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Genetic variants causing loss of sucrase-isomaltase (SI) function result in malabsorption of sucrose and starch components and the condition congenital sucrase-isomaltase deficiency (CSID). The identified genetic variants causing CSID are very rare in all surveyed populations around the globe, except the Arctic-specific c.273_274delAG loss-of-function (LoF) variant, which is common in the Greenlandic Inuit and other Arctic populations. In these populations, it is, therefore, possible to study people with loss of SI function in an unbiased way to elucidate the physiological function of SI, and investigate both short-term and long-term health effects of reduced small intestinal digestion of sucrose and starch. Importantly, a recent study of the LoF variant in Greenlanders reported that adult homozygous carriers have a markedly healthier metabolic profile. These findings indicate that SI inhibition could potentially improve metabolic health also in individuals not carrying the LoF variant, which is of great interest considering the massive number of individuals with obesity and type 2 diabetes worldwide. Therefore, the objectives of this review, are 1) to describe the biological role of SI, 2) to describe the metabolic impact of the Arctic SI LoF variant, 3) to reflect on potential mechanisms linking reduced SI function to metabolic health, and 4) to discuss what knowledge is necessary to properly evaluate whether SI inhibition is a potential therapeutic target for improving cardiometabolic health. more...

Background and aims: No prospective study have ever assessed if marine n-3 polyunsaturated fatty acids protect Inuit against cardiovascular disease as claimed. It is highly relevant as cardiovascular disease (CVD) incidence rates are rising concurrent with a westernization of diet. We aimed to assess the association between blood cell membrane phospholipid content of eicosapentaenoic acid and docosahexaenoic acid (EPA + DHA) on CVD risk in Inuit.Methods: We used data from a cohort of adult Greenlanders with follow-up in national registers. The main outcome was fatal and non-fatal CVD incidence among participants without previous CVD. The continuous effect of EPA + DHA was calculated as incidence rate ratios (IRRs) using Poisson regression with age as time scale, adjusting for age, sex, genetic admixture, lifestyle and dietary risk factors.Results: Out of 3095 eligible participants, 2924 were included. During a median follow-up of 9.7 years, 216 had their first CVD event (8.3 events/1000 person years). No association between EPA + DHA and CVD risk was seen, with IRR = 0.99 per percentage point EPA + DHA increase (95% CI: 0.95-1.03, p = 0.59). No association was seen with risk of ischemic heart disease (IHD) (IRR = 1.03, 95% CI: 0.97-1.09) and stroke (IRR = 0.98, 95% CI: 0.93-1.03) as separate outcomes or for intake of EPA and DHA.Conclusions: We can exclude that the CVD risk reduction is larger than 21% for individuals at the 75% EPA + DHA percentile compared to the 25% percentile. We need a larger sample size and/or longer follow-up to detect smaller effects and associations with IHD and/or stroke. more...

The traditional Greenlandic diet is unique with its high content of marine animals, which the Inuitmight 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 isexperiencing a transition towards a western lifestyle and a heavy burden of lifestyle diseases. Thisthesis sought to investigate the role of diet and genetics in cardiovascular disease (CVD) inGreenland 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 considerthis 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 var more...