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BACKGROUND: American Indian (AI) communities are affected by uranium exposure from abandoned mines and naturally contaminated drinking water. Few studies have evaluated geographical differences across AI communities and the role of dietary exposures. OBJECTIVE: We evaluated differences in urinary uranium levels by diet and geographical area among AI participants from the Northern Plains, the Southern Plains, and the Southwest enrolled in the Strong Heart Family Study (SHFS). METHODS: We used food frequency questionnaires to determine dietary sources related to urinary uranium levels for 1,682 SHFS participants in 2001-2003. We calculated adjusted geometric mean ratios (GMRs) of urinary uranium for an interquartile range (IQR) increase in self-reported food group consumption accounting for family clustering and adjusting for sociodemographic variables and other food groups. We determined the percentage of variability in urinary uranium explained by diet. RESULTS: Median (IQR) urinary uranium levels were 0.027 (0.012, 0.057) µg/g creatinine. Urinary uranium levels were higher in Arizona (median 0.039 µg/g) and North Dakota and South Dakota (median 0.038 µg/g) and lower in Oklahoma (median 0.019 µg/g). The adjusted percent increase (95% confidence interval) of urinary uranium levels per IQR increase in reported food intake was 20% (5%, 36%) for organ meat, 11% (1%, 23%) for cereals, and 14% (1%, 29%) for alcoholic drinks. In analyses stratified by study center, the association with organ meat was specific to North Dakota and South Dakota participants. An IQR increase in consumption of fries and chips was inversely associated with urinary uranium levels -11% (-19%, -3%). Overall, we estimated that self-reported dietary exposures explained 1.71% of variability in urine uranium levels. IMPACT: Our paper provides a novel assessment of self-reported food intake and urinary uranium levels in a cohort of American Indian participants. We identify foods (organ meat, cereals, and alcohol) positively associated with urinary uranium levels, find that organ meat consumption is only associated with urine uranium in North Dakota and South Dakota, and estimate that diet explains relatively little variation in total urinary uranium concentrations. Our findings contribute meaningful data toward a more comprehensive estimation of uranium exposure among Native American communities and support the need for high-quality assessments of water and dust uranium exposures in SHFS communities.
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Beckwith-Wiedemann spectrum (BWSp) is caused by genetic and epigenetic alterations on chromosome 11 that regulate cell growth and division. Considering the diverse phenotypic landscape in BWSp, the characterization of the CDKN1C molecular subtype remains relatively limited. Here, we investigate the role of CDKN1C in the broader BWSp phenotype. Notably, patients with CDKN1C variants appear to exhibit a different tumor risk than other BWSp molecular subtypes. We performed a comprehensive literature review using the search term "CDKN1C Beckwith" to identify 113 cases of patients with molecularly confirmed CDKN1C-BWSp. We then assessed the genotype and phenotype in a novel cohort of patients with CDKN1C-BWSp enrolled in the BWS Research Registry. Cardinal and suggestive features were evaluated for all patients reported, and tumor risk was established based on available reports. The most common phenotypes included macroglossia, omphalocele, and ear creases/pits. Tumor types reported from the literature included neuroblastoma, acute lymphocytic leukemia, superficial spreading melanoma, and intratubular germ cell neoplasia. Overall, this study identifies unique features associated with CDKN1C variants in BWSp, enabling more accurate clinical management. The absence of Wilms tumor and hepatoblastoma suggests that screening for these tumors may not be necessary, while the neuroblastoma risk warrants appropriate screening recommendations.
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BACKGROUND: Although COVID-19 infection has been associated with a number of clinical and environmental risk factors, host genetic variation has also been associated with the incidence and morbidity of infection. The CRP gene codes for a critical component of the innate immune system and CRP variants have been reported associated with infectious disease and vaccination outcomes. We investigated possible associations between COVID-19 outcome and a limited number of candidate gene variants including rs1205. METHODOLOGY/PRINCIPAL FINDINGS: The Strong Heart and Strong Heart Family studies have accumulated detailed genetic, cardiovascular risk and event data in geographically dispersed American Indian communities since 1988. Genotypic data and 91 COVID-19 adjudicated deaths or hospitalizations from 2/1/20 through 3/1/23 were identified among 3,780 participants in two subsets. Among 21 candidate variants including genes in the interferon response pathway, APOE, TMPRSS2, TLR3, the HLA complex and the ABO blood group, only rs1205, a 3' untranslated region variant in the CRP gene, showed nominally significant association in T-dominant model analyses (odds ratio 1.859, 95%CI 1.001-3.453, p = 0.049) after adjustment for age, sex, center, body mass index, and a history of cardiovascular disease. Within the younger subset, association with the rs1205 T-Dom genotype was stronger, both in the same adjusted logistic model and in the SOLAR analysis also adjusting for other genetic relatedness. CONCLUSION: A T-dominant genotype of rs1205 in the CRP gene is associated with COVID-19 death or hospitalization, even after adjustment for relevant clinical factors and potential participant relatedness. Additional study of other populations and genetic variants of this gene are warranted.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/genética , COVID-19/epidemiología , COVID-19/mortalidad , COVID-19/virología , Femenino , Masculino , Persona de Mediana Edad , SARS-CoV-2/genética , Anciano , Polimorfismo de Nucleótido Simple , Adulto , Proteína C-Reactiva/genética , Predisposición Genética a la Enfermedad , Factores de Riesgo , Genotipo , Hospitalización , Variación GenéticaRESUMEN
BACKGROUND: Chronic arsenic exposure has been associated with an increased risk of cardiovascular disease; diabetes; cancers of the lung, pancreas and prostate; and all-cause mortality in American Indian communities in the Strong Heart Study. OBJECTIVE: The Strong Heart Water Study (SHWS) designed and evaluated a multilevel, community-led arsenic mitigation program to reduce arsenic exposure among private well users in partnership with Northern Great Plains American Indian Nations. METHODS: A cluster randomized controlled trial (cRCT) was conducted to evaluate the effectiveness of the SHWS arsenic mitigation program over a 2-y period on a) urinary arsenic, and b) reported use of arsenic-safe water for drinking and cooking. The cRCT compared the installation of a point-of-use arsenic filter and a mobile Health (mHealth) program (3 phone calls; SHWS mHealth and Filter arm) to a more intensive program, which included this same program plus three home visits (3 phone calls and 3 home visits; SHWS Intensive arm). RESULTS: A 47% reduction in urinary arsenic [geometric mean (GM)=13.2 to 7.0µg/g creatinine] was observed from baseline to the final follow-up when both study arms were combined. By treatment arm, the reduction in urinary arsenic from baseline to the final follow-up visit was 55% in the mHealth and Filter arm (GM=14.6 to 6.55µg/g creatinine) and 30% in the Intensive arm (GM=11.2 to 7.82µg/g creatinine). There was no significant difference in urinary arsenic levels by treatment arm at the final follow-up visit comparing the Intensive vs. mHealth and Filter arms: GM ratio of 1.21 (95% confidence interval: 0.77, 1.90). In both arms combined, exclusive use of arsenic-safe water from baseline to the final follow-up visit significantly increased for water used for cooking (17% to 53%) and drinking (12% to 46%). DISCUSSION: Delivery of the interventions for the community-led SHWS arsenic mitigation program, including the installation of a point-of-use arsenic filter and a mHealth program on the use of arsenic-safe water (calls only, no home visits), resulted in a significant reduction in urinary arsenic and increases in reported use of arsenic-safe water for drinking and cooking during the 2-y study period. These results demonstrate that the installation of an arsenic filter and phone calls from a mHealth program presents a promising approach to reduce water arsenic exposure among private well users. https://doi.org/10.1289/EHP12548.
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Arsénico , Agua Potable , Humanos , Indio Americano o Nativo de Alaska , Arsénico/orina , Creatinina , Agua Potable/química , TelemedicinaRESUMEN
Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10-8), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all.
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Estudio de Asociación del Genoma Completo , Insuficiencia Renal Crónica , Humanos , Insuficiencia Renal Crónica/diagnóstico , Tasa de Filtración Glomerular/genética , Herencia Multifactorial/genética , Riñón/fisiologíaRESUMEN
BACKGROUND: Identifying lipidomic markers of diet quality is needed to inform the development of biomarkers of diet, and to understand the mechanisms driving the diet- coronary heart disease (CHD) association. OBJECTIVES: This study aimed to identify lipidomic markers of diet quality and examine whether these lipids are associated with incident CHD. METHODS: Using liquid chromatography-mass spectrometry, we measured 1542 lipid species from 1694 American Indian adults (aged 18-75 years, 62% female) in the Strong Heart Family Study. Participants were followed up for development of CHD through 2020. Information on the past year diet was collected using the Block Food Frequency Questionnaire, and diet quality was assessed using the Alternative Healthy Eating Index-2010 (AHEI). Mixed-effects linear regression was used to identify individual lipids cross-sectionally associated with AHEI. In prospective analysis, Cox frailty model was used to estimate the hazard ratio (HR) of each AHEI-related lipid for incident CHD. All models were adjusted for age, sex, center, education, body mass index, smoking, alcohol drinking, level of physical activity, energy intake, diabetes, hypertension, and use of lipid-lowering drugs. Multiple testing was controlled at a false discovery rate of <0.05. RESULTS: Among 1542 lipid species measured, 71 lipid species (23 known), including acylcarnitine, cholesterol esters, glycerophospholipids, sphingomyelins and triacylglycerols, were associated with AHEI. Most of the identified lipids were associated with consumption of ω-3 (n-3) fatty acids. In total, 147 participants developed CHD during a mean follow-up of 17.8 years. Among the diet-related lipids, 10 lipids [5 known: cholesterol ester (CE)(22:5)B, phosphatidylcholine (PC)(p-14:0/22:1)/PC(o-14:0/22:1), PC(p-38:3)/PC(o-38:4)B, phosphatidylethanolamine (PE)(p-18:0/20:4)/PE(o-18:0/20:4), and sphingomyelin (d36:2)A] were associated with incident CHD. On average, each standard deviation increase in the baseline level of these 5 lipids was associated with 17%-23% increased risk of CHD (from HR: 1.17; 95% CI: 1, 1.36; to HR: 1.23; 95% CI: 1.05, 1.43). CONCLUSIONS: In this study, lipidomic markers of diet quality in American Indian adults are found. Some diet-related lipids are associated with risk of CHD beyond established risk factors.
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Indio Americano o Nativo de Alaska , Enfermedad Coronaria , Adulto , Femenino , Humanos , Masculino , Ésteres del Colesterol , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/etiología , Dieta , Lipidómica , Fosfatidilcolinas , Factores de Riesgo , Triglicéridos , Adolescente , Adulto Joven , Persona de Mediana Edad , AncianoRESUMEN
OBJECTIVES: To examine the associations of dietary Mg intake with inflammatory biomarkers (C-reactive protein (CRP) and interleukin 6 (IL-6)), and the interaction of dietary Mg intake with single nucleotide polymorphism (SNP) rs3740393, a SNP related to Mg metabolism and transport, on CRP and IL-6 among American Indians (AIs). METHODS: This cross-sectional study included AI participants (n = 1,924) from the Strong Heart Family Study (SHFS). Mg intake from foods and dietary supplements was ascertained using a 119-item Block food frequency questionnaire, CRP and IL-6 were measured from blood, and SNP rs3740393 was genotyped using MetaboChip. Generalized estimating equations were used to examine associations of Mg intake, and the interaction between rs3740393 and dietary Mg, with CRP and IL-6. RESULTS: Reported Mg intake was not associated with CRP or IL-6, irrespective of genotype. A significant interaction (p-interaction = 0.018) was observed between Mg intake and rs3740393 on IL-6. Among participants with the C/C genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.04 (95% CI: -0.10 to 0.17) pg/mL higher. Among participants with the C/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.08 (95% CI: -0.21 to 0.05) pg/mL lower, and among participants with the G/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.19 (95% CI: -0.38 to -0.01) pg/mL lower. CONCLUSIONS: Mg intake may be associated with lower IL-6 with increasing dosage of the G allele at rs3740393. Future research is necessary to replicate this finding and examine other Mg-related genes that influence associations of Mg intake with inflammation.
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Proteína C-Reactiva , Interleucina-6 , Humanos , Proteína C-Reactiva/metabolismo , Interleucina-6/genética , Magnesio , Estudios Transversales , BiomarcadoresRESUMEN
BACKGROUND: Inorganic arsenic (As) may increase the risk of cardiovascular disease (CVD) and all-cause mortality through accelerated aging, which can be estimated using epigenetic-based measures. OBJECTIVES: We evaluated three DNA methylation-based aging measures (PhenoAge, GrimAge, DunedinPACE) (epigenetic aging measures) as potential mediators of the previously reported association of As exposure with CVD incidence, CVD mortality, and all-cause mortality in the Strong Heart Study (SHS), an epidemiological cohort of American Indian adults. METHODS: Blood DNA methylation and urinary As levels were measured in 2,323 SHS participants (41.5% men, mean age of 55 years old). PhenoAge and GrimAge values were calculated using a residual-based method. We tested the association of urinary As with epigenetic aging measures using linear regression, the association of epigenetic aging measures with the three health outcomes using additive hazards models, and the mediation of As-related CVD incidence, CVD mortality, and all-cause mortality by epigenetic aging measures using the product of coefficients method. RESULTS: SHS participants with higher vs. lower urinary As levels had similar PhenoAge age, older GrimAge age, and faster DunedinPACE. An interquartile range increase in urinary As was associated with higher of PhenoAge age acceleration [mean difference (95% confidence interval)=0.48 (0.17, 0.80) years], GrimAge age acceleration [0.80 (0.60, 1.00) years], and DunedinPACE [0.011 (0.005, 0.018)], after adjusting for age, sex, center location, genetic components, smoking status, and body mass index. Of the 347 incident CVD events per 100,000 person-years associated with a doubling in As exposure, 21.3% (9.1, 57.1) and 22.6% (9.5, 56.9), were attributable to differences in GrimAge and DunedinPACE, respectively. DISCUSSION: Arsenic exposure was associated with older GrimAge and faster DunedinPACE measures of biological age. Furthermore, accelerated biological aging measured from DNA methylation accounted for a relevant fraction of As-associated risk for CVD, CVD mortality, and all-cause mortality in the SHS, supporting the role of As in accelerated aging. Research of the biological underpinnings can contribute to a better understanding of the role of aging in arsenic-related disease. https://doi.org/10.1289/EHP11981.
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Arsénico , Enfermedades Cardiovasculares , Epigénesis Genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Envejecimiento , Indio Americano o Nativo de Alaska , Arsénico/toxicidad , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Metilación de ADN , MortalidadRESUMEN
The proper communication of clinically actionable findings to participants of genetic research entails important ethical considerations, but has been challenging for a variety of reasons. We document an instance of the return of individual genetic results in the context of a very rural American Indian community, in hopes of providing insight to other investigators about potentially superior or inferior courses of action. This was a case/control study of asthma among 324 pediatric participants. Subsequently, microarray genotype data became available, providing over 2 million variants, incidentally including some conferring risk for conditions for which the American College of Medical Genetics recommends return of results. The study investigators engaged in extensive consultation with the IRB, the tribal government, and local clinicians to better inform our approach. We were able to notify the two participants heterozygous for the one clinically actionable variant identified. One participant welcomed this information and proceeded to obtain further clinical work-up; the other participant declined further follow-up. While demanding considerable time and effort, the return of clinically actionable genetic results is important from both an ethical perspective and to provide an improved trust relationship with the community of research participants.
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BACKGROUND: Fine particulate matter (PM2.5) exposure is a known risk factor for numerous adverse health outcomes, with varying estimates of component-specific effects. Populations with compromised health conditions such as diabetes can be more sensitive to the health impacts of air pollution exposure. Recent trends in PM2.5 in primarily American Indian- (AI-) populated areas examined in previous work declined more gradually compared to the declines observed in the rest of the US. To further investigate components contributing to these findings, we compared trends in concentrations of six PM2.5 components in AI- vs. non-AI-populated counties over time (2000-2017) in the contiguous US. METHODS: We implemented component-specific linear mixed models to estimate differences in annual county-level concentrations of sulfate, nitrate, ammonium, organic matter, black carbon, and mineral dust from well-validated surface PM2.5 models in AI- vs. non-AI-populated counties, using a multi-criteria approach to classify counties as AI- or non-AI-populated. Models adjusted for population density and median household income. We included interaction terms with calendar year to estimate whether concentration differences in AI- vs. non-AI-populated counties varied over time. RESULTS: Our final analysis included 3108 counties, with 199 (6.4%) classified as AI-populated. On average across the study period, adjusted concentrations of all six PM2.5 components in AI-populated counties were significantly lower than in non-AI-populated counties. However, component-specific levels in AI- vs. non-AI-populated counties varied over time: sulfate and ammonium levels were significantly lower in AI- vs. non-AI-populated counties before 2011 but higher after 2011 and nitrate levels were consistently lower in AI-populated counties. CONCLUSIONS: This study indicates time trend differences of specific components by AI-populated county type. Notably, decreases in sulfate and ammonium may contribute to steeper declines in total PM2.5 in non-AI vs. AI-populated counties. These findings provide potential directives for additional monitoring and regulations of key emissions sources impacting tribal lands.
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Altered DNA methylation (DNAm) might be a biological intermediary in the pathway from smoking to lung cancer. In this study, we investigated the contribution of differential blood DNAm to explain the association between smoking and lung cancer incidence. Blood DNAm was measured in 2321 Strong Heart Study (SHS) participants. Incident lung cancer was assessed as time to event diagnoses. We conducted mediation analysis, including validation with DNAm and paired gene expression data from the Framingham Heart Study (FHS). In the SHS, current versus never smoking and pack-years single-mediator models showed, respectively, 29 and 21 differentially methylated positions (DMPs) for lung cancer with statistically significant mediated effects (14 of 20 available, and five of 14 available, positions, replicated, respectively, in FHS). In FHS, replicated DMPs showed gene expression downregulation largely in trans, and were related to biological pathways in cancer. The multimediator model identified that DMPs annotated to the genes AHRR and IER3 jointly explained a substantial proportion of lung cancer. Thus, the association of smoking with lung cancer was partly explained by differences in baseline blood DNAm at few relevant sites. Experimental studies are needed to confirm the biological role of identified eQTMs and to evaluate potential implications for early detection and control of lung cancer.
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Metilación de ADN , Neoplasias Pulmonares , Humanos , Fumar/epidemiología , Fumar Tabaco/genética , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Secuencia de Bases , Epigénesis GenéticaRESUMEN
BACKGROUND: The objective of this study was to evaluate the behavioral determinants associated with exclusive use of arsenic-safe water in the community-led Strong Heart Water Study (SHWS) arsenic mitigation program. METHODS: The SHWS is a randomized controlled trial of a community-led arsenic mitigation program designed to reduce arsenic exposure among private well users in American Indian Great Plains communities. All households received point-of-use (POU) arsenic filters installed at baseline and were followed for 2 years. Behavioral determinants selected were those targeted during the development of the SHWS program, and were assessed at baseline and follow-up. RESULTS: Among participants, exclusive use of arsenic-safe water for drinking and cooking at follow-up was associated with higher self-efficacy for accessing local resources to learn about arsenic (OR: 5.19, 95% CI: 1.48-18.21) and higher self-efficacy to resolve challenges related to arsenic in water using local resources (OR: 3.11, 95% CI: 1.11-8.71). Higher commitment to use the POU arsenic filter faucet at baseline was also a significant predictor of exclusive arsenic-safe water use for drinking (OR: 32.57, 95% CI: 1.42-746.70) and cooking (OR: 15.90, 95% CI: 1.33-189.52) at follow-up. From baseline to follow-up, the SHWS program significantly increased perceived vulnerability to arsenic exposure, self-efficacy, descriptive norms, and injunctive norms. Changing one's arsenic filter cartridge after installation was associated with higher self-efficacy to obtain arsenic-safe water for drinking (OR: 6.22, 95% CI: 1.33-29.07) and cooking (OR: 10.65, 95% CI: 2.48-45.68) and higher perceived vulnerability of personal health effects (OR: 7.79, 95% CI: 1.17-51.98) from drinking arsenic-unsafe water. CONCLUSIONS: The community-led SHWS program conducted a theory-driven approach for intervention development and evaluation that allowed for behavioral determinants to be identified that were associated with the use of arsenic safe water and changing one's arsenic filter cartridge. These results demonstrate that theory-driven, context-specific formative research can influence behavior change interventions to reduce water arsenic exposure. The SHWS can serve as a model for the design of theory-driven intervention approaches that engage communities to reduce arsenic exposure. TRIAL REGISTRATION: The SHWS is registered with ClinicalTrials.gov (Identifier: NCT03725592).
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Arsénico , Agua Potable , Contaminantes Químicos del Agua , Humanos , Arsénico/análisis , Contaminantes Químicos del Agua/análisis , Abastecimiento de AguaRESUMEN
Importance: To our knowledge, no published studies have investigated the association of ambulatory activity with risk of death among young and middle-aged American Indian individuals. The burden of chronic disease and risk of premature death is higher among American Indian individuals than among the general US population, so better understanding of the association of ambulatory activity with risk of death is needed to inform public health messaging in tribal communities. Objective: To examine the association of objectively measured ambulatory activity (ie, steps per day) with risk of death among young and middle-aged American Indian individuals. Design, Setting, and Participants: The ongoing longitudinal Strong Heart Family Study (SHFS) is being conducted with participants aged 14 to 65 years in 12 rural American Indian communities in Arizona, North Dakota, South Dakota, and Oklahoma and includes up to 20 years of follow-up (February 26, 2001, to December 31, 2020). This cohort study included SHFS participants who had available pedometer data at baseline. Data analysis was performed on June 9, 2022. Exposures: Objectively measured ambulatory activity at baseline. Main Outcomes and Measures: Outcomes of interest were total and cardiovascular-related mortality. Mixed-effects Cox proportional hazards regression was used to estimate hazard ratios for risk of death, with entry at the time of the pedometer assessment and time at risk until death or the latest adjudicated date of follow-up. Results: A total of 2204 participants were included in this study. Their mean (SD) age was 41.0 (16.8) years; 1321 (59.9%) were female and 883 (40.1%) were male. During a mean follow-up of 17.0 years (range, 0-19.9 years), 449 deaths occurred. Compared with participants in the lowest quartile of steps per day (<3126 steps), individuals in the upper 3 quartiles of steps per day had lower risk of mortality, with hazard ratios of0.72 (95% CI, 0.54-0.95) for the first quartile, 0.66 (95% CI, 0.47-0.93) for the second quartile, and 0.65 (95% CI, 0.44-0.95) for the third quartile after adjustment for age, sex, study site, education, smoking status, alcohol use, diet quality, body mass index, systolic blood pressure, prevalent diabetes, prevalent cardiovascular disease, biomarker levels (fibrinogen, low-density lipoprotein cholesterol, and triglycerides), medication use (hypertensive or lipid-lowering agents), and self-reported health status. The magnitude of the hazard ratios was similar for cardiovascular mortality. Conclusions and Relevance: In this cohort study, American Indian individuals who took at least 3126 steps/d had a lower risk of death compared with participants who accumulated fewer steps per day. These findings suggest that step counters are an inexpensive tool that offers an opportunity to encourage activity and improve long-term health outcomes.
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Enfermedades Cardiovasculares , Hipertensión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Indio Americano o Nativo de Alaska , Estudios de Cohortes , Hipertensión/epidemiología , Mortalidad Prematura , Adolescente , Adulto Joven , Adulto , AncianoRESUMEN
Arsenic is a naturally occurring toxicant in groundwater, which increases cancer and cardiovascular disease risk. American Indian populations are disproportionately exposed to arsenic in drinking water. The Strong Heart Water Study (SHWS), through a community-centered approach for intervention development and implementation, delivered an arsenic mitigation program for private well users in American Indian communities. The SHWS program comprised community-led water arsenic testing, point-of-use arsenic filter installation, and a mobile health program to promote sustained filter use and maintenance (i.e., changing the filter cartridge). Half of enrolled households received additional in-person behavior change communication and videos. Our objectives for this study were to assess successes, barriers, and facilitators in the implementation, use, and maintenance of the program among implementers and recipients. We conducted 45 semi-structured interviews with implementers and SHWS program recipients. We analyzed barriers and facilitators using the Consolidated Framework for Implementation Research and the Risks, Attitudes, Norms, Abilities, and Self-regulation model. At the implementer level, facilitators included building rapport and trust between implementers and participating households. Barriers included the remoteness of households, coordinating with community plumbers for arsenic filter installation, and difficulty securing a local supplier for replacement filter cartridges. At the recipient level, facilitators included knowledge of the arsenic health risks, perceived effectiveness of the filter, and visual cues to promote habit formation. Barriers included attitudes towards water taste and temperature and inability to procure or install replacement filter cartridges. This study offers insights into the successes and challenges of implementing an arsenic mitigation program tailored to American Indian households, which can inform future programs in partnership with these and potentially similar affected communities. Our study suggests that building credibility and trust between implementers and participants is important for the success of arsenic mitigation programs.
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Arsénico , Agua Potable , Contaminantes Químicos del Agua , Humanos , Pozos de Agua , Arsénico/análisis , Indio Americano o Nativo de Alaska , Contaminantes Químicos del Agua/análisis , Investigación CualitativaRESUMEN
Inorganic arsenic is highly toxic and carcinogenic to humans. Exposed individuals vary in their ability to metabolize arsenic, and variability in arsenic metabolism efficiency (AME) is associated with risks of arsenic-related toxicities. Inherited genetic variation in the 10q24.32 region, near the arsenic methyltransferase (AS3MT) gene, is associated with urine-based measures of AME in multiple arsenic-exposed populations. To identify potential causal variants in this region, we applied fine mapping approaches to targeted sequencing data generated for exposed individuals from Bangladeshi, American Indian, and European American populations (n = 2,357, 557, and 648 respectively). We identified three independent association signals for Bangladeshis, two for American Indians, and one for European Americans. The size of the confidence sets for each signal varied from 4 to 85 variants. There was one signal shared across all three populations, represented by the same SNP in American Indians and European Americans (rs191177668) and in strong linkage disequilibrium (LD) with a lead SNP in Bangladesh (rs145537350). Beyond this shared signal, differences in LD patterns, minor allele frequency (MAF) (e.g., rs12573221 ~13% in Bangladesh ~0.2% among American Indians), and/or heterogeneity in effect sizes across populations likely contributed to the apparent population specificity of the additional identified signals. One of our potential causal variants influences AS3MT expression and nearby DNA methylation in numerous GTEx tissue types (with rs4919690 as a likely causal variant). Several SNPs in our confidence sets overlap transcription factor binding sites and cis-regulatory elements (from ENCODE). Taken together, our analyses reveal multiple potential causal variants in the 10q24.32 region influencing AME, including a variant shared across populations, and elucidate potential biological mechanisms underlying the impact of genetic variation on AME.
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Intoxicación por Arsénico , Arsénico , Arsenicales , Humanos , Arsénico/toxicidad , Arsénico/metabolismo , Intoxicación por Arsénico/genética , Arsenicales/metabolismo , Metilación de ADN , Metiltransferasas/genética , Metiltransferasas/metabolismo , Polimorfismo de Nucleótido Simple/genética , Cromosomas Humanos Par 10RESUMEN
PURPOSE: The proper communication of clinically actionable findings to participants of genetic research entails important ethical considerations, but has been challenging for a variety of reasons. We document an instance of return of individual genetic results in the context of a very rural American Indian community, in hopes of providing insight to other investigators about potentially superior or inferior courses of action. METHODS: The original study was a case/control study of asthma among 324 pediatric participants. The study utilized a genotyping microarray assessing over 2 million variants, including one conferring risk for hypertrophic cardiomyopathy for which the American College of Medical Genetics recommends return of results to participants. The study investigators engaged in extensive consultation with the IRB, the Tribal government and local clinicians to better inform our approach. RESULTS: With some difficulty we were able to notify the 2 participants heterozygous for this variant. One participant welcomed this information and proceeded to obtain further clinical work-up; the other participant declined further follow-up. CONCLUSION: While demanding of considerable time and effort, the return of clinically actionable genetic results is important from both an ethical perspective and to provide an improved trust relationship with the community of research participants.
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Many rural populations, including American Indian communities, that use private wells from groundwater for their source of drinking and cooking water are disproportionately exposed to elevated levels of arsenic. However, programs aimed at reducing arsenic in American Indian communities are limited. The Strong Heart Water Study (SHWS) is a randomized controlled trial aimed at reducing arsenic exposure among private well users in American Indian Northern Great Plains communities. The community-led SHWS program installed point-of-use (POU) arsenic filters in the kitchen sink of households, and health promoters delivered arsenic health communication programs. In this study we evaluated the efficacy of these POU arsenic filters in removing arsenic during the two-year installation period. Participants were randomized into two arms. In the first arm households received a POU arsenic filter, and 3 calls promoting filter use (SHWS mobile health (mHealth) & filter arm). The second arm received the same filter and phone calls, and 3 in-person home visits and 3 Facebook messages (SHWS intensive arm) for program delivery. Temporal variability in water arsenic concentrations from the main kitchen faucet was also evaluated. A total of 283 water samples were collected from 50 households with private wells from groundwater (139 filter and 144 kitchen faucet samples). Ninety-three percent of households followed after baseline had filter faucet water arsenic concentrations below the arsenic maximum contaminant level of 10 µg/L at the final visit during our 2 year study period with no difference between study arms (98 % in the intensive arm vs. 94 % in the mHealth & filter arm). No significant temporal variation in kitchen arsenic concentration was observed over the study period (intraclass correlation coefficient = 0.99). This study demonstrates that POU arsenic filters installed for the community participatory SHWS program were effective in reducing water arsenic concentration in study households in both arms, even with delivery of the POU arsenic filter and mHealth program only. Furthermore, we observed limited temporal variability of water arsenic concentrations from kitchen faucet samples collected over time from private wells in our study setting.
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Arsénico , Agua Potable , Contaminantes Químicos del Agua , Humanos , Arsénico/análisis , Monitoreo del Ambiente , Agua , Indio Americano o Nativo de Alaska , Pozos de Agua , Contaminantes Químicos del Agua/análisis , Abastecimiento de Agua , Agua Potable/análisisRESUMEN
Telomeres shorten with age and shorter leukocyte telomere length (LTL) has been associated with various age-related diseases. Thus, LTL has been considered a biomarker of biological aging. Dyslipidemia is an established risk factor for most age-related metabolic disorders. However, little is known about the relationship between LTL and dyslipidemia. Lipidomics is a new biochemical technique that can simultaneously identify and quantify hundreds to thousands of small molecular lipid species. In a large population comprising 1843 well-characterized American Indians in the Strong Heart Family Study, we examined the lipidomic profile of biological aging assessed by LTL. Briefly, LTL was quantified by qPCR. Fasting plasma lipids were quantified by untargeted liquid chromatography-mass spectrometry. Lipids associated with LTL were identified by elastic net modeling. Of 1542 molecular lipids identified (518 known, 1024 unknown), 174 lipids (36 knowns) were significantly associated with LTL, independent of chronological age, sex, BMI, hypertension, diabetes status, smoking status, bulk HDL-C, and LDL-C. These findings suggest that altered lipid metabolism is associated with biological aging and provide novel insights that may enhance our understanding of the relationship between dyslipidemia, biological aging, and age-related diseases in American Indians.
Asunto(s)
Indígenas Norteamericanos , Lipidómica , Humanos , Indio Americano o Nativo de Alaska , Envejecimiento , LípidosRESUMEN
Beckwith-Wiedemann Spectrum (BWSp) is an overgrowth and cancer predisposition disorder characterized by a wide spectrum of phenotypic manifestations including macroglossia, abdominal wall defects, neonatal hypoglycemia, and predisposition to embryonal tumors. In 1981, Best and Hoekstra reported four patients with BWSp in a single family which suggested autosomal dominant inheritance, but standard clinical testing for BWSp was not available during this time. Meticulous phenotyping of this family has occurred over the past 40 years of follow-up with additional family members being identified and samples collected for genetic testing. Genetic testing revealed a pathogenic mutation in CDKN1C, consistent with the most common cause of familial BWSp. CDKN1C mutations account for just 5% of sporadic cases of BWSp. Here, we report the variable presentation of BWSp across the individuals affected by the CDKN1C mutation and other extended family members spanning multiple generations, all examined by the same physician. Additional phenotypes thought to be atypical in patients with BWSp were reported which included cardiac abnormalities. The incidence of tumors was documented in extended family members and included rhabdomyosarcoma, astrocytoma, and thyroid carcinoma, which have previously been reported in patients with BWSp. These observations suggest that in addition to the inheritance of the CDKN1C variant, there are modifying factors in this family driving the phenotypic spectrum observed. Alternative theories are suggested to explain the etiology of clinical variability including diffused mosaicism, anticipation, and the presence of additional variants tracking in the family. This study highlights the necessity of long-term follow-up in patients with BWSp and consideration of individual familial characteristics in the context of phenotype and/or (epi)genotype associations.
Asunto(s)
Astrocitoma , Síndrome de Beckwith-Wiedemann , Humanos , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patología , Familia Extendida , Fenotipo , Genotipo , Astrocitoma/genética , Impresión GenómicaRESUMEN
American Indian (AI) children experience significant disparities in asthma prevalence, severity, and burden of disease, yet few asthma education interventions are tested in this population. This study aimed to evaluate the efficacy and feasibility of the BREATHE intervention with parents and AI children, during a 3-year follow-up period (n = 108), using a randomized controlled design. Children with asthma identified by electronic medical records (EMR) were screened and matched with 2 controls. The intervention included an initial educational and 24 months of follow-up. The control group continued their usual care. The primary outcome was the frequency of EMR documented, emergency department (ED) visits or hospitalization for respiratory complaints. There was no statistical difference in mean primary outcomes (1.34 (1.98) vs 1.22 (1.95), - 0.88 to 0.63, 95% CI of the difference, p = 0.75), nor percent with any ED visit or hospitalization (29/53, 55% vs 30/55, 54%, p = 0.99) between the intervention or control groups respectively. After 365 days, there was a borderline significant difference in time to primary outcome. Although limited in power, the present study did not demonstrate a persistent effect of this intervention. We recommend that AI pediatric asthma interventions are culturally-designed, use feasible procedures, and repeat education at least every 12 months.