Epigenetic Age and the Risk of Incident Atrial Fibrillation

Circulation ◽  
2021 ◽  
Author(s):  
Jason D. Roberts ◽  
Eric Vittinghoff ◽  
Ake T. Lu ◽  
Alvaro Alonso ◽  
Biqi Wang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Population Based ◽  
Chronological Age ◽  
Biological Aging ◽  
Cox Models ◽  
Epigenetic Age ◽  
Underlying Mechanisms ◽  
Pai 1

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.

scholarly journals Exploring Epigenetic Age in Response to Intensive Relaxing Training: A Pilot Study to Slow Down Biological Age

2019 ◽  
Vol 16 (17) ◽  
pp. 3074 ◽  
Author(s):  
Pavanello ◽  
Campisi ◽  
Tona ◽  
Lin ◽  
Iliceto
Keyword(s):  
Myocardial Infarction ◽  
Age Estimation ◽  
Healthy Subjects ◽  
Molecular Mechanisms ◽  
Biological Age ◽  
Chronological Age ◽  
Biological Aging ◽  
Epigenetic Clock ◽  
Age Related ◽  
Epigenetic Age

DNA methylation (DNAm) is an emerging estimator of biological aging, i.e., the often-defined “epigenetic clock”, with a unique accuracy for chronological age estimation (DNAmAge). In this pilot longitudinal study, we examine the hypothesis that intensive relaxing training of 60 days in patients after myocardial infarction and in healthy subjects may influence leucocyte DNAmAge by turning back the epigenetic clock. Moreover, we compare DNAmAge with another mechanism of biological age, leucocyte telomere length (LTL) and telomerase. DNAmAge is reduced after training in healthy subjects (p = 0.053), but not in patients. LTL is preserved after intervention in healthy subjects, while it continues to decrease in patients (p = 0.051). The conventional negative correlation between LTL and chronological age becomes positive after training in both patients (p < 0.01) and healthy subjects (p < 0.05). In our subjects, DNAmAge is not associated with LTL. Our findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. Our study reveals that DNAmAge may represent an accurate tool to measure the effectiveness of lifestyle-based interventions in the prevention of age-related diseases.

scholarly journals Ambulatory blood pressure and long-term risk for atrial fibrillation

Heart ◽  
2018 ◽  
Vol 104 (15) ◽  
pp. 1263-1270 ◽  
Author(s):  
Valérie Tikhonoff ◽  
Tatiana Kuznetsova ◽  
Lutgarde Thijs ◽  
Nicholas Cauwenberghs ◽  
Katarzyna Stolarz-Skrzypek ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Ambulatory Blood Pressure ◽  
Population Based ◽  
European Population ◽  
Night Time ◽  
Cox Models ◽  
Increased Risk ◽  
Daytime Blood Pressure

ObjectiveData on the contribution of ambulatory blood pressure (ABP) components to the risk of developing atrial fibrillation (AF) are limited. We prospectively tested the hypothesis that ABP may represent a potentially modifiable risk factor for the development of AF in a European population study.MethodsWe recorded daytime blood pressure (BP) in 3956 subjects randomly recruited from the general population in five European countries. Of these participants, 2776 (70.2%) underwent complete 24-hour ABP monitoring. Median follow-up was 14 years. We defined daytime systolic BP load as the percentage BP readings above 135 mm Hg. The incidence of AF was assessed from ECGs obtained at baseline and follow-up and from records held by general practitioners and/or hospitals.ResultsOverall, during 58 810 person-years of follow-up, 143 participants experienced new-onset AF. In adjusted Cox models, each SD increase in baseline 24 hours, daytime and night-time systolic BP was associated with a 27% (P=0.0056), 22% (P=0.023) and 20% (P=0.029) increase in the risk for incident AF, respectively. Conventional systolic BP was borderline associated with the risk of AF (18%; P=0.06). As compared with the average population risk, participants in the lower quartile of daytime systolic BP load (<3%) had a 51% (P=0.0038) lower hazard for incident AF, whereas in the upper quartile (>38%), the risk was 46% higher (P=0.0094).ConclusionsSystolic ABP is a significant predictor of incident AF in a population-based cohort. We also observed that participants with a daytime systolic BP load >38% had significantly increased risk of incident AF.

scholarly journals COVID-19 severity is predicted by earlier evidence of accelerated aging

2020 ◽  
Author(s):  
Chia-Ling Kuo ◽  
Luke C. Pilling ◽  
Janice L Atkins ◽  
Jane AH Masoli ◽  
João Delgado ◽  
...  
Keyword(s):  
Clinical Chemistry ◽  
Accelerated Aging ◽  
Biological Age ◽  
Chronological Age ◽  
Biological Aging ◽  
Severe Illness ◽  
Mortality Data ◽  
Age Related ◽  
Underlying Mechanisms ◽  
The Uk

AbstractWith no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes [1]. While it is unclear why these diseases predispose risk, we hypothesize that increased biological age, rather than chronological age, may be driving disease-related trends in COVID-19 severity with age. To test this hypothesis, we applied our previously validated biological age measure (PhenoAge) [2] composed of chronological age and nine clinical chemistry biomarkers to data of 347,751 participants from a large community cohort in the United Kingdom (UK Biobank), recruited between 2006 and 2010. Other data included disease diagnoses (to 2017), mortality data (to 2020), and the UK national COVID-19 test results (to May 31, 2020) [3]. Accelerated aging 10-14 years prior to the start of the COVID-19 pandemic was associated with test positivity (OR=1.15 per 5-year acceleration, 95% CI: 1.08 to 1.21, p=3.2×10−6) and all-cause mortality with test-confirmed COVID-19 (OR=1.25, per 5-year acceleration, 95% CI: 1.09 to 1.44, p=0.002) after adjustment for demographics including current chronological age and pre-existing diseases or conditions. The corresponding areas under the curves were 0.669 and 0.803, respectively. Biological aging, as captured by PhenoAge, is a better predictor of COVID-19 severity than chronological age, and may inform risk stratification initiatives, while also elucidating possible underlying mechanisms, particularly those related to inflammaging.

Association between asthma control trajectories in preschoolers and disease remission

2020 ◽  
pp. 2001897
Author(s):  
Cristina Longo ◽  
Lucie Blais ◽  
Marni Brownell ◽  
Jacqueline M. Quail ◽  
Mohsen Sadatsafavi ◽  
...  
Keyword(s):  
Disease Activity ◽  
Asthma Control ◽  
Remission Rate ◽  
Meta Analysis ◽  
Population Based ◽  
Medical Visit ◽  
Cohort Entry ◽  
Cox Models ◽  
Disease Remission ◽  
Medical Visits

IntroductionEarly disease morbidity has been associated with asthma persistence in wheezing preschoolers; however, whether asthma control trajectories shortly after diagnosis could influence remission is unknown. We examined the association between asthma control trajectories 2 years post-diagnosis in preschoolers and subsequent disease remission.MethodsWe conducted a multicenter population-based retrospective cohort study consisting of 48 687 children with asthma diagnosed before 5 years old and born between 1990 and 2013 in 4 Canadian provinces who had prolonged disease activity post-diagnosis. Prolonged disease activity was defined as ≥1 medical visit or medication for asthma every 6-month period for ≥4 of the 6 periods post-diagnosis. Follow-up began at 3 years post-diagnosis (at cohort entry). Remission was defined as two consecutive years without drug claims or medical visits for asthma or asthma-like conditions following cohort entry. Asthma control trajectories, ascertained over four 6-month periods following diagnosis using a validated index, were classified as: controlled throughout, improving control, worsening control, out-of-control throughout, and fluctuating control. Adjusted Cox models estimated associations between asthma control trajectories and time-to-remission. A random-effects meta-analysis summarised province-specific Hazard Ratios (HRs).ResultsThe pooled remission rate was 8.91 (95%CI 8.80,9.02)/100 person-years. Compared to children controlled throughout, poorer asthma control was associated with incrementally lower HRs (95%CI) of remission in 4 other trajectories: improving control, 0.89 (0.82,0.96); fluctuating control, 0.78 (0.71,0.85); worsening control, 0.68 (0.62,0.75); out-of-control throughout, 0.52 (0.45,0.59).ConclusionsAsthma control trajectories 2 years following a diagnosis in preschool were associated with remission, highlighting the clinical relevance of documenting control trajectories in early life.

scholarly journals Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns

2021 ◽  
Author(s):  
Tamar Shahal ◽  
Elad Segev ◽  
Thomas Konstantinovsky ◽  
Yonit Marcus ◽  
Gabi Shefer ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Interindividual Variability ◽  
Chronological Age ◽  
Biological Aging ◽  
Epigenetic Clock ◽  
Cpg Sites ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Shed Light

Epigenetic age not only correlates with chronological age but predicts morbidity and mortality. We assumed that deconvolution of epigenetic age to its individual components could shed light on the diversity of epigenetic, and by inference, biological aging. Using the Horvath original epigenetic clock, we identified several CpG sites linked to distinct genes that quantitatively explain much of the interpersonal variability in epigenetic aging, with secretagogin and malin showing the most dominant effects. The analysis shows that the same epigenetic age for any given chronological age can be accounted for by variable contributions of identifiable CpG sites; that old epigenetic relative to chronological age is mostly explained by the same CpG sites, mapped to genes showing the highest interindividual variability differences in healthy subjects but not in subjects with type 2 diabetes. This paves the way to form personalized aging cards indicating the sources of accelerated/decelerated epigenetic aging in each examinee, en route to targeting specific sites as indicators, and perhaps treatment targets of personal undesirable age drifting.

scholarly journals Subtypes of atrial fibrillation with concomitant valvular heart disease derived from electronic health records: phenotypes, population prevalence, trends and prognosis

EP Europace ◽  
2019 ◽  
Vol 21 (12) ◽  
pp. 1776-1784 ◽  
Author(s):  
Amitava Banerjee ◽  
Victoria Allan ◽  
Spiros Denaxas ◽  
Anoop Shah ◽  
Dipak Kotecha ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Heart Disease ◽  
Aortic Stenosis ◽  
Valvular Heart Disease ◽  
Absolute Risk ◽  
Composite Endpoint ◽  
Population Based ◽  
Cox Models ◽  
Mechanical Valves ◽  
Electronic Health

Abstract Aims To evaluate population-based electronic health record (EHR) definitions of atrial fibrillation (AF) and valvular heart disease (VHD) subtypes, time trends in prevalence and prognosis. Methods and results A total of 76 019 individuals with AF were identified in England in 1998–2010 in the CALIBER resource, linking primary and secondary care EHR. An algorithm was created, implemented, and refined to identify 18 VHD subtypes using 406 diagnosis, procedure, and prescription codes. Cox models were used to investigate associations with a composite endpoint of incident stroke (ischaemic, haemorrhagic, and unspecified), systemic embolism (SSE), and all-cause mortality. Among individuals with AF, the prevalence of AF with concomitant VHD increased from 11.4% (527/4613) in 1998 to 17.6% (7014/39 868) in 2010 and also in individuals aged over 65 years. Those with mechanical valves, mitral stenosis (MS), or aortic stenosis had highest risk of clinical events compared to AF patients with no VHD, in relative [hazard ratio (95% confidence interval): 1.13 (1.02–1.24), 1.20 (1.05–1.36), and 1.27 (1.19–1.37), respectively] and absolute (excess risk: 2.04, 4.20, and 6.37 per 100 person-years, respectively) terms. Of the 95.2% of individuals with indication for warfarin (men and women with CHA2DS2-VASc ≥1 and ≥2, respectively), only 21.8% had a prescription 90 days prior to the study. Conclusion Prevalence of VHD among individuals with AF increased from 1998 to 2010. Atrial fibrillation associated with aortic stenosis, MS, or mechanical valves (compared to AF without VHD) was associated with an excess absolute risk of stroke, SSE, and mortality, but anticoagulation was underused in the pre-direct oral anticoagulant (DOAC) era, highlighting need for urgent clarity regarding DOACs in AF and concomitant VHD.

scholarly journals The relationship between epigenetic age and myocardial infarction/acute coronary syndrome and in a population based nested case-control study

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Malyutina ◽  
O Chervova ◽  
T Tillmann ◽  
V Maximov ◽  
A Ryabikov ◽  
...  
Keyword(s):  
Case Control Study ◽  
Population Based ◽  
Case Control ◽  
Chronological Age ◽  
Metabolic Factors ◽  
Coronary Syndrome ◽  
Epigenetic Age ◽  
Nested Case Control ◽  
The Relationship ◽  
Control Study

Abstract Background The measure of “epigenetic age” (EA) derived from DNA methylation (DNAm) is considered as biomarker of ageing. Objective We investigated the relationship between EA and Myocardial Infarction (MI) /Acute coronary syndrome (ACS) in a nested case-control study of the elderly population. Methods A random population sample was examined at baseline (2003/05, n=9360, age 45–69, the Russian arm of the HAPIEE Project), re-examined in 2006/08, 2015/17, and followed up for an average 15 years for fatal and non-fatal events. Using a nested case-control study design, we selected participants with incident MI/ACS (cases) and age-and sex-stratified controls among those free from baseline CVD. We performed DNAm profiling of the whole blood samples (using Illumina EPIC arrays) collected at baseline. After quality control, 135 cases and 185 controls were included in the analysis. Baseline EA was calculated using Horvath, Hannum, PhenoAge and Skin and Blood DNAm clocks; the differences between EA and chronological age (CA) were denoted as DAHr, DAHn, DAPh, DASB, respectively. Results DNAm ages calculated with Horvath's, Hannum's and Skin and Blood clocks were close to the CA; the corresponding median absolute differences (MAD) were 3.38, 3.64 and 2.79 years, and mean (SD) −0.85 (5.37), 1.96 (5.18) and 2.10 (3.94) for DAHr, DAHn and DASB respectively. As expected, PhenoAge's predictions were less precise with MAD=9.41 and DAPh mean (SD) 8.94 (6.38). The mean DAHr and DAHn were significantly higher in MI/ACS compared to controls (0.99 (5.38) vs. −1.55 (5.27), p=0.007, and 2.89 (6.37) vs. 1.28 (4.95), p=0.006 correspondingly), DASB was borderline higher in MI/ACS vs controls and DAPh was similar in cases and controls. After controlling for sex, the risk of MI/ACS was higher in DAHr terciles 2 and 3 vs. tercile 1 (OR=1.08 [95% CI 0.61–1.89], p=0.799 and OR=2.09 [1.19–3.66], p=0.010); the association was independent of smoking but it was largely explained (or mediated) by metabolic factors (blood pressure, body mass index, total and LDL-cholesterol). Similarly, the risk of MI/ACS was increased in terciles 2 and 3 of DAHn; compared with lowest tercile, the OR were 1.52 [0.86–2.71], p=0.152 and 2.41 [1.34–4.34], p=0.003), respectively; again, the association was largely explained by metabolic factors. There was no association found between baseline DAPh or DASB and the risk of MI/ACS. Conclusion In this case-control study nested in a prospective population-based cohort, we found an association between acceleration of epigenetic age and increased risk of MI/ACS independent of sex and smoking. The risk of MI/ACS was about 2-fold higher in the top tercile of difference between epigenetic and chronological age. The excess risk is appeared to be modulated by metabolic factors. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Russian Science Foundation; Russian Academy of Sciences, Sate Assignment

scholarly journals Reverse causal effect of atrial fibrillation on 17 site-specific cancer risk: A Mendelian randomization study

2021 ◽  
Author(s):  
Sehoon Park ◽  
Soojin Lee ◽  
Yaerim Kim ◽  
Semin Cho ◽  
Kwangsoo Kim ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
European Ancestry ◽  
Site Specific ◽  
A Genome ◽  
Bidirectional Association ◽  
Specific Cancer ◽  
Risk Of Cancer

AbstractBackgroundBidirectional association between atrial fibrillation (AF) and cancer was reported by observational investigations. Additional study is warranted to investigate the causal effects of AF on risk of cancer.MethodsThis study was a summary-level Mendelian randomization (MR) analysis. Genetic instrument for AF was developed from a genome-wide association study (GWAS) meta-analysis for AF including 537,409 European ancestry individuals including 55,144 AF cases. The outcome data for risk of 17 site-specific cancer from a previous GWAS meta-analysis of the UK Biobank (48,961/359,825 case/controls) and Genetic Epidemiology Research on Adult Health and Aging (16,001/50,525 case/controls) cohorts including European ancestry individuals was investigated. Inverse variance weighted method was the main MR method, supported by pleiotropy-robust sensitivity analysis including MR-Egger regression and penalized weighted median method.ResultsThe causal estimates indicated that AF was causally linked to higher risk of cancers of lung, breast, cervix, endometrium, and melanoma. MR-Egger test for directional pleiotropy indicated absence of a pleiotropy in the identified causal estimates and MR-Egger regression and median-based methods provided similarly significant findings. On the other hand, the genetic predisposition of AF was significantly associated with lower risk of esophagus/gastric cancer, but possibility of a directional pleiotropy remained in the association.ConclusionsAF is a causal factor for certain types of cancer. Appropriate cancer screening should be suggested in clinical guidelines for AF patients. Future trial is necessary to confirm whether appropriate management of AF may reduce the risk of cancer which is a major cause of deaths in AF patients.

scholarly journals Aging Clocks

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 818-819
Author(s):  
Morgan Levine
Keyword(s):  
Biological Sciences ◽  
At Risk ◽  
Risk Factor ◽  
Disease Onset ◽  
Biological Age ◽  
Chronological Age ◽  
Biological Aging ◽  
Biomarkers Of Aging ◽  
Underlying Mechanisms

Abstract While chronological age is arguably the strongest risk factor for death, disease, and disability, same-aged individuals remain heterogeneous in their susceptibilities to these various outcomes. One explanation is that chronological age is an imperfect proxy of the degree of biological aging an individual has undergone. Thus, defining measurable estimates of ‘biological age’ (in contrast to chronological age) has become a major initiative in Geroscience research. Such biomarkers of aging, or ‘aging clocks’ will 1) help identify underlying mechanisms of aging, 2) enable identification of at-risk individuals prior to disease onset, and 3) provide outcomes to assess efficacy of interventions. In this session, I will describe the various aging clocks, how they were developed, and what they track. I will also describe how aging clocks can facilitate research both within and outside of the biological sciences.

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