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Ninna Karsbæk Senftleber:
The traditional diet and genetic architecture of the Greenlandic Inuit and their cardiovascular effects

Date: 15-02-2020    Supervisor: Anders Albrechtsen

The traditional Greenlandic diet is unique with its high content of marine animals, which the Inuit might have adapted to through positive selection of specific genetic variants. In addition, Greenlanders generally have a genetic architecture different from large well-studied populations, such as Europeans, due to their unique demographic history. The modern Greenlandic population is experiencing a transition towards a western lifestyle and a heavy burden of lifestyle diseases. This thesis sought to investigate the role of diet and genetics in cardiovascular disease (CVD) in Greenland and the role of diet in the genetic adaptation.

In the first paper, we addressed the old hypothesis of the Inuit being protected from CVD by the high intake of long-chain (LC) n-3 polyunsaturated fatty acids (PUFA) from marine animals. We found no association between blood cell membrane levels of two LC n-3 PUFAs and incident CVD and we had power to reject large effect sizes of LC n-3 PUFA. Hence, the LC n-3 PUFAs do not seem to be the most important factor in managing the CVD burden.

In the second paper, we wanted to investigate what in the traditional Inuit diet that might have been driving the selection of the Inuit specific CPT1A variant rs80356779. We found that increasing intake of traditional foods was associated with a larger effect of the variant on 22:5 n-3 levels. Hence, when the Inuit years ago were living exclusively on traditional foods, the consequence of carrying the selected variant might mainly have been on 22:5 n-3 levels and we therefore consider this fatty acid to have been important for the positive selection.

In the third project we performed a genome-wide association study to identify variants associated with lipid levels in Greenlanders. We found an independent signal in the PCSK9 locus associated with LDL- and total cholesterol, and found our top genetic variants of the signal to be strongly associated with PCSK9 expression. We discuss good candidates for a causal variant. Furthermore, we constructed a simple genetic risk score and found these to explain a large proportion of the variance in the lipid traits and some to be associated with CVD.

Together, the papers highlight the large impact of genetics specific to the Greenlandic population and the importance of taking both environment and genetics into account. Hence, we cannot solely rely on studies of e.g. European populations when forming a basis for disease prevention and/or treatment in the Greenlandic population.