Heterologous Expression and Functional Characterization of Novel CYP2C9 Variants Identified in the Alaska Native People.

CYP2C9 is a major form of human liver cytochrome P450 that is responsible for the oxidative metabolism of several widely used low-therapeutic index drugs, including (S)-warfarin and phenytoin. In a cohort of Alaska Native people, ultrarare or novel CYP2C9 protein variants, M1L (rs114071557), N218I (rs780801862), and P279T (rs182132442, CYP2C9*29), are expressed with higher frequencies than the well characterized CYP2C9*2 and CYP2C9*3 alleles. We report here on their relative expression in lentivirus-infected HepG2 cells and the functional characterization of purified reconstituted enzyme variants expressed in Escherichia coli toward (S)-warfarin, phenytoin, flurbiprofen, and (S)-naproxen. In the infected HepG2 cells, robust mRNA and protein expression were obtained for wild-type, N218I, and P279T variants, but as expected, the M1L variant protein was not translated in this liver-derived cell line. His-tagged wild-type protein and the N218I and P279T variants, but not M1L, expressed well in E. coli and were highly purified after affinity chromatography. Upon reconstitution with cytochrome P450 oxidoreductase and cytochrome b5, the N218I and P279T protein variants metabolized (S)-warfarin, phenytoin, flurbiprofen, and (S)-naproxen to the expected monohydroxylated or O-demethylated metabolites. Steady-state kinetic analyses revealed that the relative catalytic efficiency ratios of (S)-warfarin metabolism by the P279T and N218I variants were 87% and 24%, respectively, of wild-type CYP2C9 protein. A similar rank ordering was observed for metabolism of phenytoin, flurbiprofen, and (S)-naproxen. We conclude that carriers of the variant N218I and, especially, the M1L alleles would be at risk of exacerbated therapeutic effects from drugs that rely on CYP2C9 for their metabolic clearance. SIGNIFICANCE STATEMENT: Novel gene variants of CYP2C9-M1L, and N218I, along with P279T (CYP2C9*29)-are expressed in Alaska Native people at relatively high frequencies. In vitro characterization of their functional effects revealed that each variant confers reduced catalytic efficiency toward several substrates, including the low-therapeutic index drugs (S)-warfarin and phenytoin. These data provide the first functional information for new, common CYP2C9 variants in this understudied population. The data may help guide dose adjustments in allele carriers, thus mitigating potential healthcare disparities.

An Alaska Native community's views on genetic research, testing, and return of results: Results from a public deliberation.

As genetic testing technology advances, genetic testing will move into standard practice in the primary care setting. Genetic research, testing, and return of results are complex topics that require input from Alaska Native and American Indian (ANAI) communities as policies are developed for implementation. This study employed a day and half long public deliberation with ANAI primary care patients to elicit value-laden views of genetic research, testing, and return of results. Participants emphasized the need for a balance between the potential for genetics research, testing, and return of results to empower individuals and improve health with the potential to expose individuals and communities to privacy breaches, discrimination, and emotional harms. Public deliberation was well received by this group of participants and elicited rich discussion on the complex topic of genetic research, testing, and return of results.

A decade on: Follow-up findings of indigenous children with bronchiectasis.

OBJECTIVE: The sole prospective longitudinal study of children with either chronic suppurative lung disease (CSLD) or bronchiectasis published in the current era was limited to a single center. We sought to extend this study by evaluating the longer-term clinical and lung function outcomes and their associated risk factors in Indigenous children of adolescents from Australia, Alaska, and New Zealand who participated in our previous CSLD or bronchiectasis studies during 2004-2010. METHODS: Between 2015 and 2018, we evaluated 131 out of 180 (72.8%) children of adolescents from the original studies at a single follow-up visit. We administered standardized questionnaires, reviewed medical records, undertook clinical examinations, performed spirometry, and scored available chest computed tomography scans. RESULTS: Participants were seen at a mean age of 12.3 years (standard deviation: 2.6) and a median of 9.0 years (range: 5.0-13.0) after their original recruitment. With increasing age, rates of acute lower respiratory infections (ALRI) declined, while lung function was mostly within population norms (median forced expiry volume in one-second = 90% predicted, interquartile range [IQR]: 81-105; forced vital capacity [FVC] = 98% predicted, IQR: 85-114). However, 43 out of 111 (38.7%) reported chronic cough episodes. Their overall global rating judged by symptoms, including ALRI frequency, examination findings, and spirometry was well (20.3%), stable (43.9%), or improved (35.8%). Multivariable regression identified household tobacco exposure and age at first ALRI-episode as independent risk factors associated with lower FVC% predicted values. CONCLUSION: Under our clinical care, the respiratory outcomes in late childhood or early adolescence are encouraging for these patient populations at high-risk of premature mortality. Prospective studies to further inform management throughout the life course into adulthood are now needed.

Developing an Epidemiologic Study to Investigate Risk Factors for Colorectal Cancer Among Alaska Native People.

Alaska Native (AN) people have among the highest rates of colorectal cancer (CRC) recorded globally. Preventing CRC is an important health priority of AN tribal health leaders and communities. Lifestyle and genetic risk and protective factors for CRC among AN people remain understudied. We have been working to establish a tribally led, community-based, comprehensive investigation of lifestyle and genetic risk and protective factors for CRC among AN people. We describe the process of initiating this research study, including conversations with key tribal health system staff. We discuss themes that arose during these conversations and literature review and describe how those themes were used during the study design and protocol development phase. This description is intended to provide guidance to other researchers working to establish community-based studies of cancer risk, particularly among tribal communities.

Timeliness of Breast Cancer Treatment Within The Alaska Tribal Health System.

PURPOSE: This study examined the time from breast cancer diagnosis to initiation of treatment among Alaska Native (AN) women. We evaluated the impact of age, cancer stage, and rural/urban residence at diagnosis. METHODS: We evaluated characteristics of women recorded in the Alaska Native Tumor Registry who received a first diagnosis of breast cancer between 2009 and 2013. Median time from diagnosis to treatment was assessed. Associations of demographic and clinical characteristics with timely initiation of treatment were evaluated using logistic regression and Cox proportional hazards models. RESULTS: Two hundred seventy-eight (278) AN women were diagnosed with invasive breast cancer in years 2009-2013. Mean age at diagnosis was 56.8 years (SD = 13.0). The median time from diagnosis to initiation of treatment was 23 days (P < .05) with most (94.6%, n = 263) meeting the ≤60-day guideline target. Time to treatment was not associated with rural/urban residence, age, or stage at cancer diagnosis. CONCLUSION: These findings indicate that most AN women diagnosed with breast cancer within the AN Tribal Health System receive timely treatment after diagnosis.

Review of built and natural environment stressors impacting American-Indian/Alaska-Native children.

Children's exposures to chemical and non-chemical stressors from their everyday environment affects their overall health and well-being. American-Indian/Alaska-Native (AI/AN) children may have a disproportionate burden of stressors from their built and natural environments when compared to children from other races/ethnicities. Our objectives were to identify chemical and non-chemical stressors from AI/AN children's built and natural environments and evaluate their linkages with health and well-being outcomes from the peer reviewed literature. Library databases (e.g. PubMed) were searched to identify studies focused on these stressors. References were excluded if they: did not discuss AI/AN children or they were not the primary cohort; discussed tribes outside the United States (U.S.); were reviews or intervention studies; or did not discuss stressors from the built/natural environments. Out of 2539 references, 35 remained. Sample populations were predominantly (70%) in New York (NY) and Alaska (AK); 14 studies reported on the same cohort. Studies with matching stressors and outcomes were few, ruling out a quantitative review. Respiratory and developmental outcomes were the main outcomes evaluated. Primary non-chemical stressors were residential proximity to polluted landscapes, lack of indoor plumbing, and indoor use of wood for heating or cooking. The main chemical stressors were volatile organic compounds (VOCs), particulate matter (PM2.5), polychlorinated biphenyls (PCBs), p,p'-DDE, hexachlorobenzene (HCB), lead, and mercury. Our qualitative review was suggestive of a potential increase in respiratory illness from indoor wood use or no plumbing, which can be used as a guide to promote healthy environments for AI/AN children. We identified limited studies (<40), demonstrating this population as understudied. Future studies need to consider: sample populations from other tribes in the U.S., stressors outside the household, other elements of the natural environment, and an evaluation of stressors from AI/AN children's total environment (built, natural, and social).

Colonized Silence: Confronting the Colonial Link in Rural Alaska Native Survivors' Non-Disclosure of Child Sexual Abuse.

Though there is evidence linking the history of colonialism and oppression of Indigenous people to the high rates of rape and child sexual abuse experienced by this population today, it is less understood how colonial processes, past and present, condition the decision to disclose or report victimization. Drawing on a survivorship storytelling study of rural Alaska Native survivors of child sexual abuse, this paper underscores the importance of centering colonialism in understanding the culture of silence surrounding sexual victimization among Indigenous people. Results show that reasons for non-disclosure are quite embedded within larger social, historical and political themes of colonialism, oppression, and marginalization. Implications for policy and praxes are discussed, as well as a broader mandate of social change to remove barriers to disclosure.

Culturally Relevant Palliative and End-of-Life Care for U.S. Indigenous Populations: An Integrative Review.

PURPOSE: American Indians/Alaska Natives (AIs/ANs) have higher rates of chronic illness and lack access to palliative/end-of-life (EOL) care. This integrative review ascertained the state of the science on culturally acceptable palliative/EOL care options for Indigenous persons in the United States. DESIGN: Databases searched: CINAHL, PubMed/MEDLINE, SocINDEX, PsycINFO, PsycARTICLES, ERIC, Health Source: Nursing/Academic Edition, and EBSCO Discovery Service 1880s-Present. Key terms used: palliative care, EOL care, and AI/AN. INCLUSION CRITERIA: peer-reviewed articles published in English. Findings/Results: Twenty-nine articles were identified, 17 remained that described culturally specific palliative/EOL care for AIs/ANs. Synthesis revealed four themes: Communication, Cultural Awareness/Sensitivity, Community Guidance for Palliative/EOL Care Programs, Barriers and two subthemes: Trust/Respect and Mistrust. DISCUSSION/CONCLUSION: Limitations are lack of research funding, geographic isolation, and stringent government requirements. Palliative/EOL care must draw on a different set of skills that honor care beyond cure provided in a culturally sensitive manner.

Unintended consequences of local alcohol restrictions in rural Alaska.

Since 1981, Alaskans have had the ability to enact by referendum local restrictions in alcohol sales, importation, and possession, known as "local options." Intended to empower rural communities to reduce alcohol abuse and associated violence and trauma, the "local option" laws have led to unintended consequences as individuals in alcohol-restricted communities seek intoxication from both legal and illegal sources of alcohol. Based on 68 interviews with 72 community members in eight rural sites in Alaska, this article examines these unintended consequences of local options restrictions and provides context to the challenges rural communities face in implementing alcohol policies.

Household water insecurity and its cultural dimensions: preliminary results from Newtok, Alaska.

Using a relational approach, I examine several cultural dimensions involved in household water access and use in Newtok, Alaska. I describe the patterns that emerge around domestic water access and use, as well as the subjective lived experiences of water insecurity including risk perceptions, and the daily work and hydro-social relationships involved in accessing water from various sources. I found that Newtok residents haul water in limited amounts from a multitude of sources, both treated and untreated, throughout the year. Household water access is tied to hydro-social relationships predicated on sharing and reciprocity, particularly when the primary treated water access point is unavailable. Older boys and young men are primarily responsible for hauling water, and this role appears to be important to male Yupik identity. Many interviewees described preferring to drink untreated water, a practice that appears related to cultural constructions of natural water sources as pure and self-purifying, as well as concerns about the safety of treated water. Concerns related to the health consequences of low water access appear to differ by gender and age, with women and elders expressing greater concern than men. These preliminary results point to the importance of understanding the cultural dimensions involved in household water access and use. I argue that institutional responses to water insecurity need to incorporate such cultural dimensions into solutions aimed at increasing household access to and use of water.

Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis.

OBJECTIVE: The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the 'shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13ß stratifies with ACPA-positive RA, while His13ßSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1*04:04 and HLA-DRB1*14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1*14:02 has a His13ßSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. METHODS: HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1*1402-class II loaded with vimentin-64Arg59-71, vimentin-64Cit59-71 and fibrinogen ß-74Cit69-81 were solved using X-ray crystallography. Vimentin-64Cit59-71-specific and vimentin59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and ß-chains were analysed using multiplex, nested PCR and sequencing. RESULTS: ACPA+ RA in INA was independently associated with HLA-DRB1*14:02. Consequent to the His13ßSer polymorphism and altered P4 pocket of HLA-DRB1*14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin59-71 were observed in patients with HLA-DRB1*14:02+ RA and at-risk ACPA- first-degree relatives. HLA-DRB1*14:02-vimentin59-71-specific and HLA-DRB1*14:02-vimentin-64Cit59-71-specific CD4+ memory T cells were phenotypically distinct populations. CONCLUSION: HLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.

Tailoring an Alcohol Intervention for American Indian Alaska Native Women of Childbearing Age: Listening to the Community.

BACKGROUND: Reduction of risky drinking in women of childbearing age is 1 strategy that may be employed to prevent fetal alcohol spectrum disorder, a sequela of prenatal alcohol exposure. Communities differ in risk and protective factors, necessitating culturally informed interventions for maximal efficacy. This article describes the modification of an existing web-based screening, brief intervention, and referral to treatment intervention to reduce risky drinking among American Indian Alaska Native (AIAN) women of childbearing age in Southern California into a peer-to-peer-based intervention using motivational interviewing (MI). METHODS: The modification process was iterative and included various community focus groups, interviews, and a final review. RESULTS: Intervention modification was required for cultural congruence. Components of the peer-to-peer intervention designed by this project included a flip chart used to guide the motivational interviewing, charts of the financial and physical costs of alcohol consumption, revised baseline and follow-up questionnaires, and guidance regarding the application of MI techniques. CONCLUSIONS: This study may inform the modification of future interventions among AIAN communities.

Indigenous Elder Insights About Conventional Care Services in Alaska: Culturally Charged Spaces.

Indigenous peoples around the world endure health and social disparities. In the United States, such disparities are typically ameliorated through conventional care services and organizations. PURPOSE: To examine points of tension that characterize culturally pluralistic care services in the United States, specifically Alaska, within context of Indigenous colonial histories. DESIGN AND METHODS: The research design is ethnographic and multisited, comprising 12 months of fieldwork across urban, rural and remote village sites in Alaska. A conceptual lens that accounts for culturally diverse social spaces where relations of power are at stake frames research presented here. This work incorporates relational and participatory action research principles with Alaska Native Elders. Ethnographic evidence was collected through multiple methods, including field notes, documents, and interviews, with ethnographic analysis involving atlas.ti. FINDINGS: Alaska Native Elders describe salient points of tension characterizing Alaska's conventional care services through the following insights: generational curses--a pain, prejudice on both sides-wounded, and value-systems clash-fighting. CONCLUSION: This article concludes with discussion about collective anxieties and implications for care services.

Polymorphisms in stearoyl coa desaturase and sterol regulatory element binding protein interact with N-3 polyunsaturated fatty acid intake to modify associations with anthropometric variables and metabolic phenotypes in Yup'ik people.

SCOPE: n-3 polyunsaturated fatty acid (n-3 PUFA) intake is associated with protection from obesity; however, the mechanisms of protection remain poorly characterized. The stearoyl CoA desaturase (SCD), insulin-sensitive glucose transporter (SLC2A4), and sterol regulatory element binding protein (SREBF1) genes are transcriptionally regulated by n-3 PUFA intake and harbor polymorphisms associated with obesity. The present study investigated how consumption of n-3 PUFA modifies associations between SCD, SLC2A4, and SREBF1 polymorphisms and anthropometric variables and metabolic phenotypes. MATERIALS AND METHODS: Anthropometric variables and metabolic phenotypes were measured in a cross-sectional sample of Yup'ik individuals (n = 1135) and 33 polymorphisms were tested for main effects and interactions using linear models that account for familial correlations. n-3 PUFA intake was estimated using red blood cell nitrogen stable isotope ratios. SCD polymorphisms were associated with ApoA1 concentration and n-3 PUFA interactions with SCD polymorphisms were associated with reduced fasting cholesterol levels and waist-to-hip ratio. SLC2A4 polymorphisms were associated with hip circumference, high-density lipoprotein and ApoA1 concentrations. SREBF1 polymorphisms were associated with low-density lipoprotein and HOMA-IR and n-3 PUFA interactions were associated with reduced fasting insulin and HOMA-IR levels. CONCLUSION: The results suggest that an individual's genotype may interact with dietary n-3 PUFAs in ways that are associated with protection from obesity-related diseases in Yup'ik people.

Dental-macrowear and diet of Tigara foragers from Point Hope, northern Alaska.

SUMMARY: Ethnographic studies indicate that Eskimo foragers are characterized by well-defined sexual division of labor and extensive use of anterior teeth as a tool, resulting in higher degrees of wear. However, little is known about the intra-population variation in molar-macrowear rates and dietary implications. Here, percentages of dentin exposure (PDE) were recorded on first mandibular molars among Tigara foragers from Point Hope (Alaska) and attempt to correlate age and sex variation in wear patterns. We found that no overall sex-related differences in PDE exist and suggest that molars did not take a part in para-masticatory or cultural practices. Strong correlation with increasing age was found as expected but males wore their teeth at higher rates than females related to masticatory demands during growth. Our findings suggest that individual variation in molar-macrowear must be attributed to biomechanics of chewing and cultural behavior rather than sexual variation in food acquisition.

Problem-gambling severity and psychiatric disorders among American-Indian/Alaska native adults.

INTRODUCTION: Little is known about the association between problem-gambling severity and psychiatric disorders among American-Indian/Alaska-Native (AI/AN) individuals. Thus, we examined these factors among a nationally representative sample of AI/AN and other American adults in the USA. METHOD: Using the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) data, we conducted separate Wald tests and multinomial logistic regression analyses comparing AI/AN to black/African American, white/Caucasian, and all other racial/ethnic groups, respectively. RESULTS: Relative to other American adults, AI/AN adults were least likely to report non-/low-frequency gambling (NG: AI/AN 66.5%, white/Caucasian 70.5%, black/African American 72.8%, other racial/ethnic group 72.3%) and most likely to report low-risk gambling (LRG: AI/AN 30.1%, white/Caucasian 26.5%, black/African American 23.4%, other racial/ethnic group 24.7%). The association between at-risk/problem-gambling (ARPG) and any past-year Axis-I disorder was stronger among AI/AN versus other American adults. Although ARPG and LRG were associated with multiple past-year Axis-I and lifetime Axis-II psychiatric disorders in both AI/AN and other American adults, LRG was more strongly associated with both Axis-I disorders (particularly major depression, generalized anxiety disorder and nicotine dependence) and Cluster-B Axis-II (particularly antisocial personality disorder) disorders in AI/AN versus other American adults. DISCUSSION: A stronger association between problem-gambling severity and past-year psychiatric disorders among AI/AN relative to other American adults suggests the importance of enhancing mental health and problem-gambling prevention and treatment strategies that may help AI/AN individuals.

Racial and Ethnic Disparities in Preterm Birth Among American Indian and Alaska Native Women.

OBJECTIVES: Preterm birth disproportionately affects American Indian/Alaska Native (AI/AN) women. This disparity in birth outcomes may stem from higher levels of exposure to psychosocial, sociodemographic, and medical risk factors. METHODS: This paper reviews relevant research related to preterm birth in American Indian and Alaska Native women. CONCLUSIONS: This narrative review examines disparities in preterm birth rates between AI/AN and other American women, and addresses several maternal risk factors and barriers that contribute to elevated preterm birth rates among this racial minority group. Additionally, this paper focuses on recent evidence that geographical location can significantly impact preterm birth rates among AI/AN women. In particular, access to care among AI/AN women and differences between rural and urban areas are discussed.

Exploration of Why Alaskans Use Complementary Medicine: A Focus Group Study.

PURPOSE: To explore why Alaskans choose to pursue complementary medicine as a health care option. DESIGN: Qualitative descriptive. METHOD: A purposive convenient recruitment methodology was used to recruit project participants. Focus groups were conducted to collect the research data. FINDINGS: Five themes were identified that highlighted why participants use complementary medicine: dissatisfaction, effective, holistic, relationship focused, and a personal journey.

Dermatology in the North American Indian/Alaska Native population.

Dermatology is greatly understudied in the American Indian/Alaska Native (AIAN) population. This topic deserves attention in light of the changing demographics of the United States and the healthcare disparities faced by AIAN, including access to dermatologic care. In this review, we discuss disorders that are more prevalent or otherwise important in the AIAN population, such as cutaneous malignancies, photodermatoses, acanthosis nigricans, connective tissue disorders, cutaneous infections, hypertrophic scar formation, and Heck's disease. We aim to provide an updated review and increase awareness of the dermatologic needs of the AIAN population.