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1.
JMIR Diabetes ; 7(1): e29107, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34994694

RESUMO

BACKGROUND: Daily routines (eg, physical activity and sleep patterns) are important for diabetes self-management. Traditional research methods are not optimal for documenting long-term daily routine patterns in participants with glycemic conditions. Mobile health offers an effective approach for collecting users' long-term daily activities and analyzing their daily routine patterns in relation to diabetes status. OBJECTIVE: This study aims to understand how routines function in diabetes self-management. We evaluate the associations of daily routine variables derived from a smartwatch with diabetes status in the electronic Framingham Heart Study (eFHS). METHODS: The eFHS enrolled the Framingham Heart Study participants at health examination 3 between 2016 and 2019. At baseline, diabetes was defined as fasting blood glucose level ≥126 mg/dL or as a self-report of taking a glucose-lowering medication; prediabetes was defined as fasting blood glucose level of 100-125 mg/dL. Using smartwatch data, we calculated the average daily step counts and estimated the wake-up times and bedtimes for the eFHS participants on a given day. We compared the average daily step counts and the intraindividual variability of the wake-up times and bedtimes of the participants with diabetes and prediabetes with those of the referents who were neither diabetic nor prediabetic, adjusting for age, sex, and race or ethnicity. RESULTS: We included 796 participants (494/796, 62.1% women; mean age 52.8, SD 8.7 years) who wore a smartwatch for at least 10 hours/day and remained in the study for at least 30 days after enrollment. On average, participants with diabetes (41/796, 5.2%) took 1611 fewer daily steps (95% CI 863-2360; P<.001) and had 12 more minutes (95% CI 6-18; P<.001) in the variation of their estimated wake-up times, 6 more minutes (95% CI 2-9; P=.005) in the variation of their estimated bedtimes compared with the referents (546/796, 68.6%) without diabetes or prediabetes. Participants with prediabetes (209/796, 26.2%) also walked fewer daily steps (P=.04) and had a larger variation in their estimated wake-up times (P=.04) compared with the referents. CONCLUSIONS: On average, participants with diabetes at baseline walked significantly fewer daily steps and had larger variations in their wake-up times and bedtimes than the referent group. These findings suggest that modifying the routines of participants with poor glycemic health may be an important approach to the self-management of diabetes. Future studies should be designed to improve the remote monitoring and self-management of diabetes.

2.
Nat Genet ; 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34837083

RESUMO

Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, identifying 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests and human aortic single nucleus RNA sequencing prioritized genes including SVIL, which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (hazard ratio = 1.43 per s.d., confidence interval 1.32-1.54, P = 3.3 × 10-20). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images.

3.
Circulation ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34587750

RESUMO

Background: The most prominent risk factor for atrial fibrillation (AF) is chronological age, however underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge, a phenomenon termed epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. Methods: Measures for 4 epigenetic clocks (Horvath, Hannum, DNAm PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 levels (DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analysis. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. Results: Among 5,600 individuals (mean age: 65.5 years; 60.1% female; 50.7% black), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. Following multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR]: 1.19; 95% confidence intervals [CI]: 1.09-1.31; p<0.01) and 15% (adjusted HR: 1.15; 95% CI: 1.05-1.25; p<0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. Conclusions: Our study identified adjusted associations between EAA measures and incident AF, suggesting biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

4.
ESC Heart Fail ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480422

RESUMO

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10-8 under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

5.
J Alzheimers Dis ; 83(2): 581-589, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334396

RESUMO

BACKGROUND: Widespread dementia detection could increase clinical trial candidates and enable appropriate interventions. Since the Clock Drawing Test (CDT) can be potentially used for diagnosing dementia-related disorders, it can be leveraged to develop a computer-aided screening tool. OBJECTIVE: To evaluate if a machine learning model that uses images from the CDT can predict mild cognitive impairment or dementia. METHODS: Images of an analog clock drawn by 3,263 cognitively intact and 160 impaired subjects were collected during in-person dementia evaluations by the Framingham Heart Study. We processed the CDT images, participant's age, and education level using a deep learning algorithm to predict dementia status. RESULTS: When only the CDT images were used, the deep learning model predicted dementia status with an area under the receiver operating characteristic curve (AUC) of 81.3% ± 4.3%. A composite logistic regression model using age, level of education, and the predictions from the CDT-only model, yielded an average AUC and average F1 score of 91.9% ±1.1% and 94.6% ±0.4%, respectively. CONCLUSION: Our modeling framework establishes a proof-of-principle that deep learning can be applied on images derived from the CDT to predict dementia status. When fully validated, this approach can offer a cost-effective and easily deployable mechanism for detecting cognitive impairment.

6.
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.

7.
J Med Internet Res ; 23(6): e25591, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34185019

RESUMO

BACKGROUND: When studied in community-based samples, the association of physical activity with blood pressure (BP) remains controversial and is perhaps dependent on the intensity of physical activity. Prior studies have not explored the association of smartwatch-measured physical activity with home BP. OBJECTIVE: We aimed to study the association of habitual physical activity with home BP. METHODS: Consenting electronic Framingham Heart Study (eFHS) participants were provided with a study smartwatch (Apple Watch Series 0) and Bluetooth-enabled home BP cuff. Participants were instructed to wear the watch daily and transmit BP values weekly. We measured habitual physical activity as the average daily step count determined by the smartwatch. We estimated the cross-sectional association between physical activity and average home BP using linear mixed effects models adjusting for age, sex, wear time, antihypertensive drug use, and familial structure. RESULTS: We studied 660 eFHS participants (mean age 53 years, SD 9 years; 387 [58.6%] women; 602 [91.2%] White) who wore the smartwatch 5 or more hours per day for 30 or more days and transmitted three or more BP readings. The mean daily step count was 7595 (SD 2718). The mean home systolic and diastolic BP (mmHg) were 122 (SD 12) and 76 (SD 8). Every 1000 increase in the step count was associated with a 0.49 mmHg lower home systolic BP (P=.004) and 0.36 mmHg lower home diastolic BP (P=.003). The association, however, was attenuated and became statistically nonsignificant with further adjustment for BMI. CONCLUSIONS: In this community-based sample of adults, higher daily habitual physical activity measured by a smartwatch was associated with a moderate, but statistically significant, reduction in home BP. Differences in BMI among study participants accounted for the majority of the observed association.


Assuntos
Exercício Físico , Hipertensão , Adulto , Pressão Sanguínea , Estudos Transversais , Eletrônica , Feminino , Humanos , Hipertensão/epidemiologia , Estudos Longitudinais , Pessoa de Meia-Idade
8.
J Med Internet Res ; 23(6): e27407, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34100766

RESUMO

BACKGROUND: The Clock Drawing Test (CDT) has been widely used in clinic for cognitive assessment. Recently, a digital Clock Drawing Text (dCDT) that is able to capture the entire sequence of clock drawing behaviors was introduced. While a variety of domain-specific features can be derived from the dCDT, it has not yet been evaluated in a large community-based population whether the features derived from the dCDT correlate with cognitive function. OBJECTIVE: We aimed to investigate the association between dCDT features and cognitive performance across multiple domains. METHODS: Participants from the Framingham Heart Study, a large community-based cohort with longitudinal cognitive surveillance, who did not have dementia were included. Participants were administered both the dCDT and a standard protocol of neuropsychological tests that measured a wide range of cognitive functions. A total of 105 features were derived from the dCDT, and their associations with 18 neuropsychological tests were assessed with linear regression models adjusted for age and sex. Associations between a composite score from dCDT features were also assessed for associations with each neuropsychological test and cognitive status (clinically diagnosed mild cognitive impairment compared to normal cognition). RESULTS: The study included 2062 participants (age: mean 62, SD 13 years, 51.6% women), among whom 36 were diagnosed with mild cognitive impairment. Each neuropsychological test was associated with an average of 50 dCDT features. The composite scores derived from dCDT features were significantly associated with both neuropsychological tests and mild cognitive impairment. CONCLUSIONS: The dCDT can potentially be used as a tool for cognitive assessment in large community-based populations.


Assuntos
Disfunção Cognitiva , Cognição , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos
9.
Liver Int ; 41(8): 1901-1908, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33969607

RESUMO

BACKGROUND: Fresh frozen plasma (FFP) transfusion is often used in the management of acute variceal haemorrhage (AVH) despite best practice advice suggesting otherwise. OBJECTIVE: We investigated if FFP transfusion affects clinical outcomes in AVH. DESIGN, SETTING AND PATIENTS: We performed a retrospective cohort study of 244 consecutive, eligible patients admitted to five tertiary health care centres between 2013 and 2018 with AVH. MAIN OUTCOME MEASUREMENTS: Multivariable regression analyses were used to study the association of FFP transfusion with mortality at 42 days (primary outcome) and failure to control bleeding at 5 days and length of stay (secondary outcomes). RESULTS: Patients who received FFP transfusion (n = 100) had higher mean Model for End Stage Liver Disease (MELD) score and more severe variceal bleeding than those who did not received FFP transfusion (n = 144). Multivariable analysis showed that FFP transfusion was associated with increased odds of mortality at 42 days (odds ratio [OR] 9.41, 95% confidence interval [CI] 3.71-23.90). FFP transfusion was also associated with failure to control bleeding at 5 days (OR 3.87, 95% CI 1.28-11.70) and length of stay >7 days (adjusted OR 1.88, 95% CI 1.03-3.42). The independent association of FFP transfusion with mortality at 42 days persisted when the cohort was restricted to high-risk patients and in patients without active bleeding. LIMITATIONS AND CONCLUSIONS: Fresh frozen plasma transfusion in AVH is independently associated with poor clinical outcomes. As this an observational study, there may be residual bias due to confounding; however, we demonstrate no benefit and potential harm with FFP transfusions in AVH.


Assuntos
Doença Hepática Terminal , Varizes Esofágicas e Gástricas , Transfusão de Componentes Sanguíneos , Estudos de Coortes , Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/terapia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Humanos , Plasma , Estudos Retrospectivos , Índice de Gravidade de Doença
10.
Heart Rhythm ; 18(9): 1500-1507, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33989782

RESUMO

BACKGROUND: P-wave signal-averaged electrocardiography (P-SAECG) quantifies atrial electrical activity. P-SAECG measures and their clinical correlates and heritability have had limited characterization in community-based cohorts. OBJECTIVE: The purpose of this study was to (1) establish reference values; (2) identify clinical risk factors associated with P-SAECG; and (3) estimate genetic heritability for P-SAECG traits. METHODS: We performed P-SAECG in 2 generations of Framingham Heart Study participants. We performed backward elimination regression models to assess associations of clinical factors with each SAECG trait (P-wave [PW] duration, root mean square voltage in terminal 40 ms [RMS40], terminal 30 ms RMS30, terminal 20 ms RMS20, RMS PW, and PW integral). We estimated the adjusted genetic heritability of P-SAECG measures using the Sequential Oligogenic Linkage Analysis Routines (SOLAR) program. RESULTS: We included 4307 participants (age 55 ± 14 years; 56% female). The reference values were derived from 1752 participants without cardiovascular risk factors. Median (2.5th percentile; 97.5th percentile) total PW duration was 118 ms (93; 146) in women and 128 ms (104; 158) in men in the reference sample, and 121 ms (94; 151) in women and 129 ms (103; 159) in the entire study cohort (broad sample). In the broad sample, after adjusting for age and sex, total PW duration was positively associated with height, weight, prevalent heart failure, history of atrial fibrillation (AF), and atrioventricular node blockers, and negatively associated with smoking, waist circumference, heart rate, and diabetes. The estimated heritability of P-SAECG traits was moderate, ranging from 11.9% for RMS30 to 24.9% for PW integral. CONCLUSION: P-SAECG traits are associated with multiple AF-related risk factors and are moderately heritable.

12.
Cardiovasc Res ; 117(7): 1632-1644, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-33751041

RESUMO

Atrial fibrillation (AF) is a common cardiac arrhythmia leading to many adverse outcomes and increased mortality. Yet the molecular mechanisms underlying AF remain largely unknown. Recent advances in high-throughput technologies make large-scale molecular profiling possible. In the past decade, multiomics studies of AF have identified a number of potential biomarkers of AF. In this review, we focus on the studies of multiomics profiles with AF risk. We summarize recent advances in the discovery of novel biomarkers for AF through multiomics studies. We also discuss limitations and future directions in risk assessment and discovery of therapeutic targets for AF.

13.
J Med Internet Res ; 23(1): e24773, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33470944

RESUMO

BACKGROUND: eCohort studies offer an efficient approach for data collection. However, eCohort studies are challenged by volunteer bias and low adherence. We designed an eCohort embedded in the Framingham Heart Study (eFHS) to address these challenges and to compare the digital data to traditional data collection. OBJECTIVE: The aim of this study was to evaluate adherence of the eFHS app-based surveys deployed at baseline (time of enrollment in the eCohort) and every 3 months up to 1 year, and to compare baseline digital surveys with surveys collected at the research center. METHODS: We defined adherence rates as the proportion of participants who completed at least one survey at a given 3-month period and computed adherence rates for each 3-month period. To evaluate agreement, we compared several baseline measures obtained in the eFHS app survey to those obtained at the in-person research center exam using the concordance correlation coefficient (CCC). RESULTS: Among the 1948 eFHS participants (mean age 53, SD 9 years; 57% women), we found high adherence to baseline surveys (89%) and a decrease in adherence over time (58% at 3 months, 52% at 6 months, 41% at 9 months, and 40% at 12 months). eFHS participants who returned surveys were more likely to be women (adjusted odds ratio [aOR] 1.58, 95% CI 1.18-2.11) and less likely to be smokers (aOR 0.53, 95% CI 0.32-0.90). Compared to in-person exam data, we observed moderate agreement for baseline app-based surveys of the Physical Activity Index (mean difference 2.27, CCC=0.56), and high agreement for average drinks per week (mean difference 0.54, CCC=0.82) and depressive symptoms scores (mean difference 0.03, CCC=0.77). CONCLUSIONS: We observed that eFHS participants had a high survey return at baseline and each 3-month survey period over the 12 months of follow up. We observed moderate to high agreement between digital and research center measures for several types of surveys, including physical activity, depressive symptoms, and alcohol use. Thus, this digital data collection mechanism is a promising tool to collect data related to cardiovascular disease and its risk factors.


Assuntos
Aplicativos Móveis/tendências , Inquéritos e Questionários , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
14.
J Am Heart Assoc ; 10(1): e018020, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33372532

RESUMO

Background Proteomic biomarkers related to cardiovascular disease risk factors may offer insights into the pathogenesis of cardiovascular disease. We investigated whether modifiable lifestyle risk factors for cardiovascular disease are associated with distinctive proteomic signatures. Methods and Results We analyzed 1305 circulating plasma proteomic biomarkers (assayed using the SomaLogic platform) in 897 FHS (Framingham Heart Study) Generation 3 participants (mean age 46±8 years; 56% women; discovery sample) and 1121 FOS (Framingham Offspring Study) participants (mean age 52 years; 54% women; validation sample). Participants were free of hypertension, diabetes mellitus, and clinical cardiovascular disease. We used linear mixed effects models (adjusting for age, sex, body mass index, and family structure) to relate levels of each inverse-log transformed protein to 3 lifestyle factors (ie, smoking, alcohol consumption, and physical activity). A Bonferroni-adjusted P value indicated statistical significance (based on number of proteins and traits tested, P<4.2×10-6 in the discovery sample; P<6.85×10-4 in the validation sample). We observed statistically significant associations of 60 proteins with smoking (37/40 top proteins validated in FOS), 30 proteins with alcohol consumption (23/30 proteins validated), and 5 proteins with physical activity (2/3 proteins associated with the physical activity index validated). We assessed the associations of protein concentrations with previously identified genetic variants (protein quantitative trait loci) linked to lifestyle-related disease traits in the genome-wide-association study catalogue. The protein quantitative trait loci were associated with coronary artery disease, inflammation, and age-related mortality. Conclusions Our cross-sectional study from a community-based sample elucidated distinctive sets of proteins associated with 3 key lifestyle factors.


Assuntos
Consumo de Bebidas Alcoólicas , Doenças Cardiovasculares , Exercício Físico/fisiologia , Fatores de Risco de Doenças Cardíacas , Estilo de Vida , Proteômica/métodos , Fumar , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Modificador do Efeito Epidemiológico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mortalidade , Locos de Características Quantitativas , Fumar/epidemiologia , Fumar/metabolismo , Estados Unidos/epidemiologia
15.
Circ Genom Precis Med ; 13(6): e003085, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33155827

RESUMO

BACKGROUND: Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes. METHODS: We generated a model of the LA noncoding genome by profiling 7 histone post-translational modifications (active: H3K4me3, H3K4me2, H3K4me1, H3K27ac, H3K36me3; repressive: H3K27me3, H3K9me3), CTCF binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions (P<0.01), applied a Markov model to classify regulatory elements, and annotated this model with matched gene expression data. We intersected chromatin states with expression quantitative trait locus, DNA methylation, and HiC chromatin interaction data from LA and left ventricle. Finally, we integrated genome-wide association data for AF and electrocardiographic traits to link disease-related variants to genes. RESULTS: Our model identified 21 epigenetic states, encompassing regulatory motifs, such as promoters, enhancers, and repressed regions. Genes were regulated by proximal chromatin states; repressive states were associated with a significant reduction in gene expression (P<2×10-16). Chromatin states were differentially methylated, promoters were less methylated than repressed regions (P<2×10-16). We identified over 15 000 LA-specific enhancers, defined by homeobox family motifs, and annotated several cardiovascular disease susceptibility loci. Intersecting AF and PR genome-wide association studies loci with long-range chromatin conformation data identified a gene interaction network dominated by NKX2-5, TBX3, ZFHX3, and SYNPO2L. CONCLUSIONS: Profiling the noncoding genome provides new insights into the gene expression and chromatin regulation in human LA tissue. These findings enabled identification of a gene network underlying AF; our experimental and analytic approach can be extended to identify molecular mechanisms for other cardiac diseases and traits.


Assuntos
Fibrilação Atrial/genética , Epigênese Genética , Redes Reguladoras de Genes , Átrios do Coração/patologia , Motivos de Aminoácidos/genética , Sequência de Bases , Cromatina/metabolismo , Metilação de DNA/genética , Elementos Facilitadores Genéticos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Doadores de Tecidos , Transcrição Genética
16.
Nat Commun ; 11(1): 4796, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963231

RESUMO

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/ß-catenin, TGF-ß and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.


Assuntos
Envelhecimento/genética , Encéfalo , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Doenças Neurodegenerativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estruturas Cromossômicas , Cognição , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
17.
PLoS One ; 15(8): e0236960, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813736

RESUMO

BACKGROUND: Circulating microRNAs may reflect or influence pathological cardiac remodeling and contribute to atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to identify candidate plasma microRNAs that are associated with echocardiographic phenotypes of atrial remodeling, and incident and prevalent AF in a community-based cohort. METHODS: We analyzed left atrial function index (LAFI) of 1788 Framingham Offspring 8 participants. We quantified expression of 339 plasma microRNAs. We examined associations between microRNA levels with LAFI and prevalent and incident AF. We constructed pathway analysis of microRNAs' predicted gene targets to identify molecular processes involved in adverse atrial remodeling in AF. RESULTS: The mean age of the participants was 66 ± 9 years, and 54% were women. Five percent of participants had prevalent AF at the initial examination and 9% (n = 157) developed AF over a median 8.6 years of follow-up (IQR 8.1-9.2 years). Plasma microRNAs were associated with LAFI (N = 73, p<0.0001). Six of these plasma microRNAs were significantly associated with incident AF, including 4 also associated with prevalent AF (microRNAs 106b, 26a-5p, 484, 20a-5p). These microRNAs are predicted to regulate genes involved in cardiac hypertrophy, inflammation, and myocardial fibrosis. CONCLUSIONS: Circulating microRNAs 106b, 26a-5p, 484, 20a-5p are associated with atrial remodeling and AF.


Assuntos
Fibrilação Atrial/sangue , Fibrilação Atrial/genética , Remodelamento Atrial/genética , MicroRNAs/sangue , MicroRNAs/genética , Idoso , Fibrilação Atrial/diagnóstico por imagem , Função do Átrio Esquerdo/genética , Função do Átrio Esquerdo/fisiologia , Remodelamento Atrial/fisiologia , Biomarcadores/sangue , Estudos de Coortes , Ecocardiografia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
18.
Circ Genom Precis Med ; 13(5): 387-395, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32822252

RESUMO

BACKGROUND: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. METHODS: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. RESULTS: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. CONCLUSIONS: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.


Assuntos
Fibrilação Atrial/genética , Eletrocardiografia , Fibrilação Atrial/etnologia , Fibrilação Atrial/fisiopatologia , Miosinas Cardíacas/genética , Conectina/genética , Variação Genética , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Cadeias Pesadas de Miosina/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Locos de Características Quantitativas , Fatores de Transcrição/genética
19.
Neuromolecular Med ; 22(4): 534-541, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32862331

RESUMO

Alzheimer's disease (AD) is a multifactorial disease that affects more than 5 million Americans. Multiple pathways might be involved in the AD pathogenesis. The implication of lipid genetic susceptibility on brain gene expression is yet to be investigated. The current study included 192 brain samples from AD patients who were enrolled in the ROSMAP study. The samples were genotyped and imputed to the HRC Reference Panel. Lipid polygenetic risk score was constructed from the weighted sum of genetic variants associated with low-density lipoprotein cholesterol (LDL-C). The gene expression was profiled by RNA sequencing, and the  association of gene expression with lipid polygenetic risk scores was tested by linear regression models adjusted for age, sex and APOE e4 alleles. Three genes were found to associate with lipid polygenetic risk scores, including HMCN2 (P = 3.6 × 10-7), PDLIM5 (P = 1.2 × 10-6), and FHL5 (P = 2.0 × 10-6). Network analysis revealed multiple related pathways, including dopaminergic synapse (P = 4.5 × 10-5), circadian entrainment (P = 1.1 × 10-4), and cholinergic synapse (P = 2.3 × 10-4). Our study underscores the importance of lipid regulation and metabolism to AD heterogeneity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , LDL-Colesterol/metabolismo , Proteínas com Domínio LIM/genética , Fatores de Transcrição/genética , Transcriptoma , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Apolipoproteína E4/genética , Escolaridade , Feminino , Redes Reguladoras de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Anotação de Sequência Molecular , Estudos Prospectivos , Risco
20.
Circ Res ; 127(10): 1253-1260, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-32842915

RESUMO

RATIONALE: A sedentary lifestyle is associated with increased risk for cardiovascular disease (CVD). Smartwatches enable accurate daily activity monitoring for physical activity measurement and intervention. Few studies, however, have examined physical activity measures from smartwatches in relation to traditional risk factors associated with future risk for CVD. OBJECTIVE: To investigate the association of habitual physical activity measured by smartwatch with predicted CVD risk in adults. METHODS AND RESULTS: We enrolled consenting FHS (Framingham Heart Study) participants in an ongoing eFHS (electronic Framingham Heart Study) at the time of their FHS research center examination. We provided participants with a smartwatch (Apple Watch Series 0) and instructed them to wear it daily, which measured their habitual physical activity as the average daily step count. We estimated the 10-year predicted risk of CVD using the American College of Cardiology/American Heart Association 2013 pooled cohort risk equation. We estimated the association between physical activity and predicted risk of CVD using linear mixed effects models adjusting for age, sex, wear time, and familial structure. Our study included 903 eFHS participants (mean age 53±9 years, 61% women, 9% non-White) who wore the smartwatch ≥5 hours per day for ≥30 days. Median daily step count was similar among men (7202 with interquartile range 3619) and women (7260 with interquartile range 3068; P=0.52). Average 10-year predicted CVD risk was 4.5% (interquartile range, 6.1%) for men and 1.2% (interquartile range, 2.2%) for women (P=1.3×10-26). Every 1000 steps higher habitual physical activity was associated with 0.18% lower predicted CVD risk (P=3.2×10-4). The association was attenuated but remained significant after further adjustment for body mass index (P=0.01). CONCLUSIONS: In this community-based sample of adults, higher daily physical activity measured by a study smartwatch was associated with lower predicted risk of CVD. Future research should examine the longitudinal association of prospectively measured daily activity and incident CVD.


Assuntos
Doenças Cardiovasculares/epidemiologia , Exercício Físico , Fatores Etários , Idoso , Computadores de Mão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Comportamento Sedentário , Fatores Sexuais
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