in 30% of Greenlanders and offers potential for early cardiovascular disease intervention

“…Cardiovascular disease (CVD) is the number one cause of death in many populations worldwide 1 . Also among Greenlanders, the CVD burden is high, and the CVD prevalence is likely to increase in the future, due to increasing life expectancy and changing lifestyle 2,3 . Therefore, additional focus on prevention and treatment of CVD is essential, also in the Greenlandic population.…”