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1.
Epidemiology ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34816807

RESUMO

BACKGROUND: Exposure to fine particulate matter (PM2.5) is an established risk factor for human mortality. However, previous US studies have been limited to select cities or regions or to population subsets (e.g., older adults). METHODS: Here, we demonstrate how to use the novel geostatistical method Bayesian Maximum Entropy to obtain estimates of PM2.5 concentrations in all contiguous US counties, 2000-2016. We then demonstrate how one could use these estimates in a traditional epidemiologic analysis examining the association between PM2.5 and rates of all-cause, cardiovascular, respiratory, and (as a negative control outcome) accidental mortality. RESULTS: We estimated that, for a 1 log(µg/m3) increase in PM2.5 concentration, the conditional all-cause mortality incidence rate ratio (IRR) was 1.029 (95% CI: 1.006, 1.053). This implies that the rate of all-cause mortality at 10 µg/m3 would be 1.020 times the rate at 5 µg/m3. IRRs were larger for cardiovascular mortality than for all-cause mortality in all gender and race-ethnicity groups. We observed larger IRRs for all-cause, non-accidental, and respiratory mortality in Black non-Hispanic Americans than White non-Hispanic Americans. However, our negative control analysis indicated the possibility for unmeasured confounding. CONCLUSIONS: We used a novel method that allowed us to estimate PM2.5 concentrations in all contiguous US counties and obtained estimates of the association between PM2.5 and mortality comparable to previous studies. Our analysis provides one example of how Bayesian Maximum Entropy could be used in epidemiologic analyses; future work could explore other ways to use this approach to inform important public health questions.

2.
Stroke ; : STROKEAHA121037388, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34743536

RESUMO

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

3.
J Alzheimers Dis ; 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34744078

RESUMO

BACKGROUND: Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain. OBJECTIVE: We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women. METHOD: Women (N = 2,142) from the Women's Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant's addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates. RESULT: Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n = 282;13%), relatively poor verbal episodic memory (poor memory; n = 216; 10%), average performance across all domains (average multi-domain; n = 974; 45%), superior memory (n = 381; 18%), and superior attention (n = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64µg/m3) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10-1.52) or superior attention (OR = 1.30; 95% CI = 1.10-1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17-1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67-0.97). CONCLUSION: Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains.

4.
J Alzheimers Dis ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34633318

RESUMO

BACKGROUND: Identification of factors that may help to preserve cognitive function in late life could elucidate mechanisms and facilitate interventions to improve the lives of millions of people. However, the large number of potential factors associated with cognitive function poses an analytical challenge. OBJECTIVE: We used data from the longitudinal Women's Health Initiative Memory Study (WHIMS) and machine learning to investigate 50 demographic, biomedical, behavioral, social, and psychological predictors of preserved cognitive function in later life. METHODS: Participants in WHIMS and two consecutive follow up studies who were at least 80 years old and had at least one cognitive assessment following their 80th birthday were classified as cognitively preserved. Preserved cognitive function was defined as having a score ≥39 on the most recent administration of the modified Telephone Interview for Cognitive Status (TICSm) and a mean score across all assessments ≥39. Cognitively impaired participants were those adjudicated by experts to have probable dementia or at least two adjudications of mild cognitive impairment within the 14 years of follow-up and a last TICSm score <  31. Random Forests was used to rank the predictors of preserved cognitive function. RESULTS: Discrimination between groups based on area under the curve was 0.80 (95%-CI-0.76-0.85). Women with preserved cognitive function were younger, better educated, and less forgetful, less depressed, and more optimistic at study enrollment. They also reported better physical function and less sleep disturbance, and had lower systolic blood pressure, hemoglobin, and blood glucose levels. CONCLUSION: The predictors of preserved cognitive function include demographic, psychological, physical, metabolic, and vascular factors suggesting a complex mix of potential contributors.

5.
Environ Health Perspect ; 129(9): 97007, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34523977

RESUMO

BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity and mortality. Short-term exposures to air pollution have been associated with AF triggering; less is known regarding associations between long-term air pollution exposures and AF incidence. OBJECTIVES: Our objective was to assess the association between long-term exposures to air pollution and distance to road on incidence of AF in a cohort of U.S. women. METHODS: We assessed the association of high resolution spatiotemporal model predictions of long-term exposures to particulate matter (PM10 and PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and distance to major roads with incidence of AF diagnosis, identified through Medicare linkage, among 83,117 women in the prospective Women's Health Initiative cohort, followed from enrollment in Medicare through December 2012, incidence of AF, or death. Using time-varying Cox proportional hazards models adjusted for age, race/ethnicity, study component, body mass index, physical activity, menopausal hormone therapy, smoking, diet quality, alcohol consumption, educational attainment, and neighborhood socioeconomic status, we estimated the relative risk of incident AF in association with each pollutant. RESULTS: A total of 16,348 incident AF cases were observed over 660,236 person-years of follow-up. Most exposure-response associations were nonlinear. NO2 was associated with risk of AF in multivariable adjusted models [Hazard Ratio (HR)=1.18; 95% confidence interval (CI): 1.13, 1.24, comparing the top to bottom quartile, p-for-trend=<0.0001]. Women living closer to roadways were at higher risk of AF (e.g., HR=1.07; 95% CI: 1.01, 1.13 for living within 50m of A3 roads, compared with ≥1,000 m, p-for-trend=0.02), but we did not observe adverse associations with exposures to PM10, PM2.5, or SO2. There were adverse associations with PM10 (top quartile HR=1.10; 95% CI: 1.05, 1.16, p-for-trend=<0.0001) and PM2.5 (top quartile HR=1.09; 95% CI: 1.03, 1.14, p-for-trend=0.002) in sensitivity models adjusting for census region. DISCUSSION: In this study of postmenopausal women, NO2 and distance to road were consistently associated with higher risk of AF. https://doi.org/10.1289/EHP7683.

6.
Environ Health Perspect ; 129(9): 97009, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34516296

RESUMO

BACKGROUND: Episodic memory decline varies by age and underlying neuropathology. Whether ambient air pollution contributes to the heterogeneity of episodic memory decline in older populations remains unclear. OBJECTIVES: We estimated associations between air pollution exposures and episodic memory decline according to pollutant, exposure time window, age, and latent class subgroups defined by episodic memory trajectories. METHODS: Participants were from the Women's Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes. Older women (n=2,056; 74-92 years of age) completed annual (2008-2018) episodic memory assessments using the telephone-based California Verbal Learning Test (CVLT). We estimated 3-y average fine particulate matter [PM with an aerodynamic diameter of ≤2.5µm (PM2.5)] and nitrogen dioxide (NO2) exposures at baseline and 10 y earlier (recent and remote exposures, respectively), using regionalized national universal kriging. Separate latent class mixed models were used to estimate associations between interquartile range increases in exposures and CVLT trajectories in women ≤80 and >80 years of age, adjusting for covariates. RESULTS: Two latent classes were identified for women ≤80 years of age (n=828), "slow-decliners" {slope=-0.12/y [95% confidence interval (CI): -0.23, -0.01] and "fast-decliners" [slope=-1.79/y (95% CI: -2.08, -1.50)]}. In the slow-decliner class, but not the fast-decliner class, PM2.5 exposures were associated with a greater decline in CVLT scores over time, with a stronger association for recent vs. remote exposures [-0.16/y (95% CI: -2.08, -0.03) per 2.88 µg/m3 and -0.11/y (95% CI: -0.22, 0.01) per 3.27 µg/m3, respectively]. Among women ≥80 years of age (n=1,128), the largest latent class comprised "steady-decliners" [slope=-1.35/y (95% CI: -1.53, -1.17)], whereas the second class, "cognitively resilient", had no decline in CVLT on average. PM2.5 was not associated with episodic memory decline in either class. A 6.25-ppb increase in recent NO2 was associated with nonsignificant acceleration of episodic memory decline in the ≤80-y-old fast-decliner class [-0.21/y (95% CI: -0.45, 0.04)], and in the >80-y-old cognitively resilient class [-0.10/y (95% CI: -0.24, 0.03)] and steady-decliner class [-0.11/y (95% CI: -0.27, 0.05)]. Associations with recent NO2 exposure in women >80 years of age were stronger and statistically significant when 267 women with incident probable dementia were excluded [e.g., -0.12/y (95% CI: -0.22, -0.02) for the cognitively resilient class]. In contrast with changes in CVLT over time, there were no associations between exposures and CVLT scores during follow-up in any subgroup. DISCUSSION: In a community-dwelling U.S. population of older women, associations between late-life exposure to ambient air pollution and episodic memory decline varied by age-related cognitive trajectories, exposure time windows, and pollutants. https://doi.org/10.1289/EHP7668.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34417803

RESUMO

BACKGROUND: Epigenetic age acceleration (AgeAccel), which indicates faster biological aging relative to chronological age, has been associated with lower cognitive function. However, the association of AgeAccel with mild cognitive impairment (MCI) or dementia is not well-understood. We examined associations of four AgeAccel measures with incident MCI and dementia. METHODS: This prospective analysis included 578 older women from the Women's Health Initiative Memory Study selected for a case-cohort study of coronary heart disease (CHD). Women were free of CHD and cognitive impairment at baseline. Associations of AgeAccel measures (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) with risks for incident adjudicated diagnoses of MCI and dementia overall and stratified by incident CHD status were evaluated. RESULTS: IEAA was not significantly associated with MCI (HR 1.23; 95% CI 0.99-1.53), dementia (HR 1.10; 95% CI 0.88-1.38), or cognitive impairment (HR 1.18; 95% CI 0.99-1.40). In stratified analysis by incident CHD status, there was a 39% (HR 1.39; 95% CI 1.07-1.81) significantly higher risk of MCI for every 5-year increase in IEAA among women who developed CHD during follow-up. Other AgeAccel measures were not significantly associated with MCI or dementia. CONCLUSION: IEAA was not significantly associated with cognitive impairment overall but was associated with impairment among women who developed CHD. Larger studies designed to examine associations of AgeAccel with cognitive impairment are needed, including exploration of whether associations are stronger in the setting of underlying vascular pathologies.

8.
J Am Coll Cardiol ; 78(1): 42-52, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34210413

RESUMO

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF. METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.


Assuntos
Hematopoiese Clonal/genética , Proteínas de Ligação a DNA/genética , Insuficiência Cardíaca , Janus Quinase 2/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Disfunção Ventricular Esquerda , Idoso , Correlação de Dados , Demografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Fatores de Risco , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/genética , Sequenciamento Completo do Exoma/métodos
9.
Circ Genom Precis Med ; 14(4): e003300, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34319147

RESUMO

BACKGROUND: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. METHODS: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). RESULTS: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. CONCLUSIONS: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

10.
Clin Epigenetics ; 13(1): 121, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078457

RESUMO

BACKGROUND: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. RESULTS: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (ß = - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (ß = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. CONCLUSION: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

11.
Genome Med ; 13(1): 74, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931109

RESUMO

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. RESULTS: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. CONCLUSIONS: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

12.
Aging Cell ; 20(6): e13366, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34050697

RESUMO

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p < 8.6 × 10-7 ) to 3.08 years (EEAA, p < 3.7 × 10-18 ). Mutations in most CHIP genes except DNA-damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p < 4.1 × 10-8 ) and coronary heart disease (CHD) (hazard ratio 3.24, p < 9.3 × 10-6 ) compared to those who were CHIP-/AgeAccelHG-. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG- were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions.

13.
Environ Res ; 198: 111211, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33895111

RESUMO

BACKGROUND: Short-duration exposure to ambient particulate matter (PM) air pollution is associated with cardiac autonomic dysfunction and prolonged ventricular repolarization. However, associations with sub-chronic exposures to coarser particulates are relatively poorly characterized as are molecular mechanisms underlying their potential relationships with cardiovascular disease. MATERIALS AND METHODS: We estimated associations between monthly mean concentrations of PM < 10 µm and 2.5-10 µm in diameter (PM10; PM2.5-10) with time-domain measures of heart rate variability (HRV) and QT interval duration (QT) among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities Study (nHRV = 82,107; nQT = 76,711). Then we examined mediation of the PM-HRV and PM-QT associations by DNA methylation (DNAm) at three Cytosine-phosphate-Guanine (CpG) sites (cg19004594, cg24102420, cg12124767) with known sensitivity to monthly mean PM concentrations in a subset of the participants (nHRV = 7,169; nQT = 6,895). After multiply imputing missing PM, electrocardiographic and covariable data, we estimated associations using attrition-weighted, linear, mixed, longitudinal models adjusting for sociodemographic, behavioral, meteorological, and clinical characteristics. We assessed mediation by estimating the proportions of PM-HRV and PM-QT associations mediated by DNAm. RESULTS: We found little evidence of PM-HRV association, PM-QT association, or mediation by DNAm. CONCLUSIONS: The findings suggest that among racially/ethnically and environmentally diverse U.S. populations, sub-chronic exposures to coarser particulates may not exert appreciable, epigenetically mediated effects on cardiac autonomic function or ventricular repolarization. Further investigation in better-powered studies is warranted, with additional focus on shorter duration exposures to finer particulates and non-electrocardiographic outcomes among relatively susceptible populations.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Aterosclerose , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Aterosclerose/induzido quimicamente , Aterosclerose/epidemiologia , Aterosclerose/genética , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Feminino , Humanos , Masculino , Material Particulado/análise , Material Particulado/toxicidade , Saúde da Mulher
14.
J Am Heart Assoc ; 10(5): e017172, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33631952

RESUMO

Background Psychosocial factors predict heart disease risk, but our understanding of underlying mechanisms is limited. We sought to evaluate the physiologic correlates of psychosocial factors by measuring their relationships with heart rate variability (HRV), a measure of autonomic health, in the ARIC (Atherosclerosis Risk in Communities) study. We hypothesize that increased psychosocial stress associates with lower HRV. Methods and Results We studied 9331 participants in ARIC with short-term HRV data at visits 2 and 4. The mean (SD) age was 54.4 (5.7) years, 55% were women, and 25% were Black. Psychosocial factors included: (1) vital exhaustion (VE), (2) anger proneness, a personality trait, and (3) perceived social support. Linear models adjusted for sociodemographic and cardiovascular risk factors. Low frequency HRV (ln ms2) was significantly lower in the highest versus lowest quartiles of VE (B=-0.14, 95% CI, -0.24 to -0.05). When comparing this effect to age (B=-0.04, 95% CI, -0.05 to -0.04), the difference was equivalent to 3.8 years of accelerated aging. Perceived social support associated with lower time-domain HRV. High VE (versus low VE) also associated with greater decreases in low frequency over time, and both anger and VE associated with greater increases in resting heart rate over time. Survival analyses were performed with Cox models, and no evidence was found that HRV explains the excess risk found with high VE and low perceived social support. Conclusions Vital exhaustion, and to a lesser extent anger and social support, were associated with worse autonomic function and greater adverse changes over time.


Assuntos
Aterosclerose/psicologia , Sistema Nervoso Autônomo/fisiopatologia , Ritmo Circadiano/fisiologia , Frequência Cardíaca/fisiologia , Descanso/fisiologia , Estresse Psicológico/fisiopatologia , Aterosclerose/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
15.
Clin Epigenetics ; 13(1): 42, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632308

RESUMO

BACKGROUND: Cardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the "Life's Simple 7" ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age. METHODS AND RESULTS: We performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women's Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score. We examined the association between CVH score and EAA using linear regression modeling adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, 50% were white and mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (~ 6 months younger age per 1 point higher CVH score, p < 0.0001), and lower intrinsic EAA (3 months younger age per 1 point higher CVH score, p < 0.028). CONCLUSIONS: These cross-sectional observations suggest a possible mechanism by which ideal CVH is associated with greater longevity.

16.
Ann Noninvasive Electrocardiol ; 26(3): e12829, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33591619

RESUMO

BACKGROUND: Electrocardiographic left ventricular hypertrophy (ECG-LVH) represents preclinical cardiovascular disease and predicts cardiovascular disease morbidity and mortality. While the newly developed Peguero-Lo Presti ECG-LVH criteria have greater sensitivity for LVH than the Cornell voltage and Sokolow-Lyon criteria, its short-term repeatability is unknown. Therefore, we characterized the short-term repeatability of Peguero-Lo Presti ECG-LVH criteria and evaluate its agreement with Cornell voltage and Sokolow-Lyon ECG-LVH criteria. METHODS: Participants underwent two resting, standard, 12-lead ECGs at each of two visits one week apart (n = 63). We defined a Peguero-Lo Presti index as a sum of the deepest S wave amplitude in any single lead and lead V4 (i.e., SD  + SV4 ) and defined Peguero-Lo Presti LVH index as ≥ 2,300 µV among women and ≥ 2,800 µV among men. We estimated repeatability as an intraclass correlation coefficient (ICC), agreement as a prevalence-adjusted bias-adjusted kappa coefficient (κ), and precision using 95% confidence intervals (CIs). RESULTS: The Peguero-Lo Presti index was repeatable: ICC (95% CI) = 0.94 (0.91-0.97). Within-visit agreement of Peguero-Lo Presti LVH was high at the first and second visits: κ (95% CI) = 0.97 (0.91-1.00) and 1.00 (1.00-1.00). Between-visit agreement of the first and second measurements at each visit was comparable: κ (95% CI) = 0.90 (0.80-1.00) and 0.93 (0.85-1.00). Agreement of Peguero-Lo Presti and Cornell or Sokolow-Lyon LVH on any one of the four ECGs was slightly lower: κ (95% CI) = 0.71 (0.54-0.89). CONCLUSION: The Peguero-Lo Presti index and LVH have excellent repeatability and agreement, which support their use in clinical and epidemiological studies.

17.
Environ Pollut ; 271: 116282, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33385889

RESUMO

The interrelationships among long-term ambient air pollution exposure, emotional distress and cognitive decline in older adulthood remain unclear. Long-term exposure may impact cognitive performance and subsequently impact emotional health. Conversely, exposure may initially be associated with emotional distress followed by declines in cognitive performance. Here we tested the inter-relationship between global cognitive ability, emotional distress, and exposure to PM2.5 (particulate matter with aerodynamic diameter <2.5 µm) and NO2 (nitrogen dioxide) in 6118 older women (aged 70.6 ± 3.8 years) from the Women's Health Initiative Memory Study. Annual exposure to PM2.5 (interquartile range [IQR] = 3.37 µg/m3) and NO2 (IQR = 9.00 ppb) was estimated at the participant's residence using regionalized national universal kriging models and averaged over the 3-year period before the baseline assessment. Using structural equation mediation models, a latent factor capturing emotional distress was constructed using item-level data from the 6-item Center for Epidemiological Studies Depression Scale and the Short Form Health Survey Emotional Well-Being scale at baseline and one-year follow-up. Trajectories of global cognitive performance, assessed by the Modified-Mini Mental State Examination (3MS) annually up to 12 years, were estimated. All effects reported were adjusted for important confounders. Increases in PM2.5 (ß = -0.144 per IQR; 95% CI = -0.261; -0.028) and NO2 (ß = -0.157 per IQR; 95% CI = -0.291; -0.022) were associated with lower initial 3MS performance. Lower 3MS performance was associated with increased emotional distress (ß = -0.008; 95% CI = -0.015; -0.002) over the subsequent year. Significant indirect effect of both exposures on increases in emotional distress mediated by exposure effects on worse global cognitive performance were present. No statistically significant indirect associations were found between exposures and 3MS trajectories putatively mediated by baseline emotional distress. Our study findings support cognitive aging processes as a mediator of the association between PM2.5 and NO2 exposure and emotional distress in later-life.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Adulto , Idoso , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Cognição , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Feminino , Humanos , Dióxido de Nitrogênio/análise , Material Particulado/análise , Angústia Psicológica
18.
Circulation ; 143(5): 410-423, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33161765

RESUMO

BACKGROUND: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. METHODS: We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease. RESULTS: The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; P=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; P=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; P=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; P<0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; P=0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; P=0.005). CONCLUSIONS: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.

19.
J Am Geriatr Soc ; 69(2): 474-484, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33205418

RESUMO

BACKGROUND/OBJECTIVES: Exposure to air pollution may contribute to both increasing depressive symptoms and decreasing episodic memory in older adulthood, but few studies have examined this hypothesis in a longitudinal context. Accordingly, we examined the association between air pollution and changes in depressive symptoms (DS) and episodic memory (EM) and their interrelationship in oldest-old (aged 80 and older) women. DESIGN: Prospective cohort data from the Women's Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes. SETTING: Geographically diverse community-dwelling population. PARTICIPANTS: A total of 1,583 dementia-free women aged 80 and older. MEASUREMENTS: Women completed up to six annual memory assessments (latent composite of East Boston Memory Test and Telephone Interview for Cognitive Status) and the 15-item Geriatric Depression Scale (GDS-15). We estimated 3-year average exposures to regional particulate matter with aerodynamic diameter below 2.5 µm (PM2.5 ) (interquartile range [IQR] = 3.35 µg/m3 ) and gaseous nitrogen dioxide (NO2 ) (IQR = 9.55 ppb) at baseline and during a remote period 10 years earlier, using regionalized national universal kriging. RESULTS: Latent change structural equation models examined whether residing in areas with higher pollutant levels was associated with annual changes in standardized EM and DS while adjusting for potential confounders. Remote NO2 (ß = .287 per IQR; P = .002) and PM2.5 (ß = .170 per IQR; P = .019) exposure was significantly associated with larger increases in standardized DS, although the magnitude of the difference, less than 1 point on the GDS-15, is of questionable clinical significance. Higher DS were associated with accelerated EM declines (ß = -.372; P = .001), with a significant indirect effect of remote NO2 and PM2.5 exposure on EM declines mediated by DS. There were no other significant indirect exposure effects. CONCLUSION: These findings in oldest-old women point to potential adverse effects of late-life exposure to air pollution on subsequent interplay between DS and EM, highlighting air pollution as an environmental health risk factor for older women.


Assuntos
Poluição do Ar , Depressão , Exposição Ambiental , Transtornos da Memória , Memória Episódica , Idoso de 80 Anos ou mais , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Cognição/fisiologia , Depressão/diagnóstico , Depressão/epidemiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/prevenção & controle , Feminino , Avaliação Geriátrica/métodos , Humanos , Vida Independente/psicologia , Vida Independente/estatística & dados numéricos , Transtornos da Memória/diagnóstico , Transtornos da Memória/epidemiologia , Entrevista Psiquiátrica Padronizada , Material Particulado/análise , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
20.
Int J Epidemiol ; 50(2): 675-684, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33354722

RESUMO

BACKGROUND: Diet quality is a risk factor for chronic disease and mortality. Differential DNA methylation across the epigenome has been associated with chronic disease risk. Whether diet quality is associated with differential methylation is unknown. This study assessed whether diet quality was associated with differential DNA methylation measured across 445 548 loci in the Women's Health Initiative (WHI) and the TwinsUK cohort. DESIGN: The discovery cohort consisted of 4355 women from the WHI. The replication cohort consisted of 571 mono- and dizygotic twins from the TwinsUK cohort. DNA methylation was measured in whole blood using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). A meta-analysis, stratified by study cohort, was performed using generalized linear models that regressed methylation on AHEI-2010, adjusting for cell composition, chip number and location, study characteristics, principal components of genetic relatedness, age, smoking status, race/ethnicity and body mass index (BMI). Statistical significance was defined as a false discovery rate < 0.05. Significant sites were tested for replication in the TwinsUK cohort, with significant replication defined by P < 0.05 and a consistent direction. RESULTS: Diet quality was significantly associated with differential DNA methylation at 428 cytosine-phosphate-guanine (CpG) sites in the discovery cohort. A total of 24 CpG sites were consistent with replication in the TwinsUK cohort, more than would be expected by chance (P = 2.7x10-4), with one site replicated in both the blood and adipose tissue (cg16379999 located in the body of SEL1L). CONCLUSIONS: Diet quality was associated with methylation at 24 CpG sites, several of which have been associated with adiposity, inflammation and dysglycaemia. These findings may provide insight into pathways through which diet influences chronic disease.


Assuntos
Epigênese Genética , Epigenoma , Ilhas de CpG/genética , Metilação de DNA , Dieta , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteínas , Saúde da Mulher
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