Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study.
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ABSTRACT:
SUBMITTER: Lin H
PROVIDER: S-EPMC5220313 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
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Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study.
Lin Honghuang H Yin Xiaoyan X Xie Zhijun Z Lunetta Kathryn L KL Lubitz Steven A SA Larson Martin G MG Ko Darae D Magnani Jared W JW Mendelson Michael M MM Liu Chunyu C McManus David D DD Levy Daniel D Ellinor Patrick T PT Benjamin Emelia J EJ
Scientific reports 20170109
Atrial fibrillation (AF) is the most common cardiac arrhythmia, but little is known about the molecular mechanisms associated with AF arrhythmogenesis. DNA methylation is an important epigenetic mechanism that regulates gene expression and downstream biological processes. We hypothesize that DNA methylation might play an important role in the susceptibility to develop AF. A total of 2,639 participants from the Offspring Cohort of Framingham Heart Study were enrolled in the current study. These p ...[more]
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Project description:BACKGROUND:Endogenous sex hormones have been related to cardiovascular outcomes and mortality. We hypothesized that sex hormones are related to atrial fibrillation (AF) in a community-based cohort of middle-aged to older men. METHODS AND RESULTS:We examined testosterone, estradiol, and dehydroepiandrosterone sulfate in relation to incident AF in men participating in the Framingham Heart Study. We assessed the 10-year risk of AF in multivariable-adjusted hazard models. The cohort consisted of 1251 men (age, 68.0±8.2 years), of whom 275 developed incident AF. We identified a significant interaction between age and testosterone and, therefore, stratified men into age 55 to 69 years (n=786), 70 to 79 years (n=351), and ?80 years (n=114). In men aged 55 to 69 years, each 1 SD decrease in testosterone was associated with hazard ratio (HR) 1.30 (95% confidence interval [CI], 1.07-1.59) for incident AF. The association between testosterone and 10-year incident AF in men 70 to 79 years did not reach statistical significance. In men?80 years, a 1 SD decrease in testosterone was associated with HR 3.53 (95% CI, 1.96-6.37) for AF risk. Estradiol was associated with incident AF (HR, 1.12; 95% CI, 1.01-1.26). Dehydroepiandrosterone sulfate had a borderline association with risk of AF that was not statistically significant (HR, 1.12; 95% CI, 0.99-1.28). CONCLUSIONS:Testosterone and estradiol are associated with incident AF in a cohort of older men. Testosterone deficiency in men?80 years is strongly associated with AF risk. The clinical and electrophysiological mechanisms underlying the associations between sex hormones and AF in older men merit continued investigation.
| S-EPMC4035016 | biostudies-literature
Project description:BackgroundThere have been conflicting reported associations between dietary factors and incident atrial fibrillation (AF).ObjectiveWe evaluated associations between consumption of alcohol, caffeine, fiber, and polyunsaturated fatty acids (PUFAs) and incident AF in the Framingham Heart Study.DesignParticipants without AF (n = 4526; 9640 examinations; mean age: 62 y; 56% women) from the original and offspring cohorts completed food-frequency questionnaires and were followed prospectively for 4 y. We examined the associations between dietary exposures and AF with Cox proportional hazards regression.ResultsA total of 296 individuals developed AF (177 men, 119 women). In multivariable analyses, there were no significant associations between examined dietary exposures and AF risk. Hazard ratios (HRs) for increasing quartiles of dietary factors were as follows: for alcohol, 0.73 (95% CI: 0.5, 1.05), 0.85 (95% CI: 0.61, 1.18), and 1.12 (95% CI: 0.83, 1.51) (P for trend = 0.48); for caffeine, 0.84 (95% CI: 0.62, 1.15), 0.87 (95% CI: 0.64, 1.2), and 0.98 (95% CI: 0.7, 1.39) (P for trend = 0.84); for total fiber, 0.86 (95% CI: 0.61, 1.2), 0.64 (95% CI: 0.44, 0.92), and 0.81 (95% CI: 0.54, 1.2) (P for trend = 0.16); and for n-3 (omega-3) PUFAs, 1.11 (95% CI: 0.81, 1.54), 0.92 (95% CI: 0.65, 1.29), and 1.18 (95% CI: 0.85, 1.64) (P for trend = 0.57; quartile 1 was the reference group). In exploratory analyses, consumption of >4 servings of dark fish/wk (5 cases and 21 individuals at risk) was significantly associated with AF risk compared with the consumption of <1 serving of dark fish/wk (HR: 6.53; 95% CI: 2.65, 16.06; P < 0.0001).ConclusionsConsumption of alcohol, caffeine, fiber, and fish-derived PUFAs was not significantly associated with AF risk. The observed adverse association between the consumption of dark fish and AF merits further investigation. Our findings suggest that the dietary exposures examined convey limited attributable risk of AF in the general population.
| S-EPMC3021424 | biostudies-literature
Project description:BackgroundAtrial fibrillation (AF) involves substantial electrophysiological, structural and contractile remodeling. We hypothesize that characterizing gene expression might uncover important pathways related to AF.Methods and resultsWe performed genome-wide whole blood transcriptomic profiling (Affymetrix Human Exon 1.0 ST Array) of 2446 participants (mean age 66 ± 9 years, 55% women) from the Offspring cohort of Framingham Heart Study. The study included 177 participants with prevalent AF, 143 with incident AF during up to 7 years follow up, and 2126 participants with no AF. We identified seven genes statistically significantly up-regulated with prevalent AF. The most significant gene, PBX1 (P = 2.8 × 10(-7)), plays an important role in cardiovascular development. We integrated differential gene expression with gene-gene interaction information to identify several signaling pathways possibly involved in AF-related transcriptional regulation. We did not detect any statistically significant transcriptomic associations with incident AF.ConclusionWe examined associations of gene expression with AF in a large community-based cohort. Our study revealed several genes and signaling pathways that are potentially involved in AF-related transcriptional regulation.
| S-EPMC4013062 | biostudies-literature
Project description:BACKGROUND:Advancing age is a prominent risk factor for atrial fibrillation (AF). Shorter telomere length is a biomarker of biological aging, but the link between shorter telomere length and increased risk of AF remains unclear. We examined the association between shorter leukocyte telomere length (LTL) and incident AF. METHODS AND RESULTS:We included AF-free participants from the observational Framingham Heart Study Offspring cohort from 1995 to 1998, who had LTL measurements. We examined the association between baseline LTL and incident AF with multivariable Cox models adjusted for age, sex, current smoking, height, weight, systolic and diastolic blood pressure, use of antihypertensive medication, diabetes mellitus, history of myocardial infarction, and history of heart failure. The study sample comprised 1143 AF-free participants (52.8% women), with mean age of 60±8 years. The mean LTL at baseline was 6.95±0.57 kb. During 15.1±4.2 years mean follow-up, 184 participants (64 women) developed AF. Chronological age was associated with increased risk of AF (hazard ratio per 10-year increase, 2.16; 95% confidence interval, 1.71-2.72). There was no significant association between LTL and incident AF (hazard ratio per 1 SD decrease LTL, 1.01; 95% confidence interval, 0.86-1.19). Our study was observational in nature; hence, we could not exclude residual confounding and we were unable to establish causal pathways. CONCLUSIONS:In our moderate-sized community-based cohort, we did not find evidence for a significant association between LTL and risk of incident AF.
| S-EPMC5721755 | biostudies-literature
Project description:The epidemiology of atrial fibrillation (AF) without comorbidities, known as 'lone AF', is uncertain. Although it has been considered a benign condition, we hypothesized that it confers a worse prognosis compared with a matched sample without AF.We described the proportion of AF without comorbidities (clinical, subclinical cardiovascular disease and triggers) among the entire AF sample in Framingham Heart Study (FHS). We compared AF without comorbidities with typical AF, and age-, sex- and cohort-matched individuals without AF, using Cox proportional hazards analysis in relation to combined cardiovascular events (stroke, heart failure, myocardial infarction), and mortality.Of 10,311 FHS participants, 1,961 were diagnosed with incident AF, among which 173 individuals had AF without comorbidities (47% women, mean age 71±12 years). AF without comorbidities had a prevalence of 1.7% of the entire cohort, and an annual incidence of 0.5 per 1000 person-years. During a median follow-up of 9.7 years after initial AF, 137 individuals with AF without comorbidities (79.2%) died and 141 individuals developed cardiovascular events (81.5%). AF without comorbidities had significantly lower mortality (HR 0.67, 95%CI 0.55-0.81, P < .001) and total cardiovascular events (HR 0.66, 95% CI 0.55-0.80, P < .001) compared with typical AF. However, mortality (HR1.43, 95% CI 1.18-1.75, P < .001) and risk of total cardiovascular events (HR 1.73, 95% CI 1.39-2.16, P < .001) were higher than age-, sex-, and cohort-matched individuals without AF.The risk of cardiovascular outcomes and mortality among individuals with AF without comorbidities is lower than typical AF, but is significantly elevated compared with matched individuals without AF.
| S-EPMC4908973 | biostudies-other
Project description:Background Prior studies relating proteomics markers to incident AF screened for limited numbers of proteins. Methods and Results We performed proteomics assays among participants from the Framingham Heart Study Offspring attending their fifth examination. Plasma protein levels (n=1373) were measured by the SOMAscan proteomic profiling platform. We used robust inference for the Cox proportional hazards model to relate each protein level with incident AF. In addition, we examined the association between AF-related genetic loci and levels of proteins associated with AF. Our study included 1885 participants (mean age 55±10 years, 54% women) who had proteomic profiles measured. A total of 349 participants developed AF during follow-up (mean follow-up 18.3 years). We observed that 8 proteins were significantly associated with incident AF after adjusting for age, sex, technical covariates, and correction for multiple testing ( P<0.05/1373=3.6×10-5). After additional adjustments for clinical factors associated with AF, ADAMTS13 and N-terminal pro-B-type natriuretic peptide remained significantly associated with the risk of incident AF (hazard ratio, 0.78; 95% CI, 0.70-0.88; and 1.44; 95% CI, 1.22-1.70, respectively; P<3.6×10-5 for both). None of the 8 proteins were encoded by genes at AF-related genetic loci previously identified by genome-wide association studies. Conclusions We identified 8 proteins associated with risk of incident AF after adjustment for age and sex; 2 proteins were associated with AF after adjustment for AF risk factors. Future studies are needed to replicate our findings, identify whether the markers are mechanistically related to AF development, and whether they are clinically useful for identification of future AF risk.
| S-EPMC6475036 | biostudies-literature
Project description:Background Increased neck circumference, a proxy for upper-body subcutaneous fat, is associated with cardiovascular risk and metabolic risk factors, accounting for body mass index (BMI) and waist circumference. The association between neck circumference and incident atrial fibrillation (AF) is unclear. The aim of current study was to evaluate the association between neck circumference and incident AF. Methods and Results We selected participants from the Framingham Heart Study aged ≥55 years without diagnosed AF and with available neck circumference, BMI, and waist circumference measurements. We defined high neck circumference as ≥14 inches in women and ≥17 inches in men on the basis of the Contal and O'Quigley changepoint method. We used Fine-Gray models to estimate subdistribution hazards ratios (sHRs) for the association between neck circumference and incident AF accounting for the competing risk of death. We adjusted models for clinical risk factors. We then additionally adjusted separately for BMI, waist circumference, and height/weight. The study sample included 4093 participants (mean age 64±7 years, 55% female). During 11.2±5.7 mean years of follow-up, incident AF occurred in 571 participants. High neck circumference was associated with incident AF (sHR for high versus low: 1.58; 95% CI, 1.32-1.90, P<0.0001). The association remained significant after adjustment for BMI (sHR, 1.51; 95% CI, 1.21-1.89; P=0.0003), waist circumference (sHR, 1.47; 95% CI, 1.18-1.83; P<0.0001), and height/weight (sHR, 1.37; 95% CI, 1.09-1.72; P=0.007). Conclusions High neck circumference was associated with incident AF adjusting for traditional adiposity measures such as BMI and waist circumference.
| S-EPMC9245798 | biostudies-literature
Project description:Atrial fibrillation (AF) results in significant morbidity and mortality. Genome-wide association studies (GWAS) have identified genetic variants associated with AF. Whether genetic variants associated with AF are also associated with atrial structure, an intermediate phenotype for AF, has had limited investigation. We sought to investigate associations between single nucleotide polymorphisms (SNPs) and atrial structure obtained by cardiovascular imaging in the Framingham Heart Study.We selected 11 SNPs that have been associated with AF in GWAS. We examined the SNPs' relations to cross-sectional left atrial (LA) dimensions (determined by transthoracic echocardiography) and LA volume (determined by cardiovascular magnetic resonance [CMR]) employing linear regression. The total sample included 1555 participants with CMR LA volume (age 60±9 years, 53% women) and 6861 participants with echocardiographic LA diameter (age 48±13 years, 52% women) measured. We employed a significance threshold of P<0.0023 to account for multiple testing of the 11 SNPs and 2 LA measures. In a primary analysis, no SNPs were significantly related to the LA measures. Likewise, in secondary analyses excluding individuals with prevalent AF (n=77, CMR sample; n=105, echocardiography sample) no SNPs were related to LA volume or diameter.In a community-based cohort, we did not identify a statistically significant association between selected SNPs associated with AF and measures of LA anatomy. Further investigations with larger longitudinally assessed samples and a broader array of SNPs may be necessary to determine the relation between genetic loci associated with AF and atrial structure.
| S-EPMC4187503 | biostudies-literature
Project description:BackgroundSocial determinants of health, in particular education and income, influence the incidence, management, and outcomes of cardiovascular diseases including atrial fibrillation (AF). Data are limited on the associations of socioeconomic status with lifetime risk of incident AF.MethodsWe selected 2172 FHS participants (51% women) who were free of AF at the index age of 55 years. We assessed educational attainment (≥college) at the last exam prior to index age and household income ($40k/50k/≥55k depending on the FHS cohort). We estimated the lifetime risk of AF as the cumulative incidence of AF, accounting for the competing risk of death, at age 95 years. We analyzed strata defined by education and household income separately, and by combining education and household income. We adjusted analyses for sex, height, weight, systolic and diastolic blood pressure, current smoking, alcohol consumption, use of antihypertensive medication, diabetes, history of myocardial infarction, and history of heart failure.ResultsOver a mean follow-up of 13 years, 265 participants developed incident AF. The lifetime risk of developing AF was 32.5% (95%CI, 26.5% to 38.5%) and 32.5% (95%CI, 28.7% to 38.3%) among participants with lower and higher education attainment (p=0.98). The lifetime risk of developing AF was 32.1% (95%CI, 26.7% to 37.5%) and 31.8% (95%CI, 26.6% to 36.9%) among participants with lower and higher household income (p=0.79). There was no evidence of interaction between education and income on lifetime risk of AF (p = 0.84). Results were similar in subgroups of women and men.ConclusionIn our community-based sample, there was no evidence of an association between education or household income and lifetime risk of AF.
| S-EPMC8984539 | biostudies-literature
Project description:Previous studies have shown several metabolic biomarkers to be associated with prevalent and incident atrial fibrillation (AF), but the results have not been replicated. We investigated metabolite profiles of 2,458 European ancestry participants from the Framingham Heart Study without AF at the index examination and followed them for 10 years for new-onset AF. Amino acids, organic acids, lipids, and other plasma metabolites were profiled by liquid chromatography-tandem mass spectrometry using fasting plasma samples. We conducted Cox proportional hazard analyses for association between metabolites and new-onset AF. We performed hypothesis-generating analysis to identify novel metabolites and hypothesis-testing analysis to confirm the previously reported associations between metabolites and AF. Mean age was 55.1 ± 9.9 years, and 53% were women. Incident AF developed in 156 participants (6.3%) in 10 years of follow-up. A total of 217 metabolites were examined, consisting of 54 positively charged metabolites, 59 negatively charged metabolites, and 104 lipids. None of the 217 metabolites met our a priori specified Bonferroni corrected level of significance in the multivariate analyses. We were unable to replicate previous results demonstrating associations between metabolites that we had measured and AF. In conclusion, in our metabolomics approach, none of the metabolites we tested were significantly associated with the risk of future AF.
| S-EPMC5097881 | biostudies-literature