Scarlett E. Hopkins

The Center for Alaska Native Health Research Study: a community-based participatory research study of obesity and chronic disease-related protective and risk factors

Objectives. To describe the background, approach and general results of the Center for Alaska Native Health Research (CANHR) study. Study Design. This was a cross-sectional Community-Based Participatory Research (CBPR) study with one tribal group to assess risk and protection for obesity and the risk factors related to chronic disease, diabetes and cardiovascular disease. Methods. A combination of biological, genetic, nutritional and psychosocial measurements were taken on 922 Alaska Native participants in ten communities in Southwestern Alaska. The paper reports on data from 753 adult participants. Results. The prevalence of type 2 diabetes is 3.3% in the sample population. Metabolic syndrome is significantly lower among the males and equal for females when compared with Caucasians in the NHANES III sample. Obesity among adults is now at the national average. Risk factors for chronic disease include a shift to a Westernized diet, stress, obesity and impaired fasting glucose and protective factors include high levels of polyunsaturated fatty acid dietary intake. Articles in this issue present specific results in these areas. Conclusions. The data strongly indicate that, in general, Yup`ik people in our study are metabolically healthy and that diet and life style provide a delicate combination of protective and risk factors. The results strongly indicate that solution focused research utilizing primary and secondary prevention strategies may provide evidence for how to intervene to prevent further increases of chronic diseases. Research that focuses on relating the intrinsic strengths of indigenous worldviews and practices with basic research may contribute to positive transformations in community health. The Center for Alaska Native Health Research Study: a community-based participatory research study of obesity and chronic disease-related protective and risk factors. Mohatt GV, Plaetke R, Klejka J, Luick B, Lardon C, Bersamin A, Hopkins S, Dondanville M, Herron J, Boyer B ABSTRACT [full text] back to issue 66(1)] OBJECTIVES: To describe the background, approach and general results of the Center for Alaska Native Health Research (CANHR) study. Study Design. This was a cross-sectional Community-Based Participatory Research (CBPR) study with one tribal group to assess risk and protection for obesity and the risk factors related to chronic disease, diabetes and cardiovascular disease. Methods. A combination of biological, genetic, nutritional and psychosocial measurements were taken on 922 Alaska Native participants in ten communities in Southwestern Alaska. The paper reports on data from 753 adult participants. Results. The prevalence of type 2 diabetes is 3.3% in the sample population. Metabolic syndrome is significantly lower among the males and equal for females when compared with Caucasians in the NHANES III sample. Obesity among adults is now at the national average. Risk factors for chronic disease include a shift to a Westernized diet, stress, obesity and impaired fasting glucose and protective factors include high levels of polyunsaturated fatty acid dietary intake. Articles in this issue present specific results in these areas. Conclusions. The data strongly indicate that, in general, Yup`ik people in our study are metabolically healthy and that diet and life style provide a delicate combination of protective and risk factors. The results strongly indicate that solution focused research utilizing primary and secondary prevention strategies may provide evidence for how to intervene to prevent further increases of chronic diseases. Research that focuses on relating the intrinsic strengths of indigenous worldviews and practices with basic research may contribute to positive transformations in community health.

Utilizing harmonization and common surveillance methods to consolidate 4 cohorts: the Western Alaska Tribal Collaborative for Health (WATCH) study

Background According to health status reports, chronic disease prevalence appears to be rising in western Alaska Native (AN) people, and accurate population-based data are needed. Four cohort studies of western AN people were conducted in the Norton Sound and Yukon-Kuskokwim regions, but none have been large enough to allow reliable estimates of rates of chronic diseases and evaluate their risk factors. Objective In this article, the methods used to combine 4 major cohort studies of rural western AN people are described and the benefits and challenges encountered in combining data and standardizing surveillance methods for these studies are discussed. Design Tribal permission was obtained for each cohort study and the consolidated study. Data from baseline exams were directly combined or harmonized into new variables. Common surveillance methods were developed and implemented to identify incidence and risk factors for cardiovascular disease (CVD) events and type 2 diabetes. Results A cohort of 4,569 western AN participants (2,116 men and 2,453 women), aged 18–95 years, was established to study CVD and diabetes prevalence. Prospective surveillance data over an average 6.7-year follow-up can now be used to study CVD and diabetes incidence and associated risk factors in a subset of 2,754 western AN participants (1,218 men and 1,536 women) who consented to initial surveillance. Conclusions The combined cohort provides statistical power to examine incidence rates and risk factors for CVD and diabetes and allows for analyses by geographic region. The data can be used to develop intervention programmes in these populations and others.

Associations of obesity with triglycerides and C-reactive protein are attenuated in adults with high red blood cell eicosapentaenoic and docosahexaenoic acids.

Background:N-3 fatty acids are associated with favorable, and obesity with unfavorable, concentrations of chronic disease risk biomarkers.Objective:We examined whether high eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid intakes, measured as percentages of total red blood cell (RBC) fatty acids, modify associations of obesity with chronic disease risk biomarkers.Methods:In a cross-sectional study of 330 Yup’ik Eskimos, generalized additive models (GAM) and linear and quadratic regression models were used to examine associations of BMI with biomarkers across RBC EPA and DHA categories.Results:Median (5th–95th percentile) RBC EPA and DHA were 2.6% (0.5–5.9%) and 7.3% (3.3–8.9%), respectively. In regression models, associations of BMI with triglycerides, glucose, insulin, C-reactive protein (CRP) and leptin differed significantly by RBC EPA and DHA. The GAM confirmed regression results for triglycerides and CRP: at low RBC EPA and RBC DHA, the predicted increases in triglycerides and CRP concentrations associated with a BMI increase from 25 to 35 were 99.5±45.3 mg/dl (106%) and 137.8±71.0 mg/dl (156%), respectively, for triglycerides and 1.2±0.7 mg/l (61%) and 0.8±1.0 mg/l (35%), respectively, for CRP. At high RBC EPA and RBC DHA, these predicted increases were 13.9±8.1 mg/dl (23%) and 12.0±12.3 mg/dl (18%), respectively, for triglycerides and 0.5±0.5 mg/l (50%) and −0.5±0.6 mg/l (−34%), respectively, for CRP.Conclusions:In this population, high RBC EPA and DHA were associated with attenuated dyslipidemia and low-grade systemic inflammation among overweight and obese persons. This may help inform recommendations for n-3 fatty acid intakes in the reduction of obesity-related disease risk.

KEEPING BUSY: A YUP'IK/CUP'IK PERSPECTIVE ON HEALTH AND AGING

Objectives. Knowledge of cultural beliefs about health and how they influence life choices and intervention is essential in forming health policy and health promotion programs to meet the growing needs of aging minority populations. This study explores cultural beliefs and practices of health and well-being of Yup`ik/Cup`ik women in two rural villages in southwestern Alaska. Study Design. Exploratory, descriptive qualitative study. Methods. Interviews were conducted with 15 mid-life and older women to address two key research questions: 1) How do Yup’ik/Cup’ik women define health and wellbeing; and 2) What environmental, social, and cultural factors contribute to healthy aging? Results. The women in this study define health aging within the framework of subsistence living-keeping busy, walking, eating subsistence foods, and respect for elders. These beliefs and practices promote a strong, active body and mind, vital components to healthy aging. Conclusions. While many health beliefs and practices appear very different from those current in research on aging, many commonalities and similarities emerge-concern for family, importance of physical activity and healthy diet. A significant finding of this study is that traditional Yup`ik/ Cup`ik ways of living parallel that of current research findings on what constitutes healthy aging in mainstream populations.

Isotopic estimates of sugar intake are related to chronic disease risk factors but not obesity in an Alaska native (Yup'ik) study population.

Background/Objectives:Sugar intake may be causally associated with chronic disease risk, either directly or by contributing to obesity. However, evidence from observational studies is mixed, in part due to the error and bias inherent in self-reported measures of sugar intake. Objective biomarkers may clarify the relationship between sugar intake and chronic disease risk. We have recently validated a biomarker of sugar intake in an Alaska Native (Yup’ik) study population that incorporates red blood cell carbon and nitrogen isotope ratios in a predictive model. This study tested associations of isotopic estimates of sugar intake with body mass index (BMI), waist circumference (WC) and a broad array of other physiological and biochemical measures of chronic disease risk in Yup’ik people.Subjects/Methods:In a cross-sectional sample of 1076 Yup’ik people, multiple linear regression was used to examine associations of sugar intake with BMI, WC and other chronic disease risk factors.Results:Isotopic estimates of sugar intake were not associated with BMI (P=0.50) or WC (P=0.85). They were positively associated with blood pressure, triglycerides (TG) and leptin, and are inversely associated with total-, high-density lipoprotein- and low-density lipoprotein-cholesterol and adiponectin.Conclusions:Isotopic estimates of sugar intake were not associated with obesity, but were adversely associated with other chronic disease risk factors in this Yup’ik study population. This first use of stable isotope markers of sugar intake may influence recommendations for sugar intake by Yup’ik people; however, longitudinal studies are required to understand associations with chronic disease incidence.

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX.

Objectives Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. Methods We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup’ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). Results We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (−1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Conclusion Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska.

Pharmacogenetic research in partnership with American Indian and Alaska Native communities

Pharmacogenetics is a subset of personalized medicine that applies knowledge about genetic variation in gene-drug pairs to help guide optimal dosing. There is a lack of data, however, about pharmacogenetic variation in underserved populations. One strategy for increasing participation of underserved populations in pharmacogenetic research is to include communities in the research process. We have established academic-community partnerships with American Indian and Alaska Native people living in Alaska and Montana to study pharmacogenetics. Key features of the partnership include community oversight of the project, research objectives that address community health priorities, and bidirectional learning that builds capacity in both the community and the research team. Engaging the community as coresearchers can help build trust to advance pharmacogenetic research objectives.

Household reporting of childhood respiratory health and air pollution in rural Alaska Native communities

Background Air pollution is an important contributor to respiratory disease in children. Objective To examine associations between household reporting of childhood respiratory conditions and household characteristics related to air pollution in Alaska Native communities. Design In-home surveys were administered in 2 rural regions of Alaska. The 12-month prevalence of respiratory conditions was summarized by region and age. Odds ratios (ORs) were calculated to describe associations between respiratory health and household and air quality characteristics. Results Household-reported respiratory health data were collected for 561 children in 328 households. In 1 region, 33.6% of children aged <5 years had a recent history of pneumonia and/or bronchitis. Children with these conditions were 2 times more likely to live in a wood-heated home, but these findings were imprecise. Resident concern with mould was associated with elevated prevalence of respiratory infections in children (ORs 1.6–2.5), while reported wheezing was associated with 1 or more smokers living in the household. Reported asthma in 1 region (7.6%) was lower than national prevalence estimates. Conclusions Findings suggest that there may be preventable exposures, including wood smoke and mould that affect childhood respiratory disease in these rural areas. Additional research is needed to quantify particulate matter 2.5 microns in aerodynamic diameter or less and mould exposures in these communities, and to objectively evaluate childhood respiratory health.

Cardiometabolic correlates of low type 2 diabetes incidence in western Alaska Native people - The WATCH study.

AIMS Previously rare among Alaska Native (AN) people, type 2 diabetes (DM2) prevalence as indicated by registry data has increased by as much as 300% in some western Alaska regions. We sought to determine prevalence and incidence of DM2 and analyze associated cardiometabolic risk factors in western AN people. METHODS DM2 and prediabetes prevalence and incidence were determined by the Western Alaska Tribal Collaborative for Health using consolidated data from cohort studies conducted during 2000-2010. Crude and age-adjusted incidence for DM2 and prediabetes were calculated using 2010 American Diabetes Association criteria. Effects of covariates on DM2 and prediabetes were determined using univariate and multivariate Cox proportional hazards analyses, adjusted for age and sex. RESULTS Excluding baseline diabetes (n=124, 4.5%), 53 cases of new DM2 were identified among 2630 participants. Age- and sex-adjusted DM2 incidence was 4.3/1000 (95% CI 2.9, 5.0) person-years over an average 5.9-year follow up. After excluding baseline prediabetes, 387 new cases of prediabetes were identified among 1841 participants; adjusted prediabetes incidence was 44.5/1000 (95% CI 39.5, 49.5) person years. Independent predictors for DM2 included age, impaired fasting glucose, and metabolic syndrome; family history of diabetes and obesity were additional independent predictors for prediabetes. CONCLUSIONS DM2 incidence in western AN people is substantially lower than that for U.S. whites; however, incidence of prediabetes is more than 10-fold higher than western AN DM2 incidence and more closely aligned with U.S. rates. Interventions aimed at achieving healthy lifestyles are needed to minimize risk factors and maximize protective factors for DM2 in this population.

Common Low-Density Lipoprotein Receptor p.G116S Variant Has a Large Effect on Plasma Low-Density Lipoprotein Cholesterol in Circumpolar Inuit Populations

Background—Inuit are considered to be vulnerable to cardiovascular disease because their lifestyles are becoming more Westernized. During sequence analysis of Inuit individuals at extremes of lipid traits, we identified 2 nonsynonymous variants in low-density lipoprotein receptor (LDLR), namely p.G116S and p.R730W. Methods and Results—Genotyping these variants in 3324 Inuit from Alaska, Canada, and Greenland showed they were common, with allele frequencies 10% to 15%. Only p.G116S was associated with dyslipidemia: the increase in LDL cholesterol was 0.54 mmol/L (20.9 mg/dL) per allele (P=5.6×10−49), which was >3× larger than the largest effect sizes seen with other common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (95% confidence interval, 2.34–3.90; P=1.7×10−17), but did not have classical familial hypercholesterolemia. In vitro, p.G116S showed 60% reduced ligand-binding activity compared with wild-type receptor. In contrast, p.R730W was associated with neither LDL cholesterol level nor altered in vitro activity. Conclusions—LDLR p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications.Inuit were long-believed to have lower CVD risk than non-indigenous populations.1–3 However, re-evaluation of population studies indicates that ischemic heart disease rates are similar between Inuit and non-Indigenous people.4 Furthermore, ongoing Westernization in many Inuit communities has intensified their exposure to CVD risk factors such as smoking, calorie-dense processed foods, and a more comfortable but also sedentary lifestyle, all of which affect CVD risk and prevalence.4–10 Among classical CVD risk factors, Inuit adults tend to have higher plasma concentrations of LDL cholesterol than non-indigenous populations.11–15 The predominant monogenic cause of elevated LDL cholesterol concentration in most global populations is familial hypercholesterolemia (FH, Online Mendelian Inheritance in Man [OMIM] 143890).16 Heterozygous FH (HeFH) prevalence may be as high as 1:200 in certain European populations, and it is a potent predisposition state for early CVD.11–13 To date, DNA sequencing and biochemical studies have identified >1,600 rare loss-of-function mutations in the gene encoding the LDL receptor (LDLR), which can increase LDL cholesterol levels by 100% or more, and underlie >95% of cases of molecularly diagnosed FH.16 But despite the relatively high levels of LDL cholesterol observed in some Inuit, the role of LDLR gene variation has not been systematically studied.13–15 We thus investigated the LDLR locus in Inuit and tested for association of variants therein with plasma lipids. Through Sanger sequencing and targeted genotyping, we found two new LDLR variants common to five Inuit subgroups from across North America and Greenland: 1) p.G116S was both dysfunctional in vitro and associated with a relatively large increase in plasma LDL cholesterol levels; while 2) p.R730W had minimal dysfunction and impact on the lipid profile.