Strong Heart Study Research Articles

Plasma lipidomic profile of depressive symptoms: a longitudinal study in a large sample of community-dwelling American Indians in the strong heart study.

Dyslipidemia has been associated with depression, but individual lipid species associated with depression remain largely unknown. The temporal relationship between lipid metabolism and the development of depression also remains to be determined. We studied 3721 fasting plasma samples from 1978 American Indians attending two exams (2001-2003, 2006-2009, mean ~5.5 years apart) in the Strong Heart Family Study. Plasma lipids were repeatedly measured by untargeted liquid chromatography-mass spectrometry (LC-MS). Depressive symptoms were assessed using the 20-item Center for Epidemiologic Studies for Depression (CES-D). Participants at risk for depression were defined as total CES-D score ≥16. Generalized estimating equation (GEE) was used to examine the associations of lipid species with incident or prevalent depression, adjusting for covariates. The associations between changes in lipids and changes in depressive symptoms were additionally adjusted for baseline lipids. We found that lower levels of sphingomyelins and glycerophospholipids and higher level of lysophospholipids were significantly associated with incident and/or prevalent depression. Changes in sphingomyelins, glycerophospholipids, acylcarnitines, fatty acids and triacylglycerols were associated with changes in depressive symptoms and other psychosomatic traits. We also identified differential lipid networks associated with risk of depression. The observed alterations in lipid metabolism may affect depression through increasing the activities of acid sphingomyelinase and phospholipase A2, disturbing neurotransmitters and membrane signaling, enhancing inflammation, oxidative stress, and lipid peroxidation, and/or affecting energy storage in lipid droplets or membrane formation. These findings illuminate the mechanisms through which dyslipidemia may contribute to depression and provide initial evidence for targeting lipid metabolism in developing preventive and therapeutic interventions for depression.

Epigenetics of type 2 diabetes and diabetes-related outcomes in the Strong Heart Study

BackgroundThe prevalence of type 2 diabetes has dramatically increased in the past years. Increasing evidence supports that blood DNA methylation, the best studied epigenetic mark, is related to diabetes risk. Few prospective studies, however, are available. We studied the association of blood DNA methylation with diabetes in the Strong Heart Study. We used limma, Iterative Sure Independence Screening and Cox regression to study the association of blood DNA methylation with fasting glucose, HOMA-IR and incident type 2 diabetes among 1312 American Indians from the Strong Heart Study. DNA methylation was measured using Illumina’s MethylationEPIC beadchip. We also assessed the biological relevance of our findings using bioinformatics analyses.ResultsAmong the 358 differentially methylated positions (DMPs) that were cross-sectionally associated either with fasting glucose or HOMA-IR, 49 were prospectively associated with incident type 2 diabetes, although no DMPs remained significant after multiple comparisons correction. Multiple of the top DMPs were annotated to genes with relevant functions for diabetes including SREBF1, associated with obesity, type 2 diabetes and insulin sensitivity; ABCG1, involved in cholesterol and phospholipids transport; and HDAC1, of the HDAC family. (HDAC inhibitors have been proposed as an emerging treatment for diabetes and its complications.)ConclusionsOur results suggest that differences in peripheral blood DNA methylation are related to cross-sectional markers of glucose metabolism and insulin activity. While some of these DMPs were modestly associated with prospective incident type 2 diabetes, they did not survive multiple testing. Common DMPs with diabetes epigenome-wide association studies from other populations suggest a partially common epigenomic signature of glucose and insulin activity.

Volume atrophy in medial temporal cortex and verbal memory scores in American Indians: Data from the Strong Heart Study.

Distinguishing Alzheimer's disease (AD) patient subgroups may optimize positive clinical outcomes. Cortical atrophy is correlated with memory deficits, but these associations are understudied in American Indians. We collected imaging and cognition data in the Strong Heart Study (SHS), a cohort of 11 tribes across three regions. We processed 1.5T MRI using FreeSurfer and iterative principal component analysis. Linear mixed models estimated volumetric associations with diabetes. Over mean 7 years follow-up (N=818 age 65-89 years), overall volume loss was 0.5% per year. Significant losses associated with diabetes were especially strong in the right hemisphere. Annualized hippocampal, parahippocampal, entorhinal atrophy were worse for men, older age, diabetes, hypertension, stroke; and associated with both encoding and retrieval memory losses. Our findings suggest that diabetes is an important risk factor in American Indians for cortical atrophy and memory loss. Future research should examine opportunities for primary prevention in this underserved population.

Intraindividual variability of cognitive performance and associations with magnetic resonance imaging in aging American Indians: Data from the Strong Heart Study

AbstractBackgroundAmerican Indians present with increased risk factors for Alzheimer’s disease and related dementias (ADRDs). Intraindividual cognitive variability (IICV), which measures the variability in performance on neuropsychological tests within a person at a single time, has been proposed as a noninvasive marker of neurodegeneration and early dementia. In this study, we investigated the hypothesis that higher IICV was related to more features of neurodegeneration on magnetic resonance imaging (MRI) measurements among older American Indians.MethodAmerican Indian participants over 64 years of age who underwent MRI and completed a battery of neuropsychological tests were included in the study (N = 750). Data from three neuropsychological tests were used to compute a multidomain IICV measure of cognition along with IICV measures representing the cognitive domains of memory, executive function and processing speed. Regression models estimated IICV associations with total brain volume, hippocampal volume, and graded white matter disease, adjusting for age, sex, education, BMI, and intracranial volume.ResultMemory, executive function and processing speed, and multidomain IICV measures were associated with total brain volume before correction for multiple comparisons. After correction with Bonferroni, only higher IICV of memory was associated with lower total brain volume (Beta = −0.20; 95%CI −0.332, −0.068; p = 0.009). Furthermore, additional adjustment of mean scores from the tests used for the variability measure resulted in loss of significance for all IICV measures, with only mean scores remaining significant. Measures of IICV were not associated with hippocampal volume or white matter disease.ConclusionThese findings suggest that IICV of memory may be associated with imaging measures related to neurodegenerative injury in older American Indians. However, these associations representing variability in cognition are smaller than those representing mean cognition. More research is needed to understand the clinical and etiologic associations for IICV measures.

Epigenetic Biomarkers of Lead Exposure and Cardiovascular Disease: Prospective Evidence in the Strong Heart Study.

Background Lead is a cardiotoxic metal with a variety of adverse health effects. In the absence of data on bone lead exposure, epigenetic biomarkers can serve as indicators of cumulative lead exposure and body burden. Herein, we leveraged novel epigenetic biomarkers of lead exposure to investigate their association with cardiovascular disease (CVD) incidence and mortality. Methods and Results Blood DNA methylation was measured using the Illumina MethylationEPIC BeadChip among 2231 participants of the Strong Heart Study (SHS) at baseline (1989-1991). Epigenetic biomarkers of lead levels in blood, patella, and tibia were estimated using previously identified cytosine-guanine dinucleotide (CpG) sites. CVD incidence and mortality data were available through 2017. Median concentrations of lead epigenetic biomarkers were 13.8 μg/g, 21.3 μg/g, and 2.9 μg/dL in tibia, patella, and blood, respectively. In adjusted models, the hazard ratio (HR) (95% CI) of CVD mortality per doubling increase in lead epigenetic biomarkers were 1.42 (1.07-1.87) for tibia lead, 1.22 (0.93-1.60) for patella lead, and 1.57 (1.16-2.11) for blood lead. The corresponding HRs for incident CVD were 0.99 (0.83-1.19), 1.07 (0.89-1.29), and 1.06 (0.87-1.30). The association between the tibia lead epigenetic biomarker and CVD mortality was modified by sex (interaction P value: 0.014), with men at increased risk (HR, 1.42 [95% CI, 1.17-1.72]) compared with women (HR, 1.04 [95% CI, 0.89-1.22]). Conclusions Tibia and blood epigenetic biomarkers were associated with increased risk of CVD mortality, potentially reflecting the cardiovascular impact of cumulative and recent lead exposures. These findings support that epigenetic biomarkers of lead exposure may capture some of the disease risk associated with lead exposure.

Educational and Clinical Associations With Longitudinal Cognitive Function and Brain Imaging in American Indians: The Strong Heart Study.

Little is known about incidence of vascular and Alzheimer dementias in American Indians. We conducted a large, heterogeneous, population-based, longitudinal cohort study of brain aging in community-dwelling American Indians aged 64-95 years from 11 tribes across 3 states, with neurologic examinations, 1.5T MRI, and extensive cognitive testing. Visit 1 in 2010-2013 (n = 817) and visit 2 in 2017-2019 (n = 403) included all willing, surviving participants. Standardized cognitive tests at both visits included Modified Mini-Mental Status Examination (MMSE), Wechsler Adult Intelligence Scale digit symbol coding (WAIS), Controlled Oral Word Association (COWA), and California Verbal Learning Test short form (CVLT). Test materials added at follow-up included Wide Range Achievement (reading) Test (WRAT) and National Alzheimer Coordinating Center Uniform Data Set cognitive battery (v3 form C2), including Montreal Cognitive Assessment (MoCA). MRI neuroradiologists coded infarcts, hemorrhages, white matter hyperintensities, sulcal atrophy, and ventricle enlargement. The mean time between examinations was 6.7 years (SD 1.1, range 3.8-9.1 years). Years of formal education had modest correlation with WRAT reading score (r = 0.45). Prevalence and incidence (respectively) of infarcts were 32% and 12.8/1,000 person-years (PYs) hemorrhages 6% and 4.4/1000 PY worsening sulci 74% and 19.0/1000 PY worsening ventricle 79% and 30.1/1000 PY worsening leukoaraiosis 44% and 26.1/1000 PY. Linear losses per year in cognitive scores were 0.6% MMSE, 1.2% WAIS, 0.6% COWA, and 2.2% CVLT. The mean MoCA scores were 18.9 (SD 4.3). These are the first data on longitudinal cognitive and imaging changes in American Indians and first reports of Alzheimer disease-related features. The mean scores in MoCA were similar or lower than standard cutoffs used to diagnose dementia in other racial/ethnic groups, suggesting that standardized cognitive tests may not perform well in this population. Test validation, adaptation, and score adjustment are warranted. Years of education were a poor proxy for premorbid function, suggesting novel methods for cognitive score contextualization is also needed in this population. Evaluation of selective survival suggests attrition from death, and frailty should be accounted for in causal analyses. Overall, these data represent a unique opportunity to examine neurology topics of critical importance to an understudied population.

Body Mass Index, White Matter Hyperintensities, and Cognitive Performance in American Indians: Data from the Strong Heart Study.

Previous studies report that obesity can be a risk and a protective factor for cognitive health. However, they have not examined whether white matter hyperintensities (WMH) mediate the association between mid- or late-life body mass index (BMI) and late-life cognitive performance. We examined this question in American Indians, a population underrepresented in neuropsychological research. We used longitudinal data from the cerebrovascular disease and its consequences in American Indians (n = 817), with BMI data collected at midlife (1989-91) and lat-life (2010-13). Cognitive data were collected in late life, with tests for general cognition, processing speed, verbal fluency, and memory. Neuroradiologist-scored WMH severity and volume using standard analysis pipelines. We examined associations among BMI, WMH severity and volume, and cognitive scores using linear regression and the Baron and Kenny method to estimate mediation. High BMI in late life was associated with a 1.79-point higher score in general cognition (95% CI 0.63-2.95, p-value = 0.002), but not the other tests. Mediated by WMH severity, high late-life BMI was associated with a 1.53-point higher score in general cognition (95% CI 0.37-2.69) and, by WMH volume, 1.63 points higher (95% CI 0.49-2.77). The association between late-life obesity and cognitive performance is stronger for females (β = 1.74, 95% CI 0.35-3.13, p-value = 0.014) than for males (β = 1.66, 95% CI -0.63-3.95, p-value = 0.158). In American Indians, high late-life BMI was positively associated with cognitive performance, with a stronger association for females. WMH severity and volume partly attenuate these associations.

Urinary Zinc and Incident Type 2 Diabetes: Prospective Evidence From the Strong Heart Study.

Hyperglycemia can increase urinary zinc excretion. We evaluated the association of higher urinary zinc level with new diagnosis of incident type 2 diabetes mellitus (T2DM) in adult populations with a high burden of T2DM from AZ, OK, and ND and SD. We also assessed the cross-sectional association of urinary zinc levels with prevalent prediabetes. We included 1,339 adults free of T2DM at baseline (1989-1991) followed through 1998-1999 in the Strong Heart Study (SHS) and 1,905 family members of SHS participants followed as part of the Strong Heart Family Study (SHFS) through 2006-2009. T2DM incidence was 14.7% (mean follow-up 6.6 years) in the SHS and 13.5% (mean follow-up 5.6 years) in the SHFS. After adjustment for sex, site, education, smoking status, BMI, and estimated glomerular filtration rate, the hazard ratio of T2DM in comparing 75th vs. 25th percentiles of urinary zinc distribution was 1.21 (95% CI 1.08, 1.36) in the SHS and 1.12 (0.96, 1.31) in the SHFS. These associations were attenuated but significant in the SHS after adjustment for HOMA of insulin resistance (HOMA-IR) score. With exclusion of participants with prediabetes at baseline, urinary zinc remained significantly associated with T2DM in the SHS. In cross-sectional analyses, prediabetes was associated with higher urinary zinc levels. Urinary zinc levels were associated with T2DM incidence and prediabetes prevalence even after adjustment for HOMA-IR in populations with a high burden of T2DM. These results highlight the importance of zinc metabolism in diabetes development.

Urinary Zinc and Incident Diabetes: Prospective Evidence from the Strong Heart Study

Urinary Zinc and Incident Diabetes: Prospective Evidence from the Strong Heart Study

Epigenetic biomarkers of lead exposure and cardiovascular disease: prospective evidence in the Strong Heart Study

Epigenetic biomarkers of lead exposure and cardiovascular disease: prospective evidence in the Strong Heart Study

Maternal DNA Methylation Signatures of Arsenic Exposure is Associated with Adult Offspring Insulin Resistance in the Strong Heart Study

Maternal DNA Methylation Signatures of Arsenic Exposure is Associated with Adult Offspring Insulin Resistance in the Strong Heart Study

Arsenic Exposure, Blood DNA Methylation and Cardiovascular Disease

Background and aim: Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. Methods: Blood DNA methylation was measured in 2321 participants of the Strong Heart Study (SHS), a prospective cohort of American Indians. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early life arsenic exposure in the apolipoprotein E knock-out (apoE-/-) mouse model of atherosclerosis. We conducted replication in three independent cohorts: the Framingham Heart Study, Women’s Health Initiative and the Multi-Ethnic Study of Atherosclerosis. Results: A total of 20 and 13 DMPs were potential mediators in the SHS for the association between arsenic and CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in the three replication cohorts. In the mouse model, differentially methylated regions (DMRs) in 20 of those genes and DMPs in 10 genes were associated with arsenic. Conclusions: Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might be an important mechanism for arsenic induced cardiovascular risk in populations with a high burden of diabetes. Keywords: Arsenic, DNA methylation, cardiovascular disease, epigenetics, American Indians

Differential uranium exposure and its association with hypertension and elevated blood pressure in American Indian communities in the Strong Heart Family Study

Background: Urinary uranium (U) is present at higher concentrations in American Indian (AI) participants in the Strong Heart Study compared to the general US population. Cardiovascular disease is the leading cause of death among American Indians, of which hypertension is an important risk factor. We evaluated the association between U exposure and incident hypertension and increased blood pressure (BP) among Strong Heart Family Study (SHFS) participants. Methods: We included 1453 SHFS participants with baseline visits in 1998-1999 or 2001–2003, and follow-up visits in 2001-2003 and/or 2006–2009. We estimated the association of urinary U exposure with changes in systolic BP and diastolic BP levels using linear regressions, and hypertension incidence using Poisson regression with robust variance, accounting for family clustering. Results: Median (IQR) urinary uranium levels were 0.029 (0.013, 0.059) μg/g creatinine. At follow-up, 17.4% of participants developed hypertension. After adjustment for sociodemographic variables, eGFR, pre-diabetes status, and BMI, comparing the highest to lowest urinary uranium quartiles, the RR (95% CI) of incident hypertension was 1.38 (1.00, 1.91) and the mean difference (95% CI) in systolic BP levels between baseline and follow-up was -2.00 (-3.83, -0.16) mmHg. After adjustment for urinary cadmium and arsenic, the corresponding RR (95% CI) was 1.44 (1.04, 1.99) and the mean difference (95% CI) for systolic BP between baseline and follow-up was -1.48 (-3.32, 0.37) mmHg. The association between uranium and blood pressure levels at follow-up was non-linear, with an increased risk at higher urinary uranium levels. Conclusions: These findings suggest moderate increased risk for hypertension at urinary uranium levels greater than 0.06 μg/g, typical of the Southwest and Great Plains, furthermore a potential association with higher systolic BP levels and higher uranium exposure levels. Further work is needed to assess the cardiovascular effects of chronic uranium exposure in US populations. Keywords: Uranium, hypertension, blood pressure

Testing gender and longitudinal measurement invariance of the SF-36 in American Indian older adults: The strong heart study.

Information about the equality of psychometric properties of the medical outcomes study (MOS) Short Form-36 (SF-36), a health status measure, across gender and across the lifespan for American Indian adults is lacking. We tested measurement invariance (configural, metric, scalar invariance) of the physical and mental components between gender and over time in a sample of 2,709 (1,054 men, 1,654 women) American Indian older adults at three time points, and across a 6-year time frame. Measurement invariance of a 2-factor higher-order model was demonstrated between gender at each time point. Tests of longitudinal invariance indicated longitudinal measurement invariance over time. Multiple-group latent means analysis indicated men had significantly higher physical and mental component latent means compared to women at each time point, and longitudinal latent means analysis found physical and mental component latent means decreased over time. The 2-factor higher-order model SF-36 is valid for American Indian older adults over a 6-year time frame. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Circulating ceramides and sphingomyelins and the risk of incident cardiovascular disease among people with diabetes: the strong heart study

BackgroundPlasma ceramides and sphingomyelins have been independently linked to diabetes risk, glucose and insulin levels, and the risk of several cardiovascular (CVD) outcomes. However, whether individual ceramide and sphingomyelin species contribute to CVD risk among people with type 2 diabetes is uncertain. Our goal was to evaluate associations of 4 ceramide and 4 sphingomyelin species with incident CVD in a longitudinal population-based study among American Indians with diabetes.MethodsThis analysis included participants with prevalent type 2 diabetes from two cohorts: a prospective cohort of 597 participants in the Strong Heart Family Study (116 incident CVD cases; mean age: 49 years; average length of follow-up: 14 years), and a nested case–control sample of 267 participants in the Strong Heart Study (78 cases of CVD and 189 controls; mean age: 61 years; average time until incident CVD in cases: 3.8 years). The average onset of diabetes was 7 years prior to sphingolipid measurement. Sphingolipid species were measured using liquid chromatography and mass spectrometry. Cox regression and logistic regression were used to assess associations of sphingolipid species with incident CVD; results were combined across cohorts using inverse-variance weighted meta-analysis.ResultsThere were 194 cases of incident CVD in the two cohorts. In meta-analysis of the 2 cohort results, higher plasma levels of Cer-16 (ceramide with acylated palmitic acid) were associated with higher CVD risk (HR per two-fold higher Cer-16: 1.85; 95% CI 1.05–3.25), and higher plasma levels of sphingomyelin species with a very long chain saturated fatty acid were associated with lower CVD risk (HR per two-fold higher SM-22: 0.48; 95% CI 0.26–0.87), although none of the associations met our pre-specified threshold for statistical significance of p = 0.006.ConclusionsWhile replication of the findings from the SHS in other populations is warranted, our findings add to a growing body of research suggesting that ceramides, in particular Cer-16, not only are associated with higher diabetes risk, but may also be associated with higher CVD risk after diabetes onset. We also find support for the hypothesis that sphingomyelins with a very long chain saturated fatty acid are associated with lower CVD risk among adults with type 2 diabetes.

Blood cadmium, lead, manganese, mercury, and selenium levels in American Indian populations: The Strong Heart Study

BackgroundMany American Indian (AI) communities are in areas affected by environmental contamination, such as toxic metals. However, studies assessing exposures in AI communities are limited. We measured blood metals in AI communities to assess historical exposure and identify participant characteristics associated with these levels in the Strong Heart Study (SHS) cohort. MethodArchived blood specimens collected from participants (n = 2014, all participants were 50 years of age and older) in Arizona, Oklahoma, and North and South Dakota during SHS Phase-III (1998–1999) were analyzed for cadmium, lead, manganese, mercury, and selenium using inductively coupled plasma triple quadrupole mass spectrometry. We conducted descriptive analyses for the entire cohort and stratified by selected subgroups, including selected demographics, health behaviors, income, waist circumference, and body mass index. Bivariate associations were conducted to examine associations between blood metal levels and selected socio-demographic and behavioral covariates. Finally, multivariate regression models were used to assess the best model fit that predicted blood metal levels. FindingsAll elements were detected in 100% of study participants, with the exception of mercury (detected in 73% of participants). The SHS population had higher levels of blood cadmium and manganese than the general U.S. population 50 years and older. The median blood mercury in the SHS cohort was at about 30% of the U.S. reference population, potentially due to low fish consumption. Participants in North Dakota and South Dakota had the highest blood cadmium, lead, manganese, and selenium, and the lowest total mercury levels, even after adjusting for covariates. In addition, each of the blood metals was associated with selected demographic, behavioral, income, and/or weight-related factors in multivariate models. These findings will help guide the tribes to develop education, outreach, and strategies to reduce harmful exposures and increase beneficial nutrient intake in these AI communities.

Lipidomic profiling in the Strong Heart Study identified American Indians at risk of chronic kidney disease

Dyslipidemia associates with and usually precedes the onset of chronic kidney disease (CKD), but a comprehensive assessment of molecular lipid species associated with risk of CKD is lacking. Here, we sought to identify fasting plasma lipids associated with risk of CKD among American Indians in the Strong Heart Family Study, a large-scale community-dwelling of individuals, followed by replication in Mexican Americans from the San Antonio Family Heart Study and Caucasians from the Australian Diabetes, Obesity and Lifestyle Study. We also performed repeated measurement analysis to examine the temporal relationship between the change in the lipidome and change in kidney function between baseline and follow-up of about five years apart. Network analysis was conducted to identify differential lipid classes associated with risk of CKD. In the discovery cohort, we found that higher baseline level of multiple lipid species, including glycerophospholipids, glycerolipids and sphingolipids, was significantly associated with increased risk of CKD, independent of age, sex, body mass index, diabetes and hypertension. Many lipid species were replicated in at least one external cohort at the individual lipid species and/or the class level. Longitudinal change in the plasma lipidome was significantly associated with change in the estimated glomerular filtration rate after adjusting for covariates, baseline lipids and the baseline rate. Network analysis identified distinct lipidomic signatures differentiating high from low-risk groups. Thus, our results demonstrated that disturbed lipid metabolism precedes the onset of CKD. These findings shed light on the mechanisms linking dyslipidemia to CKD and provide potential novel biomarkers for identifying individuals with early impaired kidney function at preclinical stages.

An epigenome-wide study of DNA methylation profiles and lung function among American Indians in the Strong Heart Study

BackgroundEpigenetic modifications, including DNA methylation (DNAm), are often related to environmental exposures, and are increasingly recognized as key processes in the pathogenesis of chronic lung disease. American Indian communities have a high burden of lung disease compared to the national average. The objective of this study was to investigate the association of DNAm and lung function in the Strong Heart Study (SHS). We conducted a cross-sectional study of American Indian adults, 45–74 years of age who participated in the SHS. DNAm was measured using the Illumina Infinium Human MethylationEPIC platform at baseline (1989–1991). Lung function was measured via spirometry, including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), at visit 2 (1993–1995). Airflow limitation was defined as FEV1 < 70% predicted and FEV1/FVC < 0.7, restriction was defined as FEV1/FVC > 0.7 and FVC < 80% predicted, and normal spirometry was defined as FEV1/FVC > 0.7, FEV1 > 70% predicted, FVC > 80% predicted. We used elastic-net models to select relevant CpGs for lung function and spirometry-defined lung disease. We also conducted bioinformatic analyses to evaluate the biological plausibility of the findings.ResultsAmong 1677 participants, 21.2% had spirometry-defined airflow limitation and 13.6% had spirometry-defined restrictive pattern lung function. Elastic-net models selected 1118 Differentially Methylated Positions (DMPs) as predictors of airflow limitation and 1385 for restrictive pattern lung function. A total of 12 DMPs overlapped between airflow limitation and restrictive pattern. EGFR, MAPK1 and PRPF8 genes were the most connected nodes in the protein–protein interaction network. Many of the DMPs targeted genes with biological roles related to lung function such as protein kinases.ConclusionWe found multiple differentially methylated CpG sites associated with chronic lung disease. These signals could contribute to better understand molecular mechanisms involved in lung disease, as assessed systemically, as well as to identify patterns that could be useful for diagnostic purposes. Further experimental and longitudinal studies are needed to assess whether DNA methylation has a causal role in lung disease.

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease.

Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis. A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic. Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

Association of protein function-altering variants with cardiometabolic traits: the strong heart study

Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), ~ 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p = 8 × 10–9) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic individuals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI (PHIL, chr6:79,650,711, p = 2.1 × 10–6; TRPM3, rs760461668, p = 5 × 10–8; SPTY2D1, rs756851199, p = 1.6 × 10–8; and TSPO, rs566547284, p = 2.4 × 10–6). PHIL encoded protein is involved in pancreatic β-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic β-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting diverse and high-risk populations to study variants absent in publicly available repositories.