Diet quality is positively associated with intake of traditional foods and does not differ by season in remote Yup'ik communities.

This study evaluated whether traditional food intake and diet quality differed by season in Yup'ik communities and examined the relationship between intake of traditional food groups and diet quality. Data were collected from 38 participants, ages 14-79 years, from two Yup'ik communities in Southwest Alaska from 2008 to 2010. Self-reported intake (24-h recalls) and dietary biomarker (nitrogen stable isotope ratio) data were collected twice in distinct seasons. Diet quality was assessed using the Healthy Eating Index. A paired sample t-test was used to test for seasonal differences in traditional food intake and diet quality, and linear regression was used to evaluate associations between traditional food intake and diet quality. Total traditional food intake and overall diet quality did not significantly differ by season, but there were differences in traditional food group intake and diet quality component scores. Diet quality was strongly associated with intake of traditional food groups including fish, tundra greens, and berries. Given the strong relationship between traditional food intake and diet quality, policies should aim to ensure continued access to traditional foods in Yup'ik communities amid environmental changes in the circumpolar North.

Obesity-Associated Dyslipidemia Is Moderated by Habitual Intake of Marine-Derived n-3 Polyunsaturated Fatty Acids in Yup'ik Alaska Native People: A Cross-Sectional Mediation-Moderation Analysis.

BACKGROUND: Obesity leads to insulin resistance, altered lipoprotein metabolism, dyslipidemia, and cardiovascular disease. The relationship between long-term intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) and prevention of cardiometabolic disease remains unresolved. OBJECTIVES: The aim of this study was to explore direct and indirect pathways between adiposity and dyslipidemia, and the degree to which n-3 PUFAs moderate adiposity-induced dyslipidemia in a population with highly variable n-3 PUFA intake from marine foods. METHODS: In total, 571 Yup'ik Alaska Native adults (18-87 y) were enrolled in this cross-sectional study. The red blood cell (RBC) nitrogen isotope ratio (15N/14N, or NIR) was used as a validated objective measure of n-3 PUFA intake. EPA and DHA were measured in RBCs. Insulin sensitivity and resistance were estimated by the HOMA2 method. Mediation analysis was conducted to evaluate the contribution of the indirect causal path between adiposity and dyslipidemia mediated through insulin resistance. Moderation analysis was used to assess the influence of dietary n-3 PUFAs on the direct and indirect paths between adiposity and dyslipidemia. Outcomes of primary interest included plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), non-HDL-C, and triglycerides (TG). RESULTS: In this Yup'ik study population, we found that up to 21.6% of the total effects of adiposity on plasma TG, HDL-C, and non-HDL-C are mediated through measures of insulin resistance or sensitivity. Moreover, RBC DHA and EPA moderated the positive association between waist circumference (WC) and TC or non-HDL-C, whereas only DHA moderated the positive association between WC and TG. However, the indirect path between WC and plasma lipids was not significantly moderated by dietary n-3 PUFAs. CONCLUSIONS: Intake of n-3 PUFAs may independently reduce dyslipidemia through the direct path resulting from excess adiposity in Yup'ik adults. NIR moderation effects suggest that additional nutrients contained in n-3 PUFA-rich foods may also reduce dyslipidemia.

Culturally adapting an evidence-based intervention to promote a healthy diet and lifestyle for Yup'ik Alaska native communities.

Underserved populations are at increased risk for obesity and related cardiovascular disease, type 2 diabetes, and other chronic diseases. Lack of access to healthy foods, sedentary behaviour, and other social environmental factors contribute to disease risk. Yup'ik Alaska Native communities are experiencing lifestyle changes that are likely to affect their cardiometabolic risks. Barrera & Castro's Cultural Adaptation Framework was used to adapt an evidence-based intervention (EBI) originally designed for Latino communities for use in Yup'ik communities. Focus groups and key informant interviews were held in two Yup'ik communities. Major themes included causes of obesity, barriers and facilitators to healthy foods and physical activity, and intervention ideas. The adaptation process was guided by a Community Planning Group of Yup'ik women and included information gathering, preliminary adaptation design, preliminary adaptation tests, and adaptation refinement. Two of the adapted educational modules were pilot tested. Involving community members as co-researchers in cultural adaptation is vital for an EBI to be effective in another population. Small group gatherings led by local lay health workers are culturally appropriate and may be an effective health promotion model in Yup'ik communities. Social environmental factors affecting healthy food availability and physical activity need further exploration.

Efficacy of Air Filtration and Education Interventions on Indoor Fine Particulate Matter and Child Lower Respiratory Tract Infections among Rural U.S. Homes Heated with Wood Stoves: Results from the KidsAIR Randomized Trial.

BACKGROUND: Millions of rural U.S. households are heated with wood stoves. Wood stove use can lead to high indoor concentrations of fine particulate matter [airborne particles ≤2.5µm in aerodynamic diameter (PM2.5)] and is associated with lower respiratory tract infection (LRTI) in children. OBJECTIVES: We assessed the impact of low-cost educational and air filtration interventions on childhood LRTI and indoor PM2.5 in rural U.S. homes with wood stoves. METHODS: The Kids Air Quality Interventions for Reducing Respiratory Infections (KidsAIR) study was a parallel three-arm (education, portable air filtration unit, control), post-only randomized trial in households from Alaska, Montana, and Navajo Nation (Arizona and New Mexico) with a wood stove and one or more children <5 years of age. We tracked LRTI cases for two consecutive winter seasons and measured indoor PM2.5 over a 6-d period during the first winter. We assessed results using two analytical frameworks: a) intervention efficacy on LRTI and PM2.5 (intent-to-treat), and b) association between PM2.5 and LRTI (exposure-response). RESULTS: There were 61 LRTI cases from 14,636 child-weeks of follow-up among 461 children. In the intent-to-treat analysis, children in the education arm [odds ratio (OR)=0.98; 95% confidence interval (CI): 0.35, 2.72] and the filtration arm (OR=1.23; 95% CI: 0.46, 3.32) had similar odds of LRTI vs. control. Geometric mean PM2.5 concentrations were similar to control in the education arm (11.77% higher; 95% CI: -16.57, 49.72) and air filtration arm (6.96% lower; 95% CI: -30.50, 24.55). In the exposure-response analysis, odds of LRTI were 1.45 times higher (95% CI: 1.02, 2.05) per interquartile range (25 µg/m3) increase in mean indoor PM2.5. DISCUSSION: We did not observe meaningful differences in LRTI or indoor PM2.5 in the air filtration or education arms compared with the control arm. Results from the exposure-response analysis provide further evidence that biomass air pollution adversely impacts childhood LRTI. Our results highlight the need for novel, effective intervention strategies in households heated with wood stoves. https://doi.org/10.1289/EHP9932.

Tribal Deliberations about Precision Medicine Research: Addressing Diversity and Inequity in Democratic Deliberation Design and Evaluation.

Deliberative democratic engagement is used around the globe to gather informed public input on contentious collective questions. Yet, rarely has it been used to convene individuals exclusively from Indigenous communities. The relative novelty of using this approach to engage tribal communities and concerns about diversity and inequities raise important methodological questions. We describe the design and quality outcomes for a 2.5-day deliberation that elicited views of American Indian and Alaska Native (AIAN) leaders about the potential value and ethical conduct of precision medicine research (PMR), an emerging approach to research that investigates the health effects of individual genetic variation in tandem with variation in health-relevant practices, social determinants, and environmental exposures. The event met key goals, such as relationship and rapport formation, cross-site learning, equality of opportunity to participate, and respect among participants in the context of disagreement.

Precision medicine research with American Indian and Alaska Native communities: Results of a deliberative engagement with tribal leaders.

PURPOSE: Amid calls for greater diversity in precision medicine research, the perspectives of Indigenous people have been underexplored. Our goals were to understand tribal leaders' views regarding the potential benefits and risks of such research, explore its priority for their communities, and identify the policies and safeguards they consider essential. This article reports on the participants' perspectives regarding governance and policy, stewardship and sharing of information and biospecimens, and informed consent. METHODS: After informal local dialogs with 21 tribal leaders, we convened a 2.5-day deliberation with tribal leaders (N = 10) in Anchorage, Alaska, in June 2019 using a combination of small group and plenary discussion, ranking, and voting exercises to explore the perspectives on precision medicine research. RESULTS: Tribal sovereignty was central to participants' ideas about precision medicine research. Although views were generally positive, provided that the appropriate controls were in place, some kinds of research were deemed unacceptable, and the collection of certain biospecimens was rejected by some participants. Differences were observed regarding the acceptability of broad consent. CONCLUSION: Tribal leaders in this study were generally supportive of precision medicine research, with the caveat that tribal oversight is essential for the establishment of research repositories and the conduct of research involving Indigenous participants.

Habitual Intake of Marine-Derived n-3 PUFAs is Inversely Associated with a Cardiometabolic Inflammatory Profile in Yup'ik Alaska Native People.

BACKGROUND: The relationship between dietary n-3 PUFAs and the prevention of cardiometabolic diseases, including type 2 diabetes, is unresolved. Examination of the association between n-3 PUFAs and chronic low-grade inflammation in a population where many individuals have had an extremely high intake of marine mammals and fish throughout their lifespan may provide important clues regarding the impact of n-3 PUFAs on health. OBJECTIVES: The aim of this study was to explore associations between concentrations of n-3 PUFAs resulting from habitual intake of natural food sources high in fish and marine mammals with immune biomarkers of metabolic inflammation and parameters of glucose regulation. METHODS: A total of 569 Yup'ik Alaska Native adults (18-87 years old) were enrolled in this cross-sectional study between December 2016 and November 2019. The RBC nitrogen isotope ratio (NIR; 15N/14N) was used as a validated measure of n-3 PUFA intake to select 165 participant samples from the first and fourth quartiles of n-3 PUFA intakes. Outcomes included 38 pro- and anti-inflammatory cytokines and 8 measures of glucose homeostasis associated with type 2 diabetes risks. These outcomes were evaluated for their associations with direct measurements of EPA, DHA, and arachidonic acid in RBCs. ANALYSIS: Linear regression was used to detect significant relationships with cytokines and n-3 PUFAs, adiposity, and glucose-related variables. RESULTS: The DHA concentration in RBC membranes was inversely associated with IL-6 (ß = -0.0066; P < 0.001); EPA was inversely associated with TNFα (ß = -0.4925; P < 0.001); and the NIR was inversely associated with Monocyte chemoattractant protein-1 (MCP-1) (ß = -0.8345; P < 0.001) and IL-10 (ß = -1.2868; P < 0.001). CONCLUSIONS: Habitual intake of marine mammals and fish rich in n-3 PUFAs in this study population of Yup'ik Alaska Native adults is associated with reduced systemic inflammation, which may contribute to the low prevalence of diseases in which inflammation plays an important role.

Seasonal variation in added sugar or sugar sweetened beverage intake in Alaska native communities: an exploratory study.

Excess added sugar intake contributes to tooth decay risk in Alaska Native communities. The goal of this exploratory study was to determine if there is seasonal variation in total added sugar intake or in the leading sources of added sugars in a Yup'ik population. Data were collected in spring and winter from 2008-2010 using self-reported intake data measured by 24-hour recall and by hair biomarker (carbon and nitrogen stable isotope). Seventy Yup'ik participants ages 14-70 years were recruited from two communities and data were collected twice from a subset of 38 participants. Self-reported added sugar intake (g/day), biomarker-predicted added sugar intake (g/day), and leading sources of added sugar were calculated. Seasonal variation was evaluated using a paired sample t-test. Total added sugar intake was 93.6 g/day and did not significantly differ by season. Sodas and other sugar-sweetened beverages (e.g. Tang, Kool-Aid) were the leading sources and added sugar from these sources did not significantly differ by season (p=.54 and p=.89, respectively). No seasonal variation in added sugar intake was detected by either self-report or biomarker. Dietary interventions that reduce intake of added sugars have the potential to reduce tooth decay in Yup'ik communities.

Indoor fine particulate matter and demographic, household, and wood stove characteristics among rural US homes heated with wood fuel.

Household heating using wood stoves is common practice in many rural areas of the United States (US) and can lead to elevated concentrations of indoor fine particulate matter (PM2.5 ). We collected 6-day measures of indoor PM2.5 during the winter and evaluated household and stove-use characteristics in homes at three rural and diverse study sites. The median indoor PM2.5 concentration across all homes was 19 µg/m3 , with higher concentrations in Alaska (median = 30, minimum = 4, maximum = 200, n = 10) and Navajo Nation homes (median = 29, minimum = 3, maximum = 105, n = 23) compared with Montana homes (median = 16, minimum = 2, maximum = 139, n = 59). Households that had not cleaned the chimney within the past year had 65% higher geometric mean PM2.5 compared to those with chimney cleaned within 6 months (95% confidence interval [CI]: -1, 170). Based on a novel wood stove grading method, homes with low-quality and medium-quality stoves had substantially higher PM2.5 compared to homes with higher-quality stoves (186% higher [95% CI: 32, 519] and 161% higher; [95% CI:27, 434], respectively). Our findings highlight the need for, and complex nature of, regionally appropriate interventions to reduce indoor air pollution in rural wood-burning regions. Higher-quality stoves and behavioral practices such as regular chimney cleaning may help improve indoor air quality in such homes.

In Vivo Functional Effects of CYP2C9 M1L, a Novel and Common Variant in the Yup'ik Alaska Native Population.

Alaska Native people are under-represented in genetic research but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of CYP2C9 in a cross-section of this population identified CYP2C9 Met1Leu (M1L), a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. M1L is present at a minor allele frequency of 6.3% in Yup'ik Alaska Native people and thus can contribute to the risk of an adverse drug response from narrow-therapeutic-index CYP2C9 substrates such as (S)-warfarin. This study's objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup'ik participants. We first confirmed the selectivity of (S)-naproxen O-demethylation by CYP2C9 using activity-phenotyped human liver microsomes and selective cytochrome P450 inhibitors and then developed and validated a novel liquid chromatography mass spectrometry method for simultaneous quantification of (S)-naproxen, (S)-O-desmethylnaproxen, and naproxen acyl glucuronide in human urine. The average ratio of (S)-O-desmethylnaproxen to unchanged (S)-naproxen in urine was 18.0 ± 8.0 (n = 11) for the homozygous CYP2C9 Met1 reference group and 10.3 ± 6.6 (n = 11) for the Leu1 variant carrier group (P = 0.011). The effect of M1L variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted. SIGNIFICANCE STATEMENT: The novel CYP2C9 Met1Leu variant in Alaska Native people was recently identified. This study validated (S)-naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the CYP2C9 Leu1 variant. The results of this pharmacogenetic-pharmacokinetic study suggest that the CYP2C9 Leu1 variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow-therapeutic-index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations.

Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function.

The frequencies of genetic variants in the CYP3A4 and CYP3A5 genes differ greatly across global populations, leading to profound differences in the metabolic activity of these enzymes and resulting drug metabolism rates, with important consequences for therapeutic safety and efficacy. Yet, the impact of genetic variants on enzyme activity are incompletely described, particularly in American Indian and Alaska Native (AIAN) populations. To characterize genetic variation in CYP3A4 and CYP3A5 and its effect on enzyme activity, we partnered with AIAN people living in two regions of Alaska: Yup'ik Alaska Native people living in the Yukon-Kuskokwim Delta region of rural southwest Alaska and AIAN people receiving care at the Southcentral Foundation in Anchorage, Alaska. We identified low frequencies of novel and known variation in CYP3A4 and CYP3A5, including low frequencies of the CYP3A4*1G and CYP3A5*1 variants, and linkage disequilibrium patterns that differed from those we previously identified in an American Indian population in western Montana. We also identified increased activity of the CYP3A4*1G allele in vitro and in vivo. We demonstrated that the CYP3A4*1G allele confers increased protein content in human lymphoblastoid cells and both increased protein content and increased activity in human liver microsomes. We confirmed enhanced CYP3A4-mediated 4ß-vitamin D hydroxylation activity in Yup'ik people with the CYP3A4*1G allele. AIAN people in Alaska and Montana who carry the CYP3A4*1G allele-coupled with low frequency of the functional CYP3A5*1 variant-may metabolize CYP3A substrates more rapidly than people with the reference CYP3A4 allele.

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.

Wood stove interventions and child respiratory infections in rural communities: KidsAir rationale and methods.

BACKGROUND: Acute lower respiratory tract infections (LRTIs) account for >27% of all hospitalizations among US children under five years of age. Residential burning of biomass for heat leads to elevated indoor levels of fine particulate matter (PM2.5) that often exceed current health based air quality standards. This is concerning as PM2.5 exposure is associated with many adverse health outcomes, including a greater than three-fold increased risk of LRTIs. Evidence-based efforts are warranted in rural and American Indian/Alaska Native (AI/AN) communities in the US that suffer from elevated rates of childhood LRTI and commonly use wood for residential heating. DESIGN: In three rural and underserved settings, we conducted a three-arm randomized controlled, post-only intervention trial in wood stove homes with children less than five years old. Education and household training on best-burn practices were introduced as one intervention arm (Tx1). This intervention was evaluated against an indoor air filtration unit arm (Tx2), as well as a control arm (Tx3). The primary outcome was LRTI incidence among children under five years of age. DISCUSSION: To date, exposure reduction strategies in wood stove homes have been either inconsistently effective or include factors that limit widespread dissemination and continued compliance in rural and economically disadvantaged populations. As part of the "KidsAIR" study described herein, the overall hypothesis was that a low-cost, educational intervention targeting indoor wood smoke PM2.5 exposures would be a sustainable approach for reducing children's risk of LRTI in rural and AI/AN communities.

The Nitrogen Isotope Ratio Is a Biomarker of Yup'ik Traditional Food Intake and Reflects Dietary Seasonality in Segmental Hair Analyses.

BACKGROUND: The nitrogen isotope ratio (NIR) is a promising index of traditional food intake for an Alaska Native (Yup'ik) population, which can be measured in blood and hair. However, the NIR has not been calibrated to high-quality measures of Yup'ik traditional food intake. OBJECTIVES: Our primary objective was to examine associations between intakes of Yup'ik traditional food groups, including fish, marine mammals, birds, land mammals, berries, greens, and total traditional foods, and the NIR. In an exploratory analysis, we also examined whether NIR analyzed sequentially along hair could reflect dietary seasonality. METHODS: We recruited 68 participants from 2 Yup'ik communities in the Yukon Kuskokwim region of Southwest Alaska (49% female, aged 14-79 y). Participants completed 4 unscheduled 24-h food recalls over the period peak of RBC and hair synthesis preceding a specimen collection visit. The NIR was measured in RBCs ( n = 68), a proximal hair section (n = 58), and sequential segments of hair from individuals in the upper 2 quartiles of traditional food intake having hair >6 cm in length, plus 2 low subsistence participants for reference (n = 18). Diet-biomarker associations were assessed using Pearson's correlation and linear regression. RESULTS: Intakes of fish, marine mammals, berries, and greens were significantly associated with the NIR. The strongest dietary association was with total traditional food intake (R2 = 0.62), which indicated that each 1‰ increase in the RBC NIR corresponded to 8% of energy from traditional foods. Hair NIR appeared to fluctuate seasonally in some individuals, peaking in the summertime. CONCLUSIONS: Findings support the use of the RBC and hair NIR to assess total traditional food intake in a Yup'ik population. Analyses of sequential hair NIR provided evidence of seasonality in traditional food intake, although seasonal variations were modest relative to interindividual variation.

Age of initiation of cigarette smoking and smokeless tobacco use among western Alaska Native people: Secondary analysis of the WATCH study.

OBJECTIVE: This study examined self-reported age of tobacco initiation (cigarette smoking and smokeless tobacco [ST] use) and explored potential sex and generational group influences on tobacco use onset among Alaska Native (AN) adult ever tobacco users. METHODS: Secondary analysis of consolidated data from the Western Alaska Tribal Collaborative for Health (WATCH) study comprised 2800 AN adult ever tobacco users (1490 women, 1310 men; mean age = 39.2 years) from two rural western Alaska regions. ST use data were limited to one region. Logistic regression was used to examine potential sex and generational group (age 18-29, 30-49, ≥50) effects on initiation at ≤13 years of age. RESULTS: Thirty-seven percent of the sample reported using any tobacco product by age 13 years. Initiation of any ST use by age 13 was greater than for cigarette smoking (52.7% vs. 18.2%), and women were more likely than men to report initiation of any ST use at ≤13 years (52.6% vs. 38.4%). Nearly one-third of ever smokers (31%) initiated in young adulthood (ages 18-29). For ST use, logistic regression analyses revealed significant sex differences (women more likely to initiate by 13 years of age than men) and generational group effects with younger and middle age groups more likely to report initiation ≤13 years compared to the eldest participants. For smoking, no sex differences were observed but the youngest generational group was more likely to report initiation by age 13 compared to the eldest group. CONCLUSIONS: Earlier age of tobacco initiation is found among younger generations of AN people. Findings highlight the need to focus prevention efforts on initiation of smoking in young adulthood and uptake of ST use among girls.

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.

Association between iq'mik smokeless tobacco use and cardiometabolic risk profile among Yup'ik Alaska Native people.

OBJECTIVE: The traditional lifestyle of Yup'ik Alaska Native people, including a diet abundant in marine-based foods and physical activity, may be cardio-protective. However, iq'mik, a traditional form of smokeless tobacco used by >50% of Yup'ik adults, could increase cardiometabolic (CM) risk. Our objective was to characterize the associations between iq'mik use and biomarkers of CM status (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], triglycerides [TG], systolic blood pressure [SBP] and diastolic blood pressure [DBP], glycated hemoglobin [HbA1c], fasting blood glucose [FBG], waist circumference [WC], and body mass index [BMI]). DESIGN: We assessed these associations using data from a cross-sectional sample of Yup'ik adults (n = 874). Current iq'mik use, demographic, and lifestyle data were collected through interviews. Fasting blood samples were collected to measure LDL-C, HDL-C, TG, HbA1c, and FBG. SBP, DBP, WC, and BMI were obtained by physical examination. We characterized the association between current iq'mik use and continuous biomarkers of CM status using multiple approaches, including adjustment for measures of Yup'ik lifestyle and a propensity score. RESULTS: Based on either adjustment method, current iq'mik use was significantly and positively associated with at least 5% higher HDL-C, and significantly associated but in an inverse direction with multiple biomarkers of CM status including 7% lower TG, 0.05% lower HbA1c, 2% lower FBG, 4% lower WC, and 4% lower BMI. Observed associations for LDL-C, SBP, and DBP varied by adjustment method. CONCLUSIONS: This inverse association between iq'mik use and cardiometabolic risk status has not been previously reported. Additional research is needed to replicate these findings and explore physiological mechanisms and/or confounding factors.

Dietary Vitamin K and Association with Hepatic Vitamin K Status in a Yup'ik Study Population from Southwestern Alaska.

SCOPE: The relationship between dietary vitamin K and plasma PIVKA-II concentration, a biomarker of hepatic vitamin K status, in a Yup'ik study population in southwestern Alaska is investigated. METHODS AND RESULTS: A total of 659 male and female, self-reported Yup'ik people, ≥14 years of age, were enrolled. Blood is collected for genotyping and plasma PIVKA-II biomarker analysis. A Yup'ik-specific dietary food frequency questionnaire is used to assess vitamin K intake. Among the participants, 22% report not consuming foods rich in vitamin K during the past year and 36% have a PIVKA-II concentration ≥ 2 ng mL-1 , indicating vitamin K insufficiency. The odds of an elevated PIVKA-II concentration are 33% lower in individuals reporting any versus no consumption of vitamin-K-rich foods. The association is significant after adjusting for CYP4F2*3 genotype. Tundra greens are high in vitamin K1 content, but an exploratory analysis suggests that subsistence meat sources have a greater effect on vitamin K status. CONCLUSIONS: A substantial proportion of the Yup'ik population exhibits vitamin K insufficiency, which is associated with low consumption of vitamin K rich foods and which might affect an individual's response to anticoagulant drugs such as warfarin that target the vitamin K cycle.

Bi-cultural dynamics for risk and protective factors for cardiometabolic health in an Alaska Native (Yup'ik) population.

Alaska Native people experience disparities in mortality from heart disease and stroke. This work attempts to better understand the relationships between socioeconomic, behavioral, and cardiometabolic risk factors among Yup'ik people of southwestern Alaska, with a focus on the role of the socioeconomic, and cultural components. Using a cross-sectional sample of 486 Yup'ik adults, we fitted a Partial Least Squares Path Model (PLS-PM) to assess the associations between components, including demographic factors [age and gender], socioeconomic factors [education, economic status, Yup'ik culture, and Western culture], behavioral factors [diet, cigarette smoking and smokeless tobacco use, and physical activity], and cardiometabolic risk factors [adiposity, triglyceride-HDL and LDL lipids, glycemia, and blood pressure]. We found relatively mild associations of education and economic status with cardiometabolic risk factors, in contrast with studies in other populations. The socioeconomic factor and participation in Yup'ik culture had potentially protective associations with adiposity, triglyceride-HDL lipids, and blood pressure, whereas participation in Western culture had a protective association with blood pressure. We also found a moderating effect of participation in Western culture on the relationships between Yup'ik culture participation and both blood pressure and LDL lipids, indicating a potentially beneficial additional effect of bi-culturalism. Our results suggest that reinforcing protective effects of both Yup'ik and Western cultures could be useful for interventions aimed at reducing cardiometabolic health disparities.