Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts.

BACKGROUND & AIMS: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency. METHODS: The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings. RESULTS: Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (ß [standard error], -2.0 [0.5] kg/m2; P = 3.1 × 10-5), body weight (-4.8 [1.4] kg; P = 5.1 × 10-4), fat percentage (-3.3% [1.0%]; P = 3.7 × 10-4), fasting triglyceride (-0.27 [0.07] mmol/L; P = 2.3 × 10-6), and remnant cholesterol (-0.11 [0.03] mmol/L; P = 4.2 × 10-5). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (ß [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10-26), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test. CONCLUSIONS: These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate.

The effect of traditional diet on glucose homoeostasis in carriers and non-carriers of a common TBC1D4 variant in Greenlandic Inuit: a randomised crossover study.

Consumption of traditional foods is decreasing amid a lifestyle transition in Greenland as incidence of type 2 diabetes (T2D) increases. In homozygous carriers of a TBC1D4 variant, conferring postprandial insulin resistance, the risk of T2D is markedly higher. We investigated the effects of traditional marine diets on glucose homoeostasis and cardio-metabolic health in Greenlandic Inuit carriers and non-carriers of the variant in a randomised crossover study consisting of two 4-week dietary interventions: Traditional (marine-based, low-carbohydrate) and Western (high in imported meats and carbohydrates). Oral glucose tolerance test (OGTT, 2-h), 14-d continuous glucose and cardio-metabolic markers were assessed to investigate the effect of diet and genotype. Compared with the Western diet, the Traditional diet reduced mean and maximum daily blood glucose by 0·17 mmol/l (95 % CI 0·05, 0·29; P = 0·006) and 0·26 mmol/l (95 % CI 0·06, 0·46; P = 0·010), respectively, with dose-dependency. Furthermore, it gave rise to a weight loss of 0·5 kg (95 % CI; 0·09, 0·90; P = 0·016) relative to the Western diet and 4 % (95 % CI 1, 9; P = 0·018) lower LDL:HDL-cholesterol, which after adjustment for weight loss appeared to be driven by HDL elevation (0·09 mmol/l (0·03, 0·15), P = 0·006). A diet-gene interaction was indicated on insulin sensitivity in the OGTT (p = 0·093), which reflected a non-significant increase of 1·4 (-0·6, 3·5) mmol/l in carrier 2-h glucose. A Traditional diet marginally improved daily glycaemic control and plasma lipid profile compared with a Westernised diet in Greenlandic Inuit. Possible adverse effects on glucose tolerance in carriers of the TBC1D4 variant warrant further studies.

Time trends and geographical patterns in suicide among Greenland Inuit.

BACKGROUND: Between 1980 and 2018 Greenland has had one of the highest suicide rates in the world with an average rate of 96 suicides per 100,000 people annually. The aim of this study is to investigate suicide rates in Greenland according to age, birth cohort, period, sex, place of residence and suicide method from 1970 until 2018. METHODS: Suicide rates were examined using register and census data from 1970-2018 among Greenland Inuit. Rates were calculated by Poisson regression in Stata and by use of Excel. In analyses of the period trends, rates were standardized according to the World Standard Population 2000-2025. RESULTS: The suicide rate has been declining since a peak at 120 suicides per 100,000 people annually in the 1980s but remained high at a rate of 81.3 suicides per 100,000 people annually from 2015-2018. Descriptive analyses point to the decrease in male suicides as the primary factor for the overall decreasing rates while the rate among women has been increasing. Simultaneously, the proportion of women who used a violent suicide method increased from 60% in 1970-1979 to 90% in 2010-2018. The highest rates are seen among young people, especially young men aged 20-24 years and youth suicide rates increased with later birth cohorts. When the rates started to increase in the 1980s both the capital Nuuk and East Greenland had the highest rates. Since then, the rate in Nuuk has declined while the rate in East Greenland was three times the national rate from 2015-2018. CONCLUSIONS: From 1970 to 1989 the suicide rate increased from 28.7 to 120.5 per 100,000 people mirroring a rapid societal transition in the post-colonial period. The rate has slowly declined from the peak in the 1980s but remains at a very high level. Young people in general are at risk, but the steady increase in the rate among women is worrying and there is a need to investigate underlying causes for this development.

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.

Concentrations of tetanus and diphtheria antibodies in vaccinated Greenlandic children aged 7-12 years exposed to marine pollutants, a cross sectional study.

Previous studies have shown immunotoxic effects of environmental chemicals, and the European Food Safety Authority (EFSA) recently identified a need for more studies on PFAS immunotoxicity in different populations. In the Arctic, populations are exposed to several environmental chemicals through marine diet, and the objective of this study was therefore to examine the association between Greenlandic children's exposure to major environmental chemicals and their concentrations of diphtheria and tetanus vaccine antibodies after vaccination. The study includes cross-sectional data from Greenlandic children aged 7-12 years examined during 2012-2015. A total of 338 children were eligible for the study, and 175 of these had available vaccination records. A parent or guardian participated in a structured interview, and a blood sample from the child was analyzed for specific antibodies against diphtheria and tetanus as well as perfluoroalkyl substances (PFASs), polychlorinated biphenyls (PCBs) and total mercury. Furthermore, for a subgroup, blood samples from pregnancy were available and analyzed for environmental contaminants. The associations between the environmental exposures and antibody concentrations and odds of having antibody concentrations below the protective level were examined in linear and logistic regression models. In crude analyses, elevated concentrations of some of the contaminants were associated with higher concentrations of diphtheria and tetanus antibodies, but the associations were reversed when adjusting for area of residence, and duration of being breastfed and including children with a known vaccination date only. Each 1 ng/mL increase in serum concentrations of perfluorohexane sulfonic acid (PFHxS) and perfluorooctane sulfonic acid (PFOS) was associated with decreases of 78 % (95 % CI: 25-94 %) and 9 % (95 % CI: 2-16 %), respectively, in diphtheria antibody concentrations. Exposure to PCBs and all PFASs was associated with markedly increased odds of having diphtheria antibody concentrations below the protective level. For each 1 ng/mL increase in serum concentrations of PFHxS, PFOS, perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), odds of not having protective levels of diphtheria antibodies were increased 6.44 times (95 % CI: 1.51-27.36), 1.14 times (95 % CI: 1.04-1.26), 1.96 times (95 % CI: 1.07-3.60), and 5.08 times (95 % CI: 1.32-19.51, respectively. No consistent associations were seen between maternal contaminant concentrations and vaccine antibody concentrations. In conclusion, we found that increased exposure to environmental chemicals among children in this Arctic population were associated with a decrease in post-vaccination antibody concentrations and with increased odds of not being protected against diphtheria despite appropriate vaccination. These findings emphasize the risk of environmental chemical exposures also in this Arctic population.

Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers.

AIMS/HYPOTHESIS: The common muscle-specific TBC1D4 p.Arg684Ter loss-of-function variant defines a subtype of non-autoimmune diabetes in Arctic populations. Homozygous carriers are characterised by elevated postprandial glucose and insulin levels. Because 3.8% of the Greenlandic population are homozygous carriers, it is important to explore possibilities for precision medicine. We aimed to investigate whether physical activity attenuates the effect of this variant on 2 h plasma glucose levels after an oral glucose load. METHODS: In a Greenlandic population cohort (n = 2655), 2 h plasma glucose levels were obtained after an OGTT, physical activity was estimated as physical activity energy expenditure and TBC1D4 genotype was determined. We performed TBC1D4-physical activity interaction analysis, applying a linear mixed model to correct for genetic admixture and relatedness. RESULTS: Physical activity was inversely associated with 2 h plasma glucose levels (ß[main effect of physical activity] -0.0033 [mmol/l] / [kJ kg-1 day-1], p = 6.5 × 10-5), and significantly more so among homozygous carriers of the TBC1D4 risk variant compared with heterozygous carriers and non-carriers (ß[interaction] -0.015 [mmol/l] / [kJ kg-1 day-1], p = 0.0085). The estimated effect size suggests that 1 h of vigorous physical activity per day (compared with resting) reduces 2 h plasma glucose levels by an additional ~0.7 mmol/l in homozygous carriers of the risk variant. CONCLUSIONS/INTERPRETATION: Physical activity improves glucose homeostasis particularly in homozygous TBC1D4 risk variant carriers via a skeletal muscle TBC1 domain family member 4-independent pathway. This provides a rationale to implement physical activity as lifestyle precision medicine in Arctic populations. DATA REPOSITORY: The Greenlandic Cardio-Metabochip data for the Inuit Health in Transition study has been deposited at the European Genome-phenome Archive ( https://www.ebi.ac.uk/ega/dacs/EGAC00001000736 ) under accession EGAD00010001428.

Social determinants of dietary patterns, food basket costs and expenditure on alcohol and tobacco amongst Greenland Inuit.

OBJECTIVE: Dietary transition, obesity and risky use of alcohol and tobacco are challenges to public health among indigenous peoples. The aim of the article was to explore the role of social position in dietary patterns and expenditures on food and other commodities. DESIGN: Countrywide population health survey. SETTING: Greenland. PARTICIPANTS: 2436 Inuit aged 15+ years. RESULTS: Less than half of the expenditures on commodities (43 %) were used to buy nutritious food, and the remaining to buy non-nutritious food (21 %), alcoholic beverages (18 %) and tobacco (18 %). Participants were classified according to five dietary patterns. The cost of a balanced diet and an unhealthy diet was similar, but the cost per 1000 kJ was higher and the energy consumption was lower for the balanced diet. Participants with low social position chose the unhealthy pattern more often than those with high social position (40 % v. 24 %; P < 0·0001), whereas those with high social position more often chose the balanced alternative. Participants with low social position spent less money on the total food basket than those with high social position but more on non-nutritious food, alcohol and tobacco. CONCLUSIONS: Cost seems to be less important than other mechanisms in the shaping of social dietary patterns and the use of alcohol and tobacco among the Inuit in Greenland. Rather than increasing the price of non-nutritious food or subsidising nutritious food, socially targeted interventions and public health promotion regarding food choice and prevention of excessive alcohol use and smoking are needed to change the purchase patterns.

The effect of household crowding and composition on health in an Inuit cohort in Greenland.

Aims: This study aims to investigate the association between household crowding and household composition and self-rated health and mental health (GHQ scale) among the Inuit in Greenland. Poor housing conditions are a concern in Greenland, especially in the villages, where socioeconomic standards in general are lower. Methods: A cohort of 1282 adults participated in two population-based surveys in Greenland, the Inuit Health in Transition survey 2005-2010 (baseline) and The Health Survey in Greenland 2014 (follow-up). Associations between household conditions at baseline and health outcomes at follow-up (poor self-rated health and mental health measured by the GHQ scale) were examined using logistic regression models, adjusting for covariates at baseline. Results: Participants living in an overcrowded dwelling (more than one person per room) at baseline were more likely to report poor self-rated health at follow-up (OR 1.47; 95% CI 1.09; 1.99) compared with those not living in an overcrowded dwelling. In addition, participants who lived alone at baseline were more likely (OR 1.98; 95% CI 1.09; 3.58) to experience poor mental health at follow-up compared with those who lived with children. Conclusions: Results indicate that household conditions are related to health in Greenland. Public health authorities should work to ensure affordable housing of good quality in all communities.

Association of food insecurity with dietary patterns and expenditure on food, alcohol and tobacco amongst indigenous Inuit in Greenland: results from a population health survey.

BACKGROUND: Amongst the indigenous Greenlandic Inuit, the experience of food insecurity has been attributed to a lack of money to buy enough food of sufficient quality to sustain a family, although a preference for alcohol and tobacco over food has also been cited. The purpose of the article was to compare dietary patterns and expenditure on food, alcoholic beverages and tobacco between survey participants who reported food insecurity and those who did not. METHODS: A countrywide cross-sectional health survey was carried out among 1886 adult Greenlandic Inuit in 2018. Diet was estimated by a food frequency questionnaire. Food insecurity status was based on the household hunger scale. Analyses were carried out by univariate general linear models adjusted for age, sex and social position. RESULTS: Nine percent of the participants reported food insecurity. Food insecurity was higher among younger participants, men and participants with low social position. Food insecure participants more often chose an unhealthy dietary pattern (43% vs. 32%) and they reported a higher energy intake. The food insecure spent the same amount of money on food as other participants but less on nutritious food and more on non-nutritious food. The cost per kilojoule (kJ) of the food of the food insecure was lower than that of the food secure (DKK 8.0 and 9.0 per 1000 kJ, respectively). The food insecure participants also spent considerably more on alcohol and tobacco. CONCLUSIONS: The results suggest that it is not only unemployment and lack of money that creates food insecurity and unhealthy dietary patterns in Greenland. Food insecure participants gave higher priority to buying non-nutritious food, alcohol and tobacco than did food secure participants. There seems to be at least two population subgroups in Greenland with poverty and substance use, respectively, as the immediate determinants for food insecurity. The results are important for the design of interventions against food insecurity and unhealthy dietary patterns.

Estimating narrow-sense heritability using family data from admixed populations.

Estimating total narrow-sense heritability in admixed populations remains an open question. In this work, we used extensive simulations to evaluate existing linear mixed-model frameworks for estimating total narrow-sense heritability in two population-based cohorts from Greenland, and compared the results with data from unadmixed individuals from Denmark. When our analysis focused on Greenlandic sib pairs, and under the assumption that shared environment among siblings has a negligible effect, the model with two relationship matrices, one capturing identity by descent and one capturing identity by state, returned heritability estimates close to the true simulated value, while using each of the two matrices alone led to downward biases. When phenotypes correlated with ancestry, heritability estimates were inflated. Based on these observations, we propose a PCA-based adjustment that recovers the true simulated heritability. We use this knowledge to estimate the heritability of ten quantitative traits from the two Greenlandic cohorts, and report differences such as lower heritability for height in Greenlanders compared with Europeans. In conclusion, narrow-sense heritability in admixed populations is best estimated when using a mixture of genetic relationship matrices on individuals with at least one first-degree relative included in the sample.

A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes.

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (ß = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (ß = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (ß = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (ß = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (ß = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders.

Fatty acids (FAs) are involved in cellular processes important for normal body function, and perturbation of FA balance has been linked to metabolic disturbances, including type 2 diabetes. An individual's level of FAs is affected by diet, lifestyle, and genetic variation. We aimed to improve the understanding of the mechanisms and pathways involved in regulation of FA tissue levels, by identifying genetic loci associated with inter-individual differences in erythrocyte membrane FA levels. We assessed the levels of 22 FAs in the phospholipid fraction of erythrocyte membranes from 2,626 Greenlanders in relation to single nucleotide polymorphisms genotyped on the MetaboChip or imputed. We identified six independent association signals. Novel loci were identified on chromosomes 5 and 11 showing strongest association with oleic acid (rs76430747 in ACSL6, beta (SE): -0.386% (0.034), p = 1.8x10-28) and docosahexaenoic acid (rs6035106 in DTD1, 0.137% (0.025), p = 6.4x10-8), respectively. For a missense variant (rs80356779) in CPT1A, we identified a number of novel FA associations, the strongest with 11-eicosenoic acid (0.473% (0.035), p = 2.6x10-38), and for variants in FADS2 (rs174570), LPCAT3 (rs2110073), and CERS4 (rs11881630) we replicated known FA associations. Moreover, we observed metabolic implications of the ACSL6 (rs76430747) and CPT1A (rs80356779) variants, which both were associated with altered HbA1c (0.051% (0.013), p = 5.6x10-6 and -0.034% (0.016), p = 3.1x10-4, respectively). The latter variant was also associated with reduced insulin resistance (HOMA-IR, -0.193 (0.050), p = 3.8x10-6), as well as measures of smaller body size, including weight (-2.676 kg (0.523), p = 2.4x10-7), lean mass (-1.200 kg (0.271), p = 1.7x10-6), height (-0.966 cm (0.230), p = 2.0x10-5), and BMI (-0.638 kg/m2 (0.181), p = 2.8x10-4). In conclusion, we have identified novel genetic determinants of FA composition in phospholipids in erythrocyte membranes, and have shown examples of links between genetic variants associated with altered FA membrane levels and changes in metabolic traits.

Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population.

AIMS/HYPOTHESIS: In a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects. METHODS: We investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model. RESULTS: Using a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in ITGA1 on chromosome 5 (OR 2.79, p = 1.8 × 10-8), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10-7). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10-8) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations. CONCLUSIONS/INTERPRETATION: We demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations. DATA AVAILABILITY: The Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/ ) under the accession EGAS00001002641.

Uncovering the genetic history of the present-day Greenlandic population.

Because of past limitations in samples and genotyping technologies, important questions about the history of the present-day Greenlandic population remain unanswered. In an effort to answer these questions and in general investigate the genetic history of the Greenlandic population, we analyzed ∼200,000 SNPs from more than 10% of the adult Greenlandic population (n = 4,674). We found that recent gene flow from Europe has had a substantial impact on the population: more than 80% of the Greenlanders have some European ancestry (on average ∼25% of their genome). However, we also found that the amount of recent European gene flow varies across Greenland and is far smaller in the more historically isolated areas in the north and east and in the small villages in the south. Furthermore, we found that there is substantial population structure in the Inuit genetic component of the Greenlanders and that individuals from the east, west, and north can be distinguished from each other. Moreover, the genetic differences in the Inuit ancestry are consistent with a single colonization wave of the island from north to west to south to east. Although it has been speculated that there has been historical admixture between the Norse Vikings who lived in Greenland for a limited period ∼600-1,000 years ago and the Inuit, we found no evidence supporting this hypothesis. Similarly, we found no evidence supporting a previously hypothesized admixture event between the Inuit in East Greenland and the Dorset people, who lived in Greenland before the Inuit.

Whole blood mercury and the risk of cardiovascular disease among the Greenlandic population.

BACKGROUND: Studies have found mercury to be associated with cardiovascular disease (CVD), however, primarily in populations with low exposure. The highest levels, and variations in the levels, of whole blood mercury (WBM) worldwide have been found in Greenland. We prospectively assessed the association between WBM and the risk of developing CVD in the Greenlandic population. METHODS: We assessed the effects of WBM levels on incident CVD among 3083 Greenlandic Inuit, participating in a population-based cohort study conducted from 2005 to 2010. WBM was measured at baseline. Participants were followed in the National Patient Registries for Denmark and Greenland and in the causes of death register for CVD events from inclusion in the study until CVD event, emigration, death or end of follow-up (30/9-2013). Using Cox regression analyses, we calculated the incidence rates and the hazard ratio of CVD events according to WBM levels. Potential interactions with sex were also investigated. RESULTS: The highest levels of WBM were found in men, who had a significantly higher median level (19 µg/L (IQR:1-44)), compared with women (15 µg/L (IQR: 1-32), (p < 0.001)). The crude hazard ratio (HR) for incident CVD was 1.00 (95% CI 1.00-1.00) for 5 µg/l increase in WBM. After adjusting for several potential confounders, there was still no association between WBM and incident CVD (HR 0.99; 95%CI:0.99-1.00). We found no interactions with sex. CONCLUSIONS: In a population with high levels of WBM, we found no association between WBM and the risk of developing CVD in Greenland.

Growth of children in Greenland exceeds the World Health Organization growth charts.

AIM: Previous studies have found high rates of stunted linear growth in Greenlandic children. We measured growth patterns in Greenland and compared them with international growth charts. METHODS: The study cohort comprised 279 healthy children aged 6-10 years in 2012. They participated in two pregnancy and birth cohorts in Greenland and longitudinal growth data as birth was extracted from their medical records. Growth reference ranges were estimated with the lambda-mu-sigma (LMS) method and compared with growth charts from Denmark and the World Health Organization (WHO). RESULTS: The children's mean length, weight and head circumference were significantly larger than the WHO growth charts (p < 0.001). We found that 21-28% of the children aged zero to one years exceeded the WHO growth chart for length by more than two standard deviations. For weight and head circumference, 9-16% of the children aged 0-10 years and 9-11% of the children from zero to two years exceeded the WHO charts by more than two standard deviations. The Danish references were exceeded to a lesser degree. CONCLUSION: This study showed that the growth of Greenlandic children up to 10 years was no longer stunted. Major determining factors suggested are genetic admixture, maternal overweight, changes in nutrition and improved health.

Indigenous and tribal peoples' health (The Lancet-Lowitja Institute Global Collaboration): a population study.

BACKGROUND: International studies of the health of Indigenous and tribal peoples provide important public health insights. Reliable data are required for the development of policy and health services. Previous studies document poorer outcomes for Indigenous peoples compared with benchmark populations, but have been restricted in their coverage of countries or the range of health indicators. Our objective is to describe the health and social status of Indigenous and tribal peoples relative to benchmark populations from a sample of countries. METHODS: Collaborators with expertise in Indigenous health data systems were identified for each country. Data were obtained for population, life expectancy at birth, infant mortality, low and high birthweight, maternal mortality, nutritional status, educational attainment, and economic status. Data sources consisted of governmental data, data from non-governmental organisations such as UNICEF, and other research. Absolute and relative differences were calculated. FINDINGS: Our data (23 countries, 28 populations) provide evidence of poorer health and social outcomes for Indigenous peoples than for non-Indigenous populations. However, this is not uniformly the case, and the size of the rate difference varies. We document poorer outcomes for Indigenous populations for: life expectancy at birth for 16 of 18 populations with a difference greater than 1 year in 15 populations; infant mortality rate for 18 of 19 populations with a rate difference greater than one per 1000 livebirths in 16 populations; maternal mortality in ten populations; low birthweight with the rate difference greater than 2% in three populations; high birthweight with the rate difference greater than 2% in one population; child malnutrition for ten of 16 populations with a difference greater than 10% in five populations; child obesity for eight of 12 populations with a difference greater than 5% in four populations; adult obesity for seven of 13 populations with a difference greater than 10% in four populations; educational attainment for 26 of 27 populations with a difference greater than 1% in 24 populations; and economic status for 15 of 18 populations with a difference greater than 1% in 14 populations. INTERPRETATION: We systematically collated data across a broader sample of countries and indicators than done in previous studies. Taking into account the UN Sustainable Development Goals, we recommend that national governments develop targeted policy responses to Indigenous health, improving access to health services, and Indigenous data within national surveillance systems. FUNDING: The Lowitja Institute.

Stable isotopes of carbon and nitrogen as markers of dietary variation among sociocultural subgroups of Inuit in Greenland.

OBJECTIVES: We assessed the use of stable isotopes of carbon and nitrogen as biomarkers for traditional versus store-bought food among the Inuit. Furthermore, we compared the isotope patterns among sociocultural population groups. METHODS: As a part of a country-wide health survey in Greenland during 2005-2010, we analyzed the isotope composition of toenails from 1025 adult Inuit and meat of common species hunted for food. Information on diet and sociocultural variables was collected by interviews. RESULTS: Weighted by sex and place of residence to the total population of Inuit in Greenland, the average δ13 C value in toenails was -20.2‰ and the δ15 N value was 12.0‰ which are higher than in a general Danish omnivorous population. Both isotopes were significantly associated with other biomarkers of marine food and with results of a Food Frequency Questionnaire (FFQ). The percentage of marine food in the diet was estimated at 21% from the mean δ13 C value, 25% from the mean δ15 N value, and 23% from the FFQ. CONCLUSION: Nail samples for analysis of stable isotopes of carbon and nitrogen were convenient to collect during a large population health survey among the Inuit. Isotope enrichment levels showed statistically significant associations with other biomarkers for consumption of marine food and with results of an FFQ and were used to estimate the percentage of marine food in the diet. Isotope levels were significantly associated with a novel score of sociocultural transition.

Association between whole blood mercury and glucose intolerance among adult Inuit in Greenland.

OBJECTIVES: The Arctic diet is partly constituted by traditional food characterized by top predator animals such as whales, walrus, and seals with high mercury content. Mercury exposure has been associated with glucose intolerance in Western populations. We studied the association between whole blood mercury and glucose intolerance in a highly exposed non-Western population METHODS: Cross-sectional study of 2640 Inuit (18+ years) with information on ancestry, smoking, waist circumference, total energy intake, and physical activity. Mercury, fasting- and 2-h plasma glucose, insulin, and c-peptide were measured in blood. Fasting participants without diabetes were classified into normal glucose tolerance, impaired glucose tolerance, impaired fasting glycemia, or type 2 diabetes. We calculated hepatic insulin resistance with homoeostatic model assessment - insulin resistance index, peripheral insulin sensitivity by ISI0,120., and relative beta cell function by c-peptide/insulin ratio. We conducted adjusted linear- and logistic regression analyses. RESULTS: For an increase in whole blood mercury of 5 µg/L we found a positive association with fasting glucose [% change=0.25 (95% CI: 0.20; 0.30); p<0.001], and 2-h glucose [% change=0.23 (95% CI: 0.05; 0.40); p=0.01]. Mercury was weakly associated with impaired fasting glycemia [OR=1.03 (95% CI: 1.02; 1.05)], and type 2 diabetes [OR=1.02 (95% CI: 1.01; 1.04)]. CONCLUSION: While the study found a weak but statistically significant association between whole blood mercury and both impaired fasting glycemia and type 2 diabetes, no associations were found with measures of underlying disturbances in glucose homoeostasis.