Evidence-based screening, clinical care and health education recommendations for Alaska Native peoples with prediabetes living in southcentral Alaska: findings from the Alaska EARTH follow-up study.

Pre-diabetes (pre-DM) is a strong predictor of diabetes (DM) over time. This study investigated how much of the recent increase in pre-DM identified among Alaska Native (AN) peoples living in urban southcentral Alaska may be due to changes in diagnostic methods. We used clinical and demographic data collected at baseline between 2004 and 2006 and at follow-up collected between 2015 and 2017 from the urban southcentral Alaska Education and Research Towards Health (EARTH) cohort. We used descriptive statistics and logistic regression to explore differences in demographic and clinical variables among the identified pre-DM groups. Of 388 participants in the follow-up study, 243 had A1c levels indicating pre-DM with only 20 demonstrating pre-DM also by fasting blood glucose (FBG). Current smoking was the sole predictor for pre-DM by A1c alone while abdominal obesity and elevated FBG-predicted pre-DM by A1c+FBG. No participants had an elevated FBG without an A1c elevation. A substantial portion of the rise in pre-DM found among urban southcentral AN peoples in the EARTH follow-up study was due to the addition of A1c testing. Pre-DM by A1c alone should be used to motivate behavioural changes that address modifiable risk factors, including smoking cessation, physical activity and weight management.

Identification of Sociodemographic, Clinical, and Genetic Factors to Aid Alaska Native and American Indian People to Successfully Quit Smoking.

INTRODUCTION: Alaska Native and American Indian (ANAI) people have a smoking prevalence of 23%. Nicotine metabolite ratio (NMR) and genetic testing may enable tailored selection of tobacco cessation medication. AIMS AND METHODS: The purpose of this study was to evaluate the relative contributions of NMR, cessation medication, demographics, and tobacco use history to cessation. Participants were recruited into an observational cohort study consisting of a baseline visit prior to their quit date and 6-week follow-up. Demographic and tobacco use surveys and blood, urine, and breath samples were collected at each visit. Electronic health records were queried for cessation medications. NMR was categorized into slow or normal nicotine metabolism phenotypes (<0.31 and ≥ 0.31, respectively). The main outcome was cessation at 6 weeks. Analyses consisted of descriptive statistics, medication and phenotype concordance, and estimates of relative risk (RR) of quitting. RESULTS: We enrolled 151 ANAI adults who smoked cigarettes daily. Two-thirds had normal nicotine metabolism phenotype. Retrospective medication and phenotype concordance was 39%. The overall quit rate was 25%. No demographic factors or tobacco use history were associated with quit success. Varenicline and bupropion increased the likelihood of quitting (RR = 2.93 [1.42, 6.03] and RR = 2.52 [1.12, 5.64], respectively) compared to nicotine replacement therapy. Non-optimal medication and phenotype concordance decreased likelihood of quit success (RR = 0.44 [0.22, 0.91]) compared to optimal concordance. CONCLUSIONS: This exploratory study found associations between quit success and tobacco cessation medication as well as medication and phenotype concordance. Additional research is needed to assess use of NMR for treatment selection among ANAI people. IMPLICATIONS: These results broadly support additional community-engaged research to improve medication and phenotype concordance in tribal health settings. Such future research on implementing meditcation and phenotype concordance holds promise to improve expectations, quit success, and health outcomes amongst individuals attempting to quit smoking.

Cancer Screening Prevalence among Participants in the Southcentral Alaska Education and Research towards Health (EARTH) Study at Baseline and Follow-Up.

Alaska Native communities are working to prevent cancer through increased cancer screening and early detection. We examined the prevalence of self-reported colorectal (CRC), cervical, and breast cancer screening among Alaska Native participants in the southcentral Alaska Education and Research toward Health (EARTH) study at baseline (2004-2006) and ten-year follow-up (2015-2017); participant characteristics associated with screening; and changes in screening prevalence over time. A total of 385 participants completed questionnaires at follow-up; 72% were women. Of those eligible for CRC screening, 53% of follow-up participants reported a CRC screening test within the past 5 years, significantly less than at baseline (70%) (p = 0.02). There was also a significant decline in cervical cancer screening between baseline and follow-up: 73% of women at follow-up vs. 90% at baseline reported screening within the past three years (p < 0.01). There was no significant difference in reported breast cancer screening between baseline (78%) and follow-up (77%). Colorectal and cervical cancer screening prevalence in an urban, southcentral Alaska Native cohort declined over 10 years of follow-up. Increased cancer screening and prevention are needed to decrease Alaska Native cancer-related morbidity and mortality.

Retention in a 6-Month Smoking Cessation Study Among Alaska Native and American Indian People.

Participant retention in longitudinal health research is necessary for generalizable results. Understanding factors that correlate with increased retention could improve retention in future studies. Here, we describe how participant and study process measures are associated with retention in a longitudinal tobacco cessation research study performed in Anchorage, Alaska. Specifically, we conducted a secondary analysis exploring retention among 151 Alaska Native and American Indian (ANAI) people and described our study processes using study retention categories from a recent meta-analysis. We found that our study processes influence retention among ANAI urban residents more than measures collected about the participant. For study process measures, calls where a participant answered and calls participants placed to the study team were associated with higher retention. Calls where the participant did not answer were associated with lower retention. For participant measures, only lower annual income was associated with lower retention at 6 weeks. Promoting communication from participants to the study team could improve retention, and alternative communication methods could be used after unsuccessful calls. Finally, categorizing our study retention strategies demonstrated that additional barrier-reduction strategies might be warranted.

Smoking Patterns Among Urban Alaska Native and American Indian Adults: The Alaska EARTH 10-Year Follow-up Study.

INTRODUCTION: Data on cigarette smoking prevalence among Alaska Native and American Indian (ANAI) people are limited to cross-sectional studies or specific subpopulations. Using data from the Alaska Education and Research toward Health (EARTH) Study 10-year follow-up, this study assessed patterns of smoking from baseline and factors associated with current use. AIMS AND METHODS: EARTH Study urban south central ANAI participants (N = 376; 73% women) provided questionnaire data on smoking at baseline and 10-year follow-up. Multivariable-adjusted logistic regression assessed whether gender, cultural factors (Tribal identity, language spoken in the home), depressive symptoms (PHQ-9), baseline smoking status, and baseline cigarettes per day (CPD) were associated with current smoking at follow-up. RESULTS: Current smoking was 27% and 23% at baseline and follow-up, respectively. Of baseline smokers, 60% reported smoking at follow-up (77% men, 52% women). From multivariable-adjusted analyses, the odds of current smoking at follow-up were lower among women than men, those who never or formerly smoked versus currently smoked at baseline, and smoking <10 CPD compared with ≥10 CPD at baseline. PHQ-9 score or cultural variables were not associated with smoking at follow-up. Smoking fewer baseline CPD was associated with former smoking status (ie, quitting) at follow-up among women, but not men. CONCLUSIONS: Our project is among the first to longitudinally explore smoking within an ANAI cohort. While we observed persistent smoking during a 10-year period, there were important differences by gender and CPD in quitting. These differences may be important to enhance the reach and efficacy of cessation interventions for ANAI people. IMPLICATIONS: This study contributes novel longitudinal information on cigarette smoking prevalence during a 10-year period among Alaska Native and American Indian (ANAI) people. Prior data on smoking prevalence among ANAI people are limited to cross-sectional studies or specific subpopulations. Our project is among the first to longitudinally explore smoking prevalence within an ANAI cohort. We observed persistent smoking during a 10-year period. The study also contributes information on differences by gender and cigarettes smoked per day in quitting. These findings have implications for enhancing the reach and efficacy of cessation interventions for ANAI people.

Nicotine metabolism and its association with CYP2A6 genotype among Indigenous people in Alaska who smoke.

Prevalence of smoking is higher in Alaska Native and American Indian (ANAI) populations living in Alaska than the general US population. Genetic factors contribute to smoking and cessation rates. The objective of this study was to compare CYP2A6 genetic variation and CYP2A6 enzyme activity toward nicotine in an ANAI population. ANAI (N = 151) people trying to quit smoking were recruited. DNA samples were genotyped for CYP2A6 variants *1X2A, *1B, *2, *4, *9, *10, *12, and *35. Multiple nicotine metabolites were measured in plasma and urine samples, including cotinine and 3'-hydroxycotinine used to determine CYP2A6 activity (e.g., nicotine metabolite ratio [NMR]). We calculated summary statistics for all of the genotypes and metabolites and assigned CYP2A6 activity scores based on known information. We studied the association of CYP2A6 variants with the NMR and smoking histories. The overall frequency of the CYP2A6*1B gain of function allele was high in the ANAI versus non-ANAI populations in other studies. Both *4 null and *9 decrease of function alleles had frequencies similar to previous studies of ANAI populations. In a multivariate analysis, the genotype-inferred CYP2A6 activity score was associated with both plasma and urine NMR (p value = 8.56E-08 and 4.08E-13, respectively). Plasma NMR was also associated with duration of smoking (p value < 0.01) but not urinary total nicotine equivalents uncorrected for creatinine (TNE9uc ) or biological sex. Urine NMR was significantly associated (p value < 0.01) with TNE9uc . Variation in NMR in this ANAI population is explained in part by CYP2A6 genetic variation.

Increase in diabetes among urban Alaska Native people in the Alaska EARTH follow-up study: A call for prediabetes screening, diagnosis, and referral for intervention.

AIMS: This study estimates incidence of diabetes (DM) and pre-DM relative to DM risk factors among relatively healthy Alaska Native and American Indian (henceforth AN) adults living in urban south central Alaska. METHODS: Baseline (2004-2006) and follow-up (2014-2017) surveys, blood samples, and medical chart review data were collected from AN adults living in south central Alaska. We analyzed associations between prevalent risk factors and incident DM and pre-DM using Cox proportional hazards and used multivariable models to identify independent predictors for both DM and pre-DM. RESULTS: Among 379 participants with follow-up data, overall DM incidence was 16.5/1,000 PY; overall pre-DM incidence was 77.6/1,000 PY, with marked differences between men and women. Prevalent cardiometabolic risk factors also varied with greater amounts of overweight in men and greater amounts of obesity in women. Controlling for age and sex, obesity, abdominal adiposity, pre-DM, and metabolic syndrome independently increased DM risk. CONCLUSION: Health care providers of AN populations must seize the opportunity to screen, refer, and treat individuals with pre-DM and other modifiable DM risk factors prior to DM diagnosis if we are to alter the epidemiologic course of disease progression in this urban AN population.

Pharmacogenomics of Nicotine Metabolism: Novel CYP2A6 and CYP2B6 Genetic Variation Patterns in Alaska Native and American Indian Populations.

INTRODUCTION: Alaska Native and American Indian (AN/AI) populations have higher tobacco use prevalence than other ethnic/racial groups. Pharmacogenetic testing to tailor tobacco cessation treatment may improve cessation rates. This study characterized polymorphic variations among AN/AI people in genes associated with metabolism of nicotine and drugs used for tobacco cessation. METHODS: Recruitment of AN/AI individuals represented six subgroups, five geographic subgroups throughout Alaska and a subgroup comprised of AIs from the lower 48 states living in Alaska. We sequenced the CYP2A6 and CYP2B6 genes to identify known and novel gain, reduced, and loss-of-function alleles, including structural variation (eg, gene deletions, duplications, and hybridizations). RESULTS: Variant allele frequencies differed substantially between AN/AI subgroups. The gene deletion CYP2A6*4 and reduced function CYP2A6*9 alleles were found at high frequency in Northern/Western subgroups and in Lower 48/Interior subgroups, respectively. The reduced function CYP2B6*6 allele was observed in all subgroups and a novel, predicted reduced function CYP2B6 variant was found at relatively high frequency in the Southeastern subgroup. CONCLUSIONS: Diverse CYP2A6 and CYP2B6 variation among the subgroups highlight the need for comprehensive pharmacogenetic testing to guide tobacco cessation therapy for AN/AI populations. IMPLICATIONS: Nicotine metabolism is largely determined by CYP2A6 genotype, and variation in CYP2A6 activity has altered the treatment success in other populations. These findings suggest pharmacogenetic-guided smoking cessation drug treatment could provide benefit to this unique population seeking tobacco cessation therapy.

Alaska Native Traditional Food and Harvesting Activity Patterns over 10 Years of Follow-Up.

BACKGROUND: Alaska Native (AN) traditional foods and associated harvesting activities are beneficial to human health. OBJECTIVE: This study assessed longitudinal self-reported traditional food use and harvesting activities among Alaska Native and American Indian (AN/AI) participants in the Alaska Education and Research Towards Health (EARTH) study. METHODS: In 2004-2006, southcentral Alaska EARTH study participants (n = 1320) completed diet and activity questionnaires which were repeated in 2015-2017; results were compared between participants who completed both questionnaires (n = 388). RESULTS: In the follow-up questionnaire, >93% of participants reported eating ≥1 traditional food in the past year. The top 3 traditional foods were fish (75%), moose (42%), and shellfish (41%). Women were more likely than men to consume traditional foods, especially fish, gathered berries, shellfish, and seal oil (P < 0.05). Participants aged ≥60 y in the original cohort were significantly more likely to consume fish and shellfish at follow-up, whereas those aged 40-59 y were the most likely of the 3 age groups to consume seal oil (P < 0.05). Between the original cohort and follow-up, there was a significant decline in the mean number of traditional foods eaten from 6.3 to 5.5, as well as reduced consumption of multiple traditional foods (P < 0.001). Over 59% of participants reported ≥1 traditional harvesting activity in the past year; this proportion did not significantly change between baseline and follow-up. Picking berries/greens (44%), cutting/smoking fish or meat (33%), and fishing (30%) were the most common activities. Participation in traditional harvesting activities was greater among women than men (P < 0.05), but did not differ by age. CONCLUSIONS: Longitudinal follow-up demonstrated that AN/AI people maintained participation in traditional harvesting activities, but the variety of traditional foods declined significantly among both men and women. Promotion of traditional foods and harvesting activities that serve as protective factors against chronic diseases may benefit this population.

Perspectives on communication and engagement with regard to collecting biospecimens and family health histories for cancer research in a rural Alaska Native community.

Precision medicine initiatives, such as Cancer Breakthrough 2020, promise to improve cancer outcomes by tailoring treatment to an individual's genes, environment, and lifestyle. This promise will fall short unless researchers successfully engage diverse communities, including those with histories of medical and research abuse. We examined a rural Alaska Native community's viewpoints about biospecimen collection and storage; interest and recall in reporting family health history; and interest and engagement in biospecimen collection for conducting a genetic test for cancer. In 2014, four focus groups were held with 28 adult Alaska Native rural community members. Thematic analysis was performed after establishing a coding scheme by team consensus. Study participants shared interest in engaging in genetic cancer research and suggested ways to improve community engagement in research. These included transparency and continuous communication with researchers at all stages of the research, clear communication about the intent of the research, and that research and results take into consideration the community's needs. These suggestions may be beneficial for future efforts to expand precision medicine research in Alaska Native communities and similar, diverse populations.

Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People.

Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites. Only the CYP2D6 variation was significantly associated with concentrations of endoxifen (P = 0.0008) and 4-hydroxytamoxifen (P = 0.0074), tamoxifen's principal active metabolites, as well as key metabolic ratios. The CYP2D6 was also the most significant predictor of active metabolites and metabolic ratios in a multivariate regression model, including all four genes as predictors, with minor roles for other CYP genes. In AIAN populations, CYP2D6 is the largest contributor to tamoxifen bioactivation, illustrating the importance of validating pharmacogenetic testing for therapy optimization in an understudied population.

Perceptions of pharmacogenetic research to guide tobacco cessation by patients, providers and leaders in a tribal healthcare setting.

AIM: Describe patients,' providers' and healthcare system leaders' perceptions of pharmacogenetic research to guide tobacco cessation treatment in an American Indian/Alaska Native primary care setting. MATERIALS & METHODS: This qualitative study used semistructured interviews with 20 American Indian/Alaska Native current or former tobacco users, 12 healthcare providers and nine healthcare system leaders. RESULTS: Participants supported pharmacogenetic research to guide tobacco cessation treatment provided that a community-based participatory research approach be employed, research closely coordinate with existing tobacco cessation services and access to pharmacogenetic test results be restricted to providers involved in tobacco cessation. CONCLUSION: Despite a history of mistrust toward genetic research in tribal communities, participants expressed willingness to support pharmacogenetic research to guide tobacco cessation treatment.

Views on electronic cigarette use in tobacco screening and cessation in an Alaska Native healthcare setting.

BACKGROUND: American Indian (AI) and Alaska Native (AN) communities confront some of the highest rates of tobacco use and its sequelae. METHODS: This formative research project sought to identify the perspectives of 41 stakeholders (community members receiving care within the healthcare system, primary care providers, and tribal healthcare system leaders) surrounding the use of pharmacogenetics toward tobacco cessation treatment in the setting of an AI/AN owned and operated health system in south central Alaska. RESULTS: Interviews were held with 20 adult AI/AN current and former tobacco users, 12 healthcare providers, and 9 tribal leaders. An emergent theme from data analysis was that current tobacco screening and cessation efforts lack information on electronic cigarette (e-cigarette) use. Perceptions of the use of e-cigarettes role in tobacco cessation varied. CONCLUSION: Preventive screening for tobacco use and clinical cessation counseling should address e-cigarette use. Healthcare provider tobacco cessation messaging should similarly address e-cigarettes.