Publications by authors named "Lyle G Best"

147 Publications

Environmental-level exposure to metals and metal-mixtures associated with spirometry-defined lung disease in American Indian adults: Evidence from the Strong Heart Study.

Environ Res 2021 Oct 13:112194. Epub 2021 Oct 13.

Department of Environmental Health Sciences, Columbia Mailman School of Public Health, 722 West 168th St. NY, NY, 10032, USA. Electronic address:

Background: American Indians have a higher burden of chronic lung disease compared to the US average. Several metals are known to induce chronic lung disease at high exposure levels; however, less is known about the role of environmental-level metal exposure. We investigated respiratory effects of exposure to single metals and metal-mixtures in American Indians who participated in the Strong Heart Study.

Methods: We included 2077 participants with data on 6 metals (As, Cd, Mo, Se, W, Zn) measured from baseline urine samples (1989-1991) and who underwent spirometry testing at follow-up (1993-1995). We used generalized linear regression to assess associations of single metals with spirometry-defined measures of airflow limitation and restrictive ventilatory pattern, and continuous spirometry. We used Bayesian Kernel Machine Regression to investigate the joint effects of the metal-mixture. Sensitivity analyses included stratifying by smoking status and diabetes.

Results: Participants were 40% male, with median age 55 years. 21% had spirometry-defined airflow limitation, and 14% had a restrictive ventilatory pattern. In individual metal analyses, Cd was associated with higher odds of airflow limitation and lower FEV1 and FEV1/FVC. Mo was associated with higher odds of restrictive ventilatory pattern and lower FVC. Metal-mixtures analyses confirmed these models. In smoking stratified analyses, the overall metal-mixture was linearly and positively associated with airflow limitation among non-smokers; Cd was the strongest contributor. For restrictive ventilatory pattern, the association with the overall metal-mixture was strong and linear among participants with diabetes and markedly attenuated among participants without diabetes. Among those with diabetes, Mo and Zn were the major contributors.

Conclusions: Environmental-level exposure to several metals was associated with higher odds of spirometry-defined lung disease in an American Indian population. Exposure to multiple metals, including Cd and Mo, may have an under-recognized adverse role on the respiratory system.
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http://dx.doi.org/10.1016/j.envres.2021.112194DOI Listing
October 2021

Spatial relationship between well water arsenic and uranium in Northern Plains native lands.

Environ Pollut 2021 Oct 25;287:117655. Epub 2021 Jun 25.

Lamont-Doherty Earth Observatory, Columbia University, USA. Electronic address:

Arsenic and uranium in unregulated private wells affect many rural populations across the US. The distribution of these contaminants in the private wells of most American Indian communities is poorly characterized, and seldom studied together. Here, we evaluate the association between drinking water arsenic and uranium levels in wells (n = 441) from three tribal regions in North Dakota and South Dakota participating in the Strong Heart Water Study. Groundwater contamination was extensive; 29% and 7% of wells exceeded maximum contaminant levels for arsenic and uranium respectively. 81% of wells had both arsenic and uranium concentrations at one-tenth of their human-health benchmark (arsenic, 1 μg/L; uranium 3 μg/L). Well arsenic and uranium concentrations were uncorrelated (r = 0.06); however, there appeared to be a spatial correlation of wells co-contaminated by arsenic and uranium associated with flow along a geologic contact. These findings indicate the importance of measuring multiple metals in well water, and to understand underlying hydrogeological conditions. The underlying mechanisms for the prevalence of arsenic and uranium across Northern Plains Tribal Lands in the US, and in particular the occurrence of both elevated arsenic and uranium in drinking water wells in this region, demands further study.
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http://dx.doi.org/10.1016/j.envpol.2021.117655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434972PMC
October 2021

Blood DNA Methylation and Incident Coronary Heart Disease: Evidence From the Strong Heart Study.

JAMA Cardiol 2021 Nov;6(11):1237-1246

Population Health Program, Texas Biomedical Research Institute, San Antonio.

Importance: American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions.

Objective: To investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model.

Design, Setting, And Participants: This prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women's Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]-Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021.

Exposure: Blood DNA methylation.

Main Outcome And Measure: Using a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts.

Results: The median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts.

Conclusions And Relevance: In this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.
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http://dx.doi.org/10.1001/jamacardio.2021.2704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340006PMC
November 2021

Cancer mortality in a population-based cohort of American Indians - The strong heart study.

Cancer Epidemiol 2021 10 19;74:101978. Epub 2021 Jul 19.

MedStar Health Research Institute, 6525 Belcrest Road, Suite 700, Hyattsville, MD, 20782, USA; Georgetown, Howard Universities Center for Clinical and Translational Research, Washington, DC, 2000, USA. Electronic address:

Background: Cancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed.

Methods: Cancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45-74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010.

Results: After a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67-7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46-10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87-6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32-0.71).

Conclusions: Regional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.
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http://dx.doi.org/10.1016/j.canep.2021.101978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455435PMC
October 2021

Rare, Protein-Altering Variants in and Arsenic Metabolism Efficiency: A Multi-Population Association Study.

Environ Health Perspect 2021 04 7;129(4):47007. Epub 2021 Apr 7.

Department of Public Health Sciences, University of Chicago (UChicago), Chicago, Illinois, USA.

Background: Common genetic variation in the arsenic methyltransferase () gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in could have even larger effects on AME, but their contribution to AME has not been investigated.

Objectives: We estimated the impact of rare, protein-coding variation in on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants.

Methods: We generated targeted DNA sequencing data for the coding regions of for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, ), Strong Heart Study (SHS, ), and New Hampshire Skin Cancer Study (NHSCS, ). We assessed the collective effects of rare (allele frequency ), protein-altering variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure).

Results: We identified 23 carriers of rare-protein-altering variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6-10% lower in carriers compared with noncarriers in HEALS [ (95% CI: , )], SHS [ (95% CI: , )], and NHSCS [ (95% CI: , )]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ (95% CI: , )].

Discussion: Rare, protein-altering variants in were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5-0.7%) carry these variants, they are associated with a 6-10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152.
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http://dx.doi.org/10.1289/EHP8152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041273PMC
April 2021

Cooking for Health: a healthy food budgeting, purchasing, and cooking skills randomized controlled trial to improve diet among American Indians with type 2 diabetes.

BMC Public Health 2021 02 15;21(1):356. Epub 2021 Feb 15.

Department of Epidemiology, University of Washington, 1410 NE Campus Parkway, Seattle, WA, 98195, USA.

Background: The prevalence of poor diet quality and type 2 diabetes are exceedingly high in many rural American Indian (AI) communities. Because of limited resources and infrastructure in some communities, implementation of interventions to promote a healthy diet is challenging-which may exacerbate health disparities by region (urban/rural) and ethnicity (AIs/other populations). It is critical to adapt existing evidence-based healthy food budgeting, purchasing, and cooking programs to be relevant to underserved populations with a high burden of diabetes and related complications. The Cooking for Health Study will work in partnership with an AI community in South Dakota to develop a culturally-adapted 12-month distance-learning-based healthy food budgeting, purchasing, and cooking intervention to improve diet among AI adults with type 2 diabetes.

Methods: The study will enroll 165 AIs with physician-diagnosed type 2 diabetes who reside on the reservation. Participants will be randomized to an intervention or control arm. The intervention arm will receive a 12-month distance-learning curriculum adapted from Cooking Matters® that focuses on healthy food budgeting, purchasing, and cooking skills. In-person assessments at baseline, month 6 and month 12 will include completion of the Nutrition Assessment Shared Resources Food Frequency Questionnaire and a survey to assess frequency of healthy and unhealthy food purchases. Primary outcomes of interest are: (1) change in self-reported intake of sugar-sweetened beverages (SSBs); and (2) change in the frequency of healthy and unhealthy food purchases. Secondary outcomes include: (1) change in self-reported food budgeting skills; (2) change in self-reported cooking skills; and (3) a mixed-methods process evaluation to assess intervention reach, fidelity, satisfaction, and dose delivered/received.

Discussion: Targeted and sustainable interventions are needed to promote optimal health in rural AI communities. If effective, this intervention will reduce intake of SSBs and the purchase of unhealthy foods; increase the purchase of healthy foods; and improve healthy food budgeting and cooking skills among AIs with type 2 diabetes - a population at high risk of poor health outcomes. This work will help inform future health promotion efforts in resource-limited settings.

Trial Registration: This study was registered on ClinicalTrials.gov on October 9, 2018 with Identifier NCT03699709 .
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http://dx.doi.org/10.1186/s12889-021-10308-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883757PMC
February 2021

Arsenic, blood pressure, and hypertension in the Strong Heart Family Study.

Environ Res 2021 04 11;195:110864. Epub 2021 Feb 11.

Department of Epidemiology, Emory University, Atlanta, GA, USA; Department of Environmental Health, Emory University, Atlanta, GA, USA.

Background: Arsenic has been associated with hypertension, though it is unclear whether associations persist at the exposure concentrations (e.g. <100 μg/L) in drinking water occurring in parts of the Western United States.

Methods: We assessed associations between arsenic biomarkers and systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension in the Strong Heart Family Study, a family-based cohort of American Indians from the Northern plains, Southern plains, and Southwest. We included 1910 participants from three study centers with complete baseline visit data (2001-2003) in the cross-sectional analysis of all three outcomes, and 1453 participants in the prospective analysis of incident hypertension (follow-up 2006-2009). We used generalized estimating equations with exchangeable correlation structure conditional on family membership to estimate the association of arsenic exposure biomarker levels with SBP or DBP (linear regressions) or hypertension prevalence and incidence (Poisson regressions), adjusting for urine creatinine, urine arsenobetaine, and measured confounders.

Results: We observed cross-sectional associations for a two-fold increase in inorganic and methylated urine arsenic species of 0.64 (95% CI: 0.07, 1.35) mm Hg for SBP, 0.49 (95% CI: 0.03, 1.02) mm Hg for DBP, and a prevalence ratio of 1.10 (95% CI: 1.01, 1.21) for hypertension in fully adjusted models. During follow-up, 14% of subjects developed hypertension. We observed non-monotonic relationships between quartiles of arsenic and incident hypertension. Effect estimates were null for incident hypertension with continuous exposure metrics. Stratification by study site revealed elevated associations in Arizona, the site with the highest arsenic levels, while results for Oklahoma and North and South Dakota were largely null. Blood pressure changes with increasing arsenic concentrations were larger for those with diabetes at baseline.

Conclusions: Our results suggest a modest cross-sectional association of arsenic exposure biomarkers with blood pressure, and possible non-linear effects on incident hypertension.
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http://dx.doi.org/10.1016/j.envres.2021.110864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021390PMC
April 2021

Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure.

Environ Health Perspect 2020 06 30;128(6):67015. Epub 2020 Jun 30.

Department of Environmental Health Science, Columbia University, New York, New York, USA.

Background: Chronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes.

Objectives: We investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, creatinine: 11.7 (10.6)].

Methods: DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species.

Results: In adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (). After Bonferroni correction, 5 CpGs remained associated with total urinary As (), located in , , , , . We identified one DMR on chromosome 11 (chr11:2,322,050-2,323,247), annotated to ; genes.

Discussion: This is one of the first epigenome-wide association studies to investigate As exposure and locus-specific DNA methylation using the Illumina MethylationEPIC array and the largest epigenome-wide study of As exposure. The top DMP was located in , a gene involved in cystine/glutamate transport and the biosynthesis of glutathione, an antioxidant that may protect against As-induced oxidative stress. Additional DMPs were located in genes associated with tumor development and glucose metabolism. Further research is needed, including research in more diverse populations, to investigate whether As-related DNA methylation signatures are associated with gene expression or may serve as biomarkers of disease development. https://doi.org/10.1289/EHP6263.
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http://dx.doi.org/10.1289/EHP6263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534587PMC
June 2020

Correction to: Low-moderate arsenic exposure and respiratory health in American Indian communities in the Strong Heart Study.

Environ Health 2020 Feb 26;19(1):24. Epub 2020 Feb 26.

Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St, Baltimore, MD, USA.

The original version of this article [1], published on 28 November 2019, contained incorrect title. In this Correction the affected part of the article is shown.
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http://dx.doi.org/10.1186/s12940-020-00576-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043028PMC
February 2020

Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study.

Sci Rep 2019 11 29;9(1):17899. Epub 2019 Nov 29.

Department of Nutrition, and UNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA.

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25-44%; P < 3 × 10) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p < 3 × 10) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p <6× 10). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p < 7.1 × 10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation.
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http://dx.doi.org/10.1038/s41598-019-52924-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884539PMC
November 2019

Low-moderate arsenic exposure and respiratory in American Indian communities in the Strong Heart Study.

Environ Health 2019 11 28;18(1):104. Epub 2019 Nov 28.

Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St, Baltimore, MD, USA.

Background: Arsenic exposure through drinking water is an established lung carcinogen. Evidence on non-malignant lung outcomes is less conclusive and suggests arsenic is associated with lower lung function. Studies examining low-moderate arsenic (< 50 μg/L), the level relevant for most populations, are limited. We evaluated the association of arsenic exposure with respiratory health in American Indians from the Northern Plains, the Southern Plains and the Southwest United States, communities with environmental exposure to inorganic arsenic through drinking water.

Methods: The Strong Heart Study is a prospective study of American Indian adults. This analysis used urinary arsenic measurements at baseline (1989-1991) and spirometry at Visit 2 (1993-1995) from 2132 participants to evaluate associations of arsenic exposure with airflow obstruction, restrictive pattern, self-reported respiratory disease, and symptoms.

Results: Airflow obstruction was present in 21.5% and restrictive pattern was present in 14.4%. The odds ratio (95% confidence interval) for obstruction and restrictive patterns, based on the fixed ratio definition, comparing the 75th to 25th percentile of arsenic, was 1.17 (0.99, 1.38) and 1.27 (1.01, 1.60), respectively, after adjustments, and 1.28 (1.02, 1.60) and 1.33 (0.90, 1.50), respectively, based on the lower limit of normal definition. Arsenic was associated with lower percent predicted FEV1 and FVC, self-reported emphysema and stopping for breath.

Conclusion: Low-moderate arsenic exposure was positively associated with restrictive pattern, airflow obstruction, lower lung function, self-reported emphysema and stopping for breath, independent of smoking and other lung disease risk factors. Findings suggest that low-moderate arsenic exposure may contribute to restrictive lung disease.
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http://dx.doi.org/10.1186/s12940-019-0539-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883619PMC
November 2019

Trends in Cardiovascular Disease Morbidity and Mortality in American Indians Over 25 Years: The Strong Heart Study.

J Am Heart Assoc 2019 11 25;8(21):e012289. Epub 2019 Oct 25.

MedStar Health Research Institute Georgetown/Howard University Center for Clinical and Translational Sciences Hyattsville MD.

Background American Indians experience high rates of cardiovascular disease. We evaluated whether cardiovascular disease incidence, mortality, and prevalence changed over 25 years among American Indians aged 30 to 85. Methods and Results The SHS (Strong Heart Study) and SHFS (Strong Heart Family Study) are prospective studies of cardiovascular disease in American Indians. Participants enrolled in 1989 to 1990 or 2000 to 2003 with birth years from 1915 to 1984 were followed for cardiovascular disease events through 2013. We used Poisson regression to analyze data for 5627 individuals aged 30 to 85 years during follow-up. Outcomes reflect change in age-specific cardiovascular disease incidence, mortality, and prevalence, stratified by sex. To illustrate generational change, 5-year relative risk compared most recent birth years for ages 45, 55, 65, and 75 to same-aged counterparts born 1 generation (23-25 years) earlier. At all ages, cardiovascular disease incidence was lower for people with more recent birth years. Cardiovascular disease mortality declined consistently among men, while prevalence declined among women. Generational comparisons were similar for women aged 45 to 75 (relative risk, 0.39-0.46), but among men magnitudes strengthened from age 45 to 75 (relative risk, 0.91-0.39). For cardiovascular disease mortality, risk was lower in the most recent versus the earliest birth years for women (relative risk, 0.56-0.83) and men (relative risk, 0.40-0.54), but results for women were inconclusive. Conclusions Cardiovascular disease incidence declined over a generation in an American Indian cohort. Mortality declined more for men, while prevalence declined more for women. These trends might reflect more improvement in case survival among men compared with women.
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http://dx.doi.org/10.1161/JAHA.119.012289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898852PMC
November 2019

Genetic analysis of hsCRP in American Indians: The Strong Heart Family Study.

PLoS One 2019 17;14(10):e0223574. Epub 2019 Oct 17.

Department of Nutrition and Nutrition Research Institute, University of North Carolina, Chapel Hill, North Carolina, United States of America.

Background: Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations.

Methods: The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses.

Results: CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10-20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10-7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10-4.

Conclusion: In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223574PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797125PMC
March 2020

Dietary determinants of inorganic arsenic exposure in the Strong Heart Family Study.

Environ Res 2019 Oct 1;177:108616. Epub 2019 Aug 1.

Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA.

Background: Chronic exposure to inorganic arsenic (iAs) in the US occurs mainly through drinking water and diet. Although American Indian (AI) populations have elevated urinary arsenic concentrations compared to the general US population, dietary sources of arsenic exposure in AI populations are not well characterized.

Methods: We evaluated food frequency questionnaires to determine the major dietary sources of urinary arsenic concentrations (measured as the sum of arsenite, arsenate, monomethylarsonate, and dimethylarsinate, ΣAs) for 1727 AI participants in the Strong Heart Family Study (SHFS). We compared geometric mean ratios (GMRs) of urinary ΣAs for an interquartile range (IQR) increase in reported food group consumption. Exploratory analyses were stratified by gender and study center.

Results: In fully adjusted generalized estimating equation models, the percent increase (95% confidence interval) of urinary ΣAs per increase in reported food consumption corresponding to the IQR was 13% (5%, 21%) for organ meat, 8% (4%, 13%) for rice, 7% (2%, 13%) for processed meat, and 4% (1%, 7%) for non-alcoholic drinks. In analyses stratified by study center, the association with organ meat was only observed in North/South Dakota. Consumption of red meat [percent increase -7% (-11%, -3%)] and fries and chips [-6% (-10%, -2%)] was inversely associated with urinary ΣAs.

Conclusions: Organ meat, processed meat, rice, and non-alcoholic drinks contribute to ΣAs exposure in the SHFS population. Organ meat is a unique source of ΣAs exposure for North and South Dakota participants and may reflect local food consumption. Further studies should comprehensively evaluate drinking water arsenic in SHFS communities and determine the relative contribution of diet and drinking water to total arsenic exposure.
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http://dx.doi.org/10.1016/j.envres.2019.108616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748659PMC
October 2019

Associations of diet soda and non-caloric artificial sweetener use with markers of glucose and insulin homeostasis and incident diabetes: the Strong Heart Family Study.

Eur J Clin Nutr 2020 02 28;74(2):322-327. Epub 2019 Jun 28.

Department of Epidemiology, University of Washington, Seattle, WA, USA.

Background/objectives: Non-caloric artificial sweeteners (NAS) are marketed as healthier alternatives to sugar, but the relationship between consumption of NAS and development of diabetes is unclear. This study assessed the associations of diet soda and NAS consumption with (1) early markers of insulin and glucose homeostasis (cross-sectionally) and (2) incident diabetes (over an average of 8 years of follow-up) among American Indians, a population with high rates of obesity.

Subjects/methods: The study population included Strong Heart Family Study participants without cardiovascular disease or diabetes who participated in the 2007-2009 study exam (n = 1359). Diet soda and NAS consumption were assessed using a Block food frequency questionnaire and supplemental NAS questionnaire at the study exam. Fasting plasma glucose and insulin were measured during the study exam after a 12-h overnight fast. Participants were followed for incident diabetes through December 2017 using a single phone interview and medical record review; diabetes was identified by self-report and confirmed by documentation in medical records. Associations of diet soda and NAS consumption with fasting insulin, glucose, and incident diabetes were assessed using generalized estimating equations (fasting insulin and glucose analyses) and parametric survival models with Weibull distributions (incident diabetes analyses).

Results: Just under half of participants reported regularly consuming diet soda (40%) or using NAS to sweeten their beverages (41%). During an average 8 years of follow-up, we identified 98 cases of incident diabetes. After correction for multiple comparisons, there were no statistically significant associations of reported diet soda and NAS consumption with fasting insulin, fasting glucose, or incident diabetes.

Conclusions: Although reported consumption of diet soda and NAS were high, neither were associated with diabetes risk.
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http://dx.doi.org/10.1038/s41430-019-0461-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934923PMC
February 2020

Characterizing the local food environment and grocery-store decision making among a large American Indian community in the north-central USA: qualitative results from the Healthy Foods Healthy Families Feasibility Study.

Public Health Nutr 2019 10 24;22(14):2653-2661. Epub 2019 May 24.

Department of Epidemiology, Cardiovascular Health Research Unit, School of Public Health, University of Washington, 1959 NE Pacific Street, Box 357236, Seattle, WA 98195, USA.

Objective: Perceptions of social-contextual food environments and associated factors that influence food purchases are understudied in American Indian (AI) communities. The purpose of the present study was to: (i) understand the perceived local food environment; (ii) investigate social-contextual factors that influence family food-purchasing choices; and (iii) identify diet intervention strategies.

Design: This qualitative study consisted of focus groups with primary household shoppers and key-informant interviews with food retailers, local government food assistance programme directors and a dietitian. An inductive, constant comparison approach was used to identify major themes.

Setting: A large AI reservation community in the north-central USA.

Participants: Four focus groups (n 31) and seven key-informant interviews were conducted in February and May 2016.

Results: Perceptions of both the higher cost of healthy foods and limited access to these foods influenced the types of foods participants purchased. Dependence on government assistance programmes and the timing of benefits also contributed to the types of foods purchased. Participants described purchasing foods based on the dietary needs and preferences of their children. Suggestions for improving the purchase and consumption of healthy foods included: culturally relevant and family-centred cooking classes and workshops focused on monthly food budgeting. Participants also emphasized the importance of involving the entire community in healthy eating initiatives.

Conclusions: Cost and access were the major perceived barriers to healthy eating in this large rural AI community. Recommended interventions included: (i) family-friendly and culturally relevant cooking classes; (ii) healthy food-budgeting skills training; and (iii) approaches that engage the entire community.
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http://dx.doi.org/10.1017/S1368980019001095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718325PMC
October 2019

Socioeconomic and Environmental Risk Factors for Pediatric Asthma in an American Indian Community.

Acad Pediatr 2019 08 17;19(6):631-637. Epub 2019 May 17.

Seattle Children's Hospital (B Kinghorn, AM Fretts, CJ Karr, and M Rosenfeld), University of Washington, Seattle; Missouri Breaks Industries Research Inc. (RA O'Leary and LG Best), Eagle Butte, SD; Turtle Mountain Community College (LG Best), Belcourt, ND.

Background: American Indian (AI)/Alaska Native children have increased asthma prevalence, morbidity, and mortality compared to non-Hispanic white children. Our study sought to examine environmental and socioeconomic factors of asthma among children in an AI community.

Methods: This case-control study included children with physician-diagnosed asthma and age-matched controls, ages 6 through 17 years, in an AI community. Diagnosis and clinical characteristics were obtained from medical record review. Home visits included interviews regarding sociodemographic and household environmental exposures, physical exams, spirometry, and asthma control questionnaires (cases only).

Results: Among the 108 asthma cases and 215 controls, 64% had an annual household income of <$25,000. Children with asthma had significantly higher odds of living in a multi-unit dwelling (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.2-4.4) or in residences with rodent or insect infestation (OR, 2.1; 95% CI, 1.1-3.8) and were less likely to live in homes with more than 8 occupants (OR, 0.5; 95% CI, 0.3-0.9). Also, there was a trend for lower caregiver education level, unmarried caregiver marital status, and annual household income level of <$25,000 in univariate analysis. However, after adjustment for socioeconomic status and household environmental factors, these estimates were not significant. Nearly half of cases had poorly controlled asthma and reported persistent cough, wheeze, and dyspnea, yet only 24% reported using a controller medication.

Conclusions: In this low-income AI community, we identified several social and environmental determinants of asthma, which were mediated by socioeconomic status and other household environmental factors, suggesting a complex interplay between socioeconomic status and environmental exposures. Furthermore, many children with asthma reported poor asthma control.
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http://dx.doi.org/10.1016/j.acap.2019.05.006DOI Listing
August 2019

Myocardial mechano-energetic efficiency and insulin resistance in non-diabetic members of the Strong Heart Study cohort.

Cardiovasc Diabetol 2019 04 30;18(1):56. Epub 2019 Apr 30.

Weill Cornell Med, New York, NY, USA.

Background: Myocardial energetic efficiency (MEE), is a strong predictor of CV events in hypertensive patient and is reduced in patients with diabetes and metabolic syndrome. We hypothesized that severity of insulin resistance (by HOMA-IR) negatively influences MEE in participants from the Strong Heart Study (SHS).

Methods: We selected non-diabetic participants (n = 3128, 47 ± 17 years, 1807 women, 1447 obese, 870 hypertensive) free of cardiovascular (CV) disease, by merging two cohorts (Strong Heart Study and Strong Heart Family Study, age range 18-93). MEE was estimated as stroke work (SW = systolic blood pressure [SBP] × stroke volume [SV])/"double product" of SBP × heart rate (HR), as an estimate of O consumption, which can be simplified as SV/HR ratio and expressed in ml/sec. Due to the strong correlation, MEE was normalized by left ventricular (LV) mass (MEEi).

Results: Linear trend analyses showed that with increasing quartiles of HOMA-IR patients were older, more likely to be women, obese and hypertensive, with a trend toward a worse lipid profile (all p for trend < 0.001), progressive increase in LV mass index, stroke index and cardiac index and decline of wall mechanics (all p < 0.0001). In multivariable regression, after adjusting for confounders, and including a kinship coefficient to correct for relatedness, MEEi was negatively associated with HOMA-IR, independently of significant associations with age, sex, blood pressure, lipid profile and central obesity (all p < 0.0001).

Conclusions: Severity of insulin resistance has significant and independent negative impact on myocardial mechano-energetic efficiency in nondiabetic individual from a population study of American Indians. Trial registration number NCT00005134, Name of registry: Strong Heart Study, URL of registry: https://clinicaltrials.gov/ct2/show/NCT00005134 , Date of registration: May 25, 2000, Date of enrolment of the first participant to the trial: September 1988.
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http://dx.doi.org/10.1186/s12933-019-0862-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492323PMC
April 2019

The association of mannose binding lectin genotype and immune response to Chlamydia pneumoniae: The Strong Heart Study.

PLoS One 2019 10;14(1):e0210640. Epub 2019 Jan 10.

Department of Microbiology, The Ohio State University, Columbus, OH, United States of America.

Cardiovascular disease (CVD) is an important contributor to morbidity and mortality in American Indian communities. The Strong Heart Study (SHS) was initiated in response to the need for population based estimates of cardiovascular disease in American Indians. Previous studies within SHS have identified correlations between heart disease and deficiencies in mannose binding lectin (MBL), a motif recognition molecule of the innate immune system. MBL mediates the immune response to invading pathogens including Chlamydia pneumoniae (Cp), which has also been associated with the development and progression of CVD. However, a link between MBL2 genotype and Cp in contributing to heart disease has not been established. To address this, SHS collected baseline Cp antibody titers (IgA and IgG) and MBL2 genotypes for common functional variants from 553 individuals among twelve participating tribes. A single nucleotide polymorphism (SNP) in the promoter, designated X/Y, correlated significantly with increased Cp IgG titer levels, whereas another promoter SNP (H/L) did not significantly influence antibody levels to Cp. Two variants within exon 1 of MBL2, the A and B alleles, also displayed significant association with Cp antibody titers. Some MBL2 genotypes were absent from the population, suggesting linkage disequilibrium may be operating within the SHS cohort. Additional factors, such as increasing age and socioeconomic status, were also associated with increased Cp IgG antibody titers. This study demonstrates that MBL2 genotype associates with immune reactivity to C. pneumoniae in the SHS cohort. Thus, MBL2 may contribute to the progression of cardiovascular disease (CVD) among American Indians indirectly through pathogen interactions in addition to its previously defined roles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210640PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328205PMC
October 2019

The Strong Heart Water Study: Informing and designing a multi-level intervention to reduce arsenic exposure among private well users in Great Plains Indian Nations.

Sci Total Environ 2019 Feb 18;650(Pt 2):3120-3133. Epub 2018 Sep 18.

Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205, USA. Electronic address:

Elevated arsenic exposure from drinking water is associated with an increased risk of cardiovascular disease, diabetes, kidney disease, and skin, lung, and bladder cancer. Arsenic contamination in groundwater supplies disproportionately affects rural populations using private wells. Arsenic mitigation programs for American Indian communities are limited. There is an urgent need for targeted approaches to reduce arsenic exposure for at-risk communities using private wells. Formative research was conducted to inform and design a community-based arsenic mitigation intervention for Lakota and Dakota Nations in the Great Plains Area of the United States, where, in some communities, one-quarter of private wells are estimated to have elevated arsenic. Formative research included semi-structured interviews, a community workshop, intervention-planning workshops, and a pilot study of the developed intervention. Community members prioritize aesthetic qualities of water (e.g. taste, color), safety, and other situational factors (e.g. cost) when considering their drinking and cooking water. Although water safety is a concern, awareness and concern for arsenic vary substantially within communities. To reduce arsenic exposure, community members recommended communication of water test results, home visits for intervention delivery, and reminders to use arsenic-safe water. Findings informed the development of an intervention to prevent arsenic exposure through drinking water and cooking, including health promotion messages and household items to facilitate use of an arsenic removal device (e.g. tankards to store filtered water). The pilot study indicated promising acceptability and operability of the developed intervention. This research provides a model for the development of environmental health interventions in partnership with American Indian and other private well-using communities.
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http://dx.doi.org/10.1016/j.scitotenv.2018.09.204DOI Listing
February 2019

Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study.

Front Genet 2018 12;9:466. Epub 2018 Oct 12.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS). We examined the association of variants, previously associated with cardiometabolic traits (∼200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing ( < 4.13 × 10). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near (rs2961831, = 6.39 × 10). In the replication study, we found a signal at rs4607517 near ( = 0.01). Variants near candidate diabetes genes (especially and ) were also nominally associated with HOMA-IR and cHOMA-B. We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at , , and with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.
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http://dx.doi.org/10.3389/fgene.2018.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194194PMC
October 2018

Arsenic, one carbon metabolism and diabetes-related outcomes in the Strong Heart Family Study.

Environ Int 2018 12 12;121(Pt 1):728-740. Epub 2018 Oct 12.

Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, NY, New York, United States of America; Department of Environmental Health & Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.

Background: Inorganic arsenic exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. A more efficient arsenic metabolism profile (lower MMA%, higher DMA%) has been associated with reduced risk for arsenic-related health outcomes; however, this profile has also been associated with increased risk for diabetes-related outcomes. The mechanism behind these contrasting associations is equivocal; we hypothesized one carbon metabolism (OCM) may play a role.

Methods: We evaluated the association between OCM-related variables (nutrient intake and genetic variants) and both arsenic metabolism biomarkers (iAs%, MMA% and DMA%) and diabetes-related outcomes (metabolic syndrome, diabetes, HOMA2-IR and waist circumference) in 935 participants free of prevalent diabetes and metabolic syndrome from the Strong Heart Family Study, a family-based prospective cohort comprised of American Indian tribal members aged 14+ years.

Results: Of the 935 participants free of both diabetes and metabolic syndrome at baseline, 279 (29.8%) developed metabolic syndrome over a median of 5.3 years of follow-up and of the 1458 participants free of diabetes at baseline, 167 (11.3%) developed diabetes over follow-up. OCM nutrients were not associated with arsenic metabolism, however, higher vitamin B was associated with diabetes-related outcomes (higher HOMA2-IR and increased risk for diabetes and metabolic syndrome). A polymorphism in an OCM-related gene, methionine synthase (MTR), was associated with both higher MMA% (β = 2.57, 95% CI: 0.22, 4.92) and lower HOMA2-IR (GMR = 0.79, 95% CI = 0.66, 0.93 per 5 years of follow-up). Adjustment for OCM variables did not affect previously reported associations between arsenic metabolism and diabetes-related outcomes; however, the association between the MTR variant and diabetes-related outcomes were attenuated after adjustment for arsenic metabolism.

Conclusions: Our findings suggest MMA% may be a partial mediator in the association between OCM and diabetes-related outcomes. Additional mediation analyses with longer follow-up period are needed to confirm this finding. Further research is needed to determine whether excess B vitamin intake is associated with increased risk for diabetes-related outcomes.
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http://dx.doi.org/10.1016/j.envint.2018.09.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221918PMC
December 2018

Targeted metabolomics to understand the association between arsenic metabolism and diabetes-related outcomes: Preliminary evidence from the Strong Heart Family Study.

Environ Res 2019 01 27;168:146-157. Epub 2018 Sep 27.

Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA; Department of Environmental Health & Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

Background: Inorganic arsenic exposure is ubiquitous and both exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. A more efficient arsenic metabolism profile (lower MMA%, higher DMA%) has been associated with reduced risk for arsenic-related health outcomes. This profile, however, has also been associated with increased risk for diabetes-related outcomes.

Objectives: The mechanism behind these conflicting associations is unclear; we hypothesized the one-carbon metabolism (OCM) pathway may play a role.

Methods: We evaluated the influence of OCM on the relationship between arsenic metabolism and diabetes-related outcomes (HOMA2-IR, waist circumference, fasting plasma glucose) using metabolomic data from an OCM-specific and P180 metabolite panel measured in plasma, arsenic metabolism measured in urine, and HOMA2-IR and FPG measured in fasting plasma. Samples were drawn from baseline visits (2001-2003) in 59 participants from the Strong Heart Family Study, a family-based cohort study of American Indians aged ≥14 years from Arizona, Oklahoma, and North/South Dakota.

Results: In unadjusted analyses, a 5% increase in DMA% was associated with higher HOMA2-IR (geometric mean ratio (GMR)= 1.13 (95% CI: 1.03, 1.25)) and waist circumference (mean difference=3.66 (0.95, 6.38). MMA% was significantly associated with lower HOMA2-IR and waist circumference. After adjustment for OCM-related metabolites (SAM, SAH, cysteine, glutamate, lysophosphatidylcholine 18.2, and three phosphatidlycholines), associations were attenuated and no longer significant.

Conclusions: These preliminary results indicate that the association of lower MMA% and higher DMA% with diabetes-related outcomes may be influenced by OCM status, either through confounding, reverse causality, or mediation.
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http://dx.doi.org/10.1016/j.envres.2018.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298442PMC
January 2019

Arsenic in groundwater in private wells in rural North Dakota and South Dakota: Water quality assessment for an intervention trial.

Environ Res 2019 01 15;168:41-47. Epub 2018 Sep 15.

Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St, Baltimore, MD 21205, USA. Electronic address:

Elevated exposure to arsenic disproportionately affects populations relying on private well water in the United States (US). This includes many American Indian (AI) communities where naturally occurring arsenic is often above 10 µg/L, the current US Environmental Protection Agency safety standard. The Strong Heart Water Study is a randomized controlled trial aiming to reduce arsenic exposure to private well water users in AI communities in North Dakota and South Dakota. In preparation for this intervention, 371 households were included in a community water arsenic testing program to identify households with arsenic ≥10 µg/L by inductively coupled plasma mass spectrometry (ICP-MS). Arsenic ≥10 µg/L was found in 97/371 (26.1%) households; median water arsenic concentration was 6.3 µg/L, ranging from <1-198 µg/L. Silica was identified as a water quality parameter that could impact the efficacy of arsenic removal devices to be installed. A low-range field rapid arsenic testing kit evaluated in a small number of households was found to have low accuracy; therefore, not an option for the screening of affected households in this setting. In a pilot study of the effectiveness of a point-of-use adsorptive media water filtration device for arsenic removal, all devices installed removed arsenic below 1 µg/L at both installation and 9 months post-installation. This study identified a relatively high burden of arsenic in AI study communities as well as an effective water filtration device to reduce arsenic in these communities. The long-term efficacy of a community based arsenic mitigation program in reducing arsenic exposure and preventing arsenic related disease is being tested as part of the Strong Heart Water Study.
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http://dx.doi.org/10.1016/j.envres.2018.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296218PMC
January 2019

Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Hum Mol Genet 2018 08;27(16):2940-2953

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.
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http://dx.doi.org/10.1093/hmg/ddy211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077792PMC
August 2018

Association of low-moderate urine arsenic and QT interval: Cross-sectional and longitudinal evidence from the Strong Heart Study.

Environ Pollut 2018 Sep 26;240:894-902. Epub 2018 May 26.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA.

Epidemiologic studies suggest that chronic exposure to arsenic is related to cardiovascular disease (CVD), but the pathophysiological link remains uncertain. We evaluated the association of chronic low-moderate arsenic exposure and arsenic metabolism with baseline difference and annual change in ECG measures (QT interval, JT interval, PR interval, QRS duration, and QT dispersion) using linear mixed models in the Strong Heart Study main cohort (N = 1174, median age 55 years) and family study (N = 1695 diabetes-free, median age 36 years). At baseline, arsenic exposure was measured as the sum of inorganic and methylated species in urine (ΣAs) and arsenic metabolism was measured as the relative percentage of arsenic species. Median ΣAs and Bazett heart rate-corrected QT interval (QTc) were 8.6 μg/g creatinine and 424 ms in the main cohort and 4.3 μg/g and 414 ms in the family study, respectively. In the main cohort, a comparison of the highest to lowest ΣAs quartile (>14.4 vs. <5.2 μg/g creatinine) was associated with a 5.3 (95% CI: 1.2, 9.5) ms higher mean baseline QTc interval but no difference in annual change in QTc interval. In the family study, a comparison of the highest to lowest quartile (>7.1 vs. <2.9 μg/g creatinine) was associated with a 3.2 (95% CI: 0.6, 5.7) ms higher baseline QTc interval and a 0.6 (95% CI: 0.04, 1.2) ms larger annual increase in QTc interval. Associations with JTc interval were similar but stronger in magnitude compared to QTc interval. Arsenic exposure was largely not associated with PR interval, QRS duration or QT dispersion. Similar to arsenic exposure, a pattern of lower %MMA and higher %DMA was associated with longer baseline QTc interval in both cohorts and with a larger annual change in QTc interval in the family study. Chronic low-moderate arsenic exposure and arsenic metabolism were associated with prolonged ventricular repolarization.
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http://dx.doi.org/10.1016/j.envpol.2018.04.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339816PMC
September 2018

Arsenic-gene interactions and beta-cell function in the Strong Heart Family Study.

Toxicol Appl Pharmacol 2018 06 3;348:123-129. Epub 2018 Apr 3.

Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, United States; Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, United States. Electronic address:

We explored arsenic-gene interactions influencing pancreatic beta-cell activity in the Strong Heart Family Study (SHFS). We considered 42 variants selected for associations with either beta-cell function (31 variants) or arsenic metabolism (11 variants) in the SHFS. Beta-cell function was calculated as homeostatic model - beta corrected for insulin resistance (cHOMA-B) by regressing homeostatic model - insulin resistance (HOMA-IR) on HOMA-B and adding mean HOMA-B. Arsenic exposure was dichotomized at the median of the sum of creatinine-corrected inorganic and organic arsenic species measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS). Additive GxE models for cHOMA-B were adjusted for age and ancestry, and accounted for family relationships. Models were stratified by center (Arizona, Oklahoma, North Dakota and South Dakota) and meta-analyzed. The two interactions between higher vs. lower arsenic and SNPs for cHOMA-B that were nominally significant at P < 0.05 were with rs10738708 (SNP overall effect -3.91, P = 0.56; interaction effect with arsenic -31.14, P = 0.02) and rs4607517 (SNP overall effect +16.61, P = 0.03; interaction effect with arsenic +27.02, P = 0.03). The corresponding genes GCK and TUSC1 suggest oxidative stress and apoptosis as possible mechanisms for arsenic impacts on beta-cell function. No interactions were Bonferroni-significant (1.16 × 10). Our findings are suggestive of oligogenic moderation of arsenic impacts on pancreatic β-cell endocrine function, but were not Bonferroni-significant.
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http://dx.doi.org/10.1016/j.taap.2018.03.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961497PMC
June 2018

The Association of Arsenic Exposure and Arsenic Metabolism With the Metabolic Syndrome and Its Individual Components: Prospective Evidence From the Strong Heart Family Study.

Am J Epidemiol 2018 08;187(8):1598-1612

Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.

Inorganic arsenic exposure is ubiquitous, and both exposure and interindividual differences in its metabolism have been associated with cardiometabolic risk. However, the associations of arsenic exposure and arsenic metabolism with the metabolic syndrome (MetS) and its individual components are relatively unknown. We used Poisson regression with robust variance to evaluate the associations of baseline arsenic exposure (urinary arsenic levels) and metabolism (relative percentage of arsenic species over their sum) with incident MetS and its individual components (elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, hypertension, and elevated fasting plasma glucose) in 1,047 participants from the Strong Heart Family Study, a prospective family-based cohort study in American Indian communities (baseline visits were held in 1998-1999 and 2001-2003, follow-up visits in 2001-2003 and 2006-2009). Over the course of follow-up, 32% of participants developed MetS. An interquartile-range increase in arsenic exposure was associated with a 1.19-fold (95% confidence interval: 1.01, 1.41) greater risk of elevated fasting plasma glucose concentration but not with other individual components of the MetS or MetS overall. Arsenic metabolism, specifically lower percentage of monomethylarsonic acid and higher percentage of dimethylarsinic acid, was associated with higher risk of overall MetS and elevated waist circumference but not with any other MetS component. These findings support the hypothesis that there are contrasting and independent associations of arsenic exposure and arsenic metabolism with metabolic outcomes which may contribute to overall diabetes risk.
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http://dx.doi.org/10.1093/aje/kwy048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070055PMC
August 2018

Physical activity and telomere length in American Indians: the Strong Heart Study.

Eur J Epidemiol 2018 May 7;33(5):497-500. Epub 2018 Feb 7.

Department of Epidemiology, Division of Genetic Epidemiology, University of Florida, 2004 Mowry Road, PO Box 100231, Gainesville, FL, 32611, USA.

Telomere length, a marker of biological aging, has been associated with many chronic diseases, but its relations with physical activity remains unclear. The purpose of this study was to examine the association of objectively measured ambulatory activity with leukocyte telomere length (LTL), a marker of biological aging, among American Indians. This cross-sectional study included 2312 AI participants from the Strong Heart Family Study. Steps per day were measured using Accusplit AE120 pedometers. Quantitative PCR was used to measure LTL. Generalized estimating equations were used to examine the associations of steps per day with LTL. The median steps per day over a 1 week period was 5118 steps (interquartile range = 3163-7576 steps). Compared to participants in the lowest quartile of steps per day, participants in the upper three quartiles of steps per day had longer LTL: beta ± SE = 0.0195 ± 0.0144, 0.0273 ± 0.0139, and 0.0375 ± 0.0143 T/S ratio units longer (p trend = 0.010) after adjustment for potential confounders. These data suggest that ambulatory activity is associated with LTL. Further studies are needed to determine the mechanism by which ambulatory activity influences LTL.
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http://dx.doi.org/10.1007/s10654-018-0363-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310229PMC
May 2018
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