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.

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.

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.

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.

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.

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.

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.

Declines in traditional marine food intake and vitamin D levels from the 1960s to present in young Alaska Native women.

OBJECTIVE: To measure the trends in traditional marine food intake and serum vitamin D levels in Alaska Native women of childbearing age (20-29 years old) from the 1960s to the present. DESIGN: We measured a biomarker of traditional food intake, the δ15N value, and vitamin D level, as 25-hydroxycholecalciferol (25(OH)D3) concentration, in 100 serum samples from 20-29-year-old women archived in the Alaska Area Specimen Bank, selecting twenty-five per decade from the 1960s to the 1990s. We compared these with measurements of red-blood-cell δ15N values and serum 25(OH)D3 concentrations from 20-29-year-old women from the same region collected during the 2000s and 2010s in a Center for Alaska Native Health Research study. SETTING: The Yukon Kuskokwim Delta region of south-west Alaska. SUBJECTS: Alaska Native women (n 319) aged 20-29 years at the time of specimen collection. RESULTS: Intake of traditional marine foods, as measured by serum δ15N values, decreased significantly each decade from the 1960s through the 1990s, then remained constant from the 1990s through the present (F 5,306=77·4, P<0·0001). Serum vitamin D concentrations also decreased from the 1960s to the present (F 4,162=26·1, P<0·0001). CONCLUSIONS: Consumption of traditional marine foods by young Alaska Native women dropped significantly between the 1960s and the 1990s and was associated with a significant decline in serum vitamin D concentrations. Studies are needed to evaluate the promotion of traditional marine foods and routine vitamin D supplementation during pregnancy for this population.

Genetics, Diet, and Season Are Associated with Serum 25-Hydroxycholecalciferol Concentration in a Yup'ik Study Population from Southwestern Alaska.

BACKGROUND: Low blood vitamin D concentration is a concern for people living in circumpolar regions, where sunlight is insufficient for vitamin D synthesis in winter months and the consumption of traditional dietary sources of vitamin D is decreasing. OBJECTIVE: The objective was to characterize the effects of diet, genetic variation, and season on serum 25-hydroxycholecalciferol [25(OH)D3] concentrations in Yup'ik Alaska Native people living in rural southwest Alaska. METHODS: This study was a cross-sectional design that assessed the associations of traditional diet (via a biomarker, the RBC δ(15)N value), age, gender, body mass index (BMI), community location, and genotype of select single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2, subfamily R, peptide 1 (CYP2R1), 7-dehydrocholesterol reductase (DHCR7), and vitamin D binding protein (GC) with serum 25(OH)D3 concentrations in 743 Yup'ik male and female participants, aged 14-93 y, recruited between September 2009 and December 2013. RESULTS: Yup'ik participants, on average, had adequate concentrations of serum 25(OH)D3 (31.1 ± 1.0 ng/mL). Variations in diet, BMI, age, gender, season of sample collection, and inland or coastal community geography were all significantly associated with serum 25(OH)D3 concentration. In models not adjusting for other covariates, age, diet, and seasonal effects explained 33.7%, 20.7%, and 9.8%, respectively, of variability in serum 25(OH)D3 concentrations. Of the 8 SNPs interrogated in CYP2R1 and DHCR7, only rs11023374 in CYP2R1 was significantly associated with serum 25(OH)D3, explaining 1.5% of variability. The GC haplotype explained an additional 2.8% of variability. Together, age, diet, gender, season of sample collection, BMI, geography of the community, and genotype at rs11023374 explained 52.5% of the variability in serum 25(OH)D3 concentrations. CONCLUSIONS: Lower consumption of the traditional diet was associated with lower serum concentrations of 25(OH)D3. Younger adults and youth in this community may be at increased risk of adverse outcomes associated with vitamin D insufficiency compared with older members of the community, especially during seasons of low sunlight exposure, because of lower consumption of dietary sources of vitamin D.

Sex, Adiposity, and Hypertension Status Modify the Inverse Effect of Marine Food Intake on Blood Pressure in Alaska Native (Yup'ik) People.

BACKGROUND: Alaska Native people currently have a higher prevalence of hypertension than do nonnative Alaskans, although in the 1950s hypertension was rare among Alaska Native people. A novel biomarker of marine foods, the nitrogen isotope ratio (δ¹5N) in RBCs was shown to be negatively associated with systolic and diastolic blood pressure. Few studies have examined how individual characteristics modify the association of marine food intake with blood pressure. OBJECTIVE: This exploratory analysis examined whether sex, adiposity, and hypertension modify the inverse association between marine food intake and blood pressure. METHODS: We used covariate-adjusted linear models to describe the association between δ¹5N and blood pressure in 873 adult Alaska Native (Yup'ik) people who resided in 8 communities in southwest Alaska. We separately stratified by sex, body mass index (BMI) group, abdominal obesity, and hypertension status and assessed the interaction between δ¹5N and participant characteristics on blood pressure via likelihood ratio tests. RESULTS: The association between δ¹5N and systolic blood pressure was modified by sex, BMI status, and abdominal obesity, with the inverse association observed only in the male (ß = -1.5; 95% CI: -2.4, -0.6 : , nonobese BMI (ß = -1.7; 95% CI: -2.5, -1.0), and non-abdominally obese (ß = -1.6; 95% CI: -2.4, -0.9) strata (all P-interaction < 0.0001). A reduction in diastolic blood pressure associated with δ¹5N was observed in the nonobese BMI (ß = -1.1; 95% CI: -1.7, -0.5) and non-abdominally obese (ß = -1.1; 95% CI: -1.7, -0.5) strata, although only the interaction between BMI group and δ¹5N with diastolic blood pressure was significant. The inverse association between δ¹5N and both systolic and diastolic blood pressure was observed in nonhypertensive individuals, although the comparison had limited power. The results were consistent with those identified by using combined RBC concentrations of eicosapentaenoic acid and docosahexaenoic acid as the biomarker of marine food intake, although the associations identified by using δ¹5N were larger. CONCLUSIONS: Obesity status modified the inverse association between marine food intake and both systolic and diastolic blood pressure in adult Alaska Native (Yup'ik) people. The inverse association between δ¹5N and systolic blood pressure was also modified by sex.

Stable isotope models of sugar intake using hair, red blood cells, and plasma, but not fasting plasma glucose, predict sugar intake in a Yup'ik study population.

Objectively measured biomarkers will help to resolve the controversial role of sugar intake in the etiology of obesity and related chronic diseases. We recently validated a dual-isotope model based on RBC carbon (δ(13)C) and nitrogen (δ(15)N) isotope ratios that explained a large percentage of the variation in self-reported sugar intake in a Yup'ik study population. Stable isotope ratios can easily be measured from many tissues, including RBCs, plasma, and hair; however, it is not known how isotopic models of sugar intake compare among these tissues. Here, we compared self-reported sugar intake with models based on RBCs, plasma, and hair δ(13)C and δ(15)N in Yup'ik people. We also evaluated associations of sugar intake with fasting plasma glucose δ(13)C. Finally, we evaluated relations between δ(13)C and δ(15)N values in hair, plasma, RBCs, and fasting plasma glucose to allow comparison of isotope ratios across tissue types. Models using RBCs, plasma, or hair isotope ratios explained similar amounts of variance in total sugar, added sugar, and sugar-sweetened beverage intake (∼53%, 48%, and 34%, respectively); however, the association with δ(13)C was strongest for models based on RBCs and hair. There were no associations with fasting plasma glucose δ(13)C (R(2) = 0.03). The δ(13)C and δ(15)N values of RBCs, plasma, and hair showed strong, positive correlations; the slopes of these relations did not differ from 1. This study demonstrates that RBC, plasma, and hair isotope ratios predict sugar intake and provides data that will allow comparison of studies using different sample types.

A stable isotope biomarker of marine food intake captures associations between n-3 fatty acid intake and chronic disease risk in a Yup'ik study population, and detects new associations with blood pressure and adiponectin.

The nitrogen isotope ratio (δ(15)N) of RBCs has been proposed as a biomarker of marine food intake in Yup'ik people based on strong associations with RBC eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, EPA and DHA derive from marine fats, whereas elevated δ(15)N derives from marine protein, and these dietary components may have different biologic effects. Whether δ(15)N is similarly associated with chronic disease risk factors compared with RBC EPA and DHA is not known. We used covariate-adjusted linear models to describe biomarker associations with chronic disease risk factors in Yup'ik people, first in a smaller (n = 363) cross-sectional study population using RBC EPA, DHA, and δ(15)N, and then in a larger (n = 772) cross-sectional study population using δ(15)N only. In the smaller sample, associations of RBC EPA, DHA, and δ(15)N with obesity and chronic disease risk factors were similar in direction and significance: δ(15)N was positively associated with total, HDL, and LDL cholesterol, apolipoprotein A-I, and insulin-like growth factor binding protein-3 (IGFBP-3), and inversely associated with triglycerides. Based on comparisons between covariate-adjusted ß-coefficients, EPA was more strongly associated with circulating lipids and lipoproteins, whereas δ(15)N was more strongly associated with adipokines, the inflammatory marker interleukin-6, and IGFBP-3. In the larger sample there were new findings for this population: δ(15)N was inversely associated with blood pressure and there was a significant association (with inverse linear and positive quadratic terms) with adiponectin. In conclusion, δ(15)N is a valid measure for evaluating associations between EPA and DHA intake and chronic disease risk in Yup'ik people and may be used in larger studies. By measuring δ(15)N, we report beneficial associations of marine food intake with blood pressure and adiponectin, which may contribute to a lower incidence of some chronic diseases in Yup'ik people.

DNA methylation patterns are associated with n-3 fatty acid intake in Yup'ik people.

A large body of evidence links a high dietary intake of n-3 (ω-3) polyunsaturated fatty acids (PUFAs) with improved cardiometabolic outcomes. Recent studies suggested that the biologic processes underlying the observed associations may involve epigenetic changes, specifically DNA methylation. To evaluate changes in methylation associated with n-3 PUFA intake, we conducted an epigenome-wide methylation association study of long-chain n-3 PUFA intake and tested associations between the diabetes- and cardiovascular disease-related traits. We assessed DNA methylation at ∼470,000 cytosine-phosphate-guanine (CpG) sites in a cross-sectional study of 185 Yup'ik Alaska Native individuals representing the top and bottom deciles of PUFA intake. Linear regression models were used to test for the associations of interest, adjusting for age, sex, and community group. We identified 27 differentially methylated CpG sites at biologically relevant regions that reached epigenome-wide significance (P < 1 × 10⁻7). Specifically, regions on chromosomes 3 (helicase-like transcription factor), 10 (actin α 2 smooth muscle/Fas cell surface death receptor), and 16 (protease serine 36/C16 open reading frame 67) each harbored 2 significant correlates of n-3 PUFA intake. In conclusion, we present promising evidence of association between several biologically relevant epigenetic markers and long-term intake of marine-derived n-3 PUFAs.

All-cause, cardiovascular, and cancer mortality in western Alaska Native people: western Alaska Tribal Collaborative for Health (WATCH).

OBJECTIVES: We determined all-cause, cardiovascular disease (CVD), and cancer mortality in western Alaska Native people and examined agreement between death certificate information and adjudicated cause of deaths. METHODS: Data from 4 cohort studies were consolidated. Death certificates and medical records were reviewed and adjudicated according to standard criteria. We compared adjudicated CVD and cancer deaths with death certificates by calculating sensitivity, specificity, predictive values, and κ statistics. RESULTS: Men (n = 2116) and women (n = 2453), aged 18 to 95 years, were followed an average of 6.7 years. The major cause of death in men was trauma (25%), followed by CVD (19%) and cancer (13%). The major cause of death in women was CVD (24%), followed by cancer (19%) and trauma (8%). Stroke rates in both genders were higher than those of US Whites. Only 56% of deaths classified as CVD by death certificate were classified as CVD by standard criteria; discordance was higher among men (55%) than women (32%; κs = 0.4 and 0.7). CONCLUSIONS: We found lower rates for coronary heart disease death but high rates of stroke mortality. Death certificates overestimated CVD mortality; concordance between the 2 methods is better for cancer mortality. The results point to the importance of cohort studies in this population in providing data to assist in health care planning.

Enculturation, perceived stress, and physical activity: implications for metabolic risk among the Yup'ik--the Center for Alaska Native Health Research Study.

OBJECTIVES: American Indians and Alaska Natives (ANs) report among the lowest levels of physical activity in the USA, but there is very little systematic research examining the determinants of physical activity patterns in these populations. This study investigated the relationships between enculturation (or cultural traditionality), psychosocial stress, and physical activity in a community-based sample of Yup'ik women and men living in rural AN communities. Associations between these variables and several metabolic risk factors were also examined. DESIGN: A sample of 488 Yup'ik participants (284 women and 204 men) from six villages in the Yukon-Kuskokwim Delta region completed a wellness survey and an array of physiological assessments [e.g., body mass index (BMI), blood pressure]. A subset of 179 participants also completed a 3-day pedometer assessment of physical activity. RESULTS: Multivariate linear regression models indicated that participants who were more enculturated (i.e., living more of a traditional lifestyle) and who experienced lower levels of psychosocial stress were significantly more physically active. In turn, both lower levels of psychosocial stress and higher levels of physical activity were associated with lower BMI, lower percent body fat, and lower waist circumference. CONCLUSIONS: Findings underscore the importance of gaining a culturally specific understanding of physical activity patterns in indigenous groups in order to inform effective health promotion strategies.

Building partnerships in community-based participatory research: budgetary and other cost considerations.

Community-based participatory research (CBPR) is an important framework for partnering with communities to reduce health disparities. Working in partnership with community incurs additional costs, some that can be represented in a budget summary page and others that are tied to the competing demands placed on community and academic partners. These cost considerations can inform development of community-academic partnerships. We calculated costs from a case study based on an ongoing CBPR project involving a Community Planning Group (CPG) of community co-researchers in rural Alaska and a bicultural liaison group who help bridge communication between CPG and academic co-researchers. Budget considerations specific to CBPR include travel and other communication-related costs, compensation for community partners, and food served at meetings. We also identified sources of competing demands for community and academic partners. Our findings can inform budget discussions in community-academic partnerships. Discussions of competing demands on community partners' time can help plan timelines for CBPR projects. Our findings may also inform discussions about tenure and promotion policies that may represent barriers to participation in CBPR for academic researchers.

Carbon and nitrogen stable isotope ratios predict intake of sweeteners in a Yup'ik study population.

The carbon isotope ratio (δ¹³C) is elevated in corn- and cane sugar-based foods and has recently shown associations with sweetener intake in multiple U.S. populations. However, a high carbon isotope ratio is not specific to corn- and sugar cane-based sweeteners, as other foods, including meats and fish, also have elevated δ¹³C. This study examines whether the inclusion of a second marker, the nitrogen isotope ratio (δ¹5N), can control for confounding dietary effects on δ¹³C and improve the validity of isotopic markers of sweetener intake. The study participants are from the Yup'ik population of southwest Alaska and consume large and variable amounts of fish and marine mammals known to have elevated carbon and nitrogen isotope ratios. Sixty-eight participants completed 4 weekly 24-h recalls followed by a blood draw. RBC δ¹³C and δ¹5N were used to predict sweetener intake, including total sugars, added sugars, and sugar-sweetened beverages. A model including both δ¹³C and δ¹5N explained more than 3 times as much of the variation in sweetener intake than did a model using only δ¹³C. Because carbon and nitrogen isotope ratios are simultaneously determined in a single, high-throughput analysis, this dual isotope marker provides a simple method to improve the validity of stable isotope markers of sweetener intake with no additional cost. We anticipate that this multi-isotope approach will have utility in any population where a stable isotope biomarker is elevated in several food groups and there are appropriate "covariate" isotopes to control for intake of foods not of research interest.