Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits ...and have a critical role in physiological and disease processes.
To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78x10(-12)), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself.
This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment.
Technical variation plays an important role in microarray-based gene expression studies, and batch effects explain a large proportion of this noise. It is therefore mandatory to eliminate technical ...variation while maintaining biological variability. Several strategies have been proposed for the removal of batch effects, although they have not been evaluated in large-scale longitudinal gene expression data. In this study, we aimed at identifying a suitable method for batch effect removal in a large study of microarray-based longitudinal gene expression. Monocytic gene expression was measured in 1092 participants of the Gutenberg Health Study at baseline and 5-year follow up. Replicates of selected samples were measured at both time points to identify technical variability. Deming regression, Passing-Bablok regression, linear mixed models, non-linear models as well as ReplicateRUV and ComBat were applied to eliminate batch effects between replicates. In a second step, quantile normalization prior to batch effect correction was performed for each method. Technical variation between batches was evaluated by principal component analysis. Associations between body mass index and transcriptomes were calculated before and after batch removal. Results from association analyses were compared to evaluate maintenance of biological variability. Quantile normalization, separately performed in each batch, combined with ComBat successfully reduced batch effects and maintained biological variability. ReplicateRUV performed perfectly in the replicate data subset of the study, but failed when applied to all samples. All other methods did not substantially reduce batch effects in the replicate data subset. Quantile normalization plus ComBat appears to be a valuable approach for batch correction in longitudinal gene expression data.
Atrial fibrillation (AF) is the most common sustained arrhythmia in women and men worldwide. During the past century, a range of risk factors has been associated with AF, severe complications from ...the arrhythmia have been identified, and its prevalence has been increasing steadily. Whereas evidence has accumulated regarding sex-specific differences in coronary heart disease and stroke, the differences between women and men with AF has received less attention. We review the current literature on sex-specific differences in the epidemiology of AF, including incidence, prevalence, risk factors, and genetics, and in the pathophysiology and the clinical presentation and prognosis of patients with this arrhythmia. We highlight current knowledge gaps and areas that warrant future research, which might advance understanding of variation in the risk factors and complications of AF, and ultimately aid more-tailored management of the arrhythmia.
Summary Background Atrial fibrillation contributes to substantial increases in morbidity and mortality. We aimed to develop a risk score to predict individuals' absolute risk of developing the ...condition, and to provide a framework for researchers to assess new risk markers. Methods We assessed 4764 participants in the Framingham Heart Study from 8044 examinations (55% women, 45–95 years of age) undertaken between June, 1968, and September, 1987. Thereafter, participants were monitored for the first event of atrial fibrillation for a maximum of 10 years. Multivariable Cox regression identified clinical risk factors associated with development of atrial fibrillation in 10 years. Secondary analyses incorporated routine echocardiographic measurements (5152 participants, 7156 examinations) to reclassify the risk of atrial fibrillation and to assess whether these measurements improved risk prediction. Findings 457 (10%) of the 4764 participants developed atrial fibrillation. Age, sex, body-mass index, systolic blood pressure, treatment for hypertension, PR interval, clinically significant cardiac murmur, and heart failure were associated with atrial fibrillation and incorporated in a risk score (p<0·05, except body-mass index p=0·08), clinical model C statistic 0·78 (95% CI 0·76–0·80). Risk of atrial fibrillation in 10 years varied with age: more than 15% risk was recorded in 53 (1%) participants younger than 65 years, compared with 783 (27%) older than 65 years. Additional incorporation of echocardiographic measurements to enhance the risk prediction model only slightly improved the C statistic from 0·78 (95% CI 0·75–0·80) to 0·79 (0·77–0·82), p=0·005. Echocardiographic measurements did not improve risk reclassification (p=0·18). Interpretation From clinical factors readily accessible in primary care, our risk score could help to identify risk of atrial fibrillation for individuals in the community, assess technologies or markers for improvement of risk prediction, and target high-risk individuals for preventive measures. Funding US National Institutes of Health.
Circulating microRNAs (miRNAs) have been described as potential diagnostic biomarkers in cardiovascular disease and in particular, coronary artery disease (CAD). Few studies were undertaken to ...perform analyses with regard to risk stratification of future cardiovascular events. miR-126, miR-197 and miR-223 are involved in endovascular inflammation and platelet activation and have been described as biomarkers in the diagnosis of CAD. They were identified in a prospective study in relation to future myocardial infarction.
The aim of our study was to further evaluate the prognostic value of these miRNAs in a large prospective cohort of patients with documented CAD.
Levels of miR-126, miR-197 and miR-223 were evaluated in serum samples of 873 CAD patients with respect to the endpoint cardiovascular death. miRNA quantification was performed using real time polymerase chain reaction (RT-qPCR).
The median follow-up period was 4 years (IQR 2.78-5.04). The median age of all patients was 64 years (IQR 57-69) with 80.2% males. 38.9% of the patients presented with acute coronary syndrome (ACS), 61.1% were diagnosed with stable angina pectoris (SAP). Elevated levels of miRNA-197 and miRNA-223 reliably predicted future cardiovascular death in the overall group (miRNA-197: hazard ratio (HR) 1.77 per one standard deviation (SD) increase (95% confidence interval (CI) 1.20; 2.60), p = 0.004, C-index 0.78; miRNA-223: HR 2.23 per one SD increase (1.20; 4.14), p = 0.011, C-index 0.80). In ACS patients the prognostic power of both miRNAs was even higher (miRNA-197: HR 2.24 per one SD increase (1.25; 4.01), p = 0.006, C-index 0.89); miRA-223: HR 4.94 per one SD increase (1.42; 17.20), p = 0.012, C-index 0.89).
Serum-derived circulating miRNA-197 and miRNA-223 were identified as predictors for cardiovascular death in a large patient cohort with CAD. These results reinforce the assumption that circulating miRNAs are promising biomarkers with prognostic value with respect to future cardiovascular events.
Summary Background Comprehensive long-term data on atrial fibrillation trends in men and women are scant. We aimed to provide such data through analysis of the Framingham cohort over 50 years. ...Methods We investigated trends in incidence, prevalence, and risk factors for atrial fibrillation and its association with stroke and mortality after onset in 9511 participants enrolled in the Framingham Heart Study between 1958 and 2007. We analysed trends within 10 year groups (1958–67, 1968–77, 1978–87, 1988–97, and 1998–2007), stratified by sex. Findings During 50 years of observation (202 417 person-years), 1544 cases of new-onset atrial fibrillation occurred (of whom 723 47% were women). Between 1958–67 and 1998–2007, age-adjusted prevalence of atrial fibrillation quadrupled from 20·4 to 96·2 cases per 1000 person-years in men and from 13·7 to 49·4 cases per 1000 person-years in women; age-adjusted incidence increased from 3·7 to 13·4 new cases per 1000 person-years in men and from 2·5 to 8·6 new cases per 1000 person-years in women (ptrend <0·0001 for all comparisons). For atrial fibrillation diagnosed by electrocardiograph (ECG) during routine Framingham examinations, age-adjusted prevalence per 1000 person-years increased (12·6 in 1958–67 to 25·7 in 1998–2007 in men, ptrend =0·0007; 8·1 to 11·8 in women, ptrend =0·009). However, age-adjusted incidence of atrial fibrillation by Framingham Heart Study ECGs did not change significantly with time. Although the prevalence of most risk factors changed over time, their associated hazards for atrial fibrillation changed little. Multivariable-adjusted proportional hazards models revealed a 74% (95% CI 50–86%) decrease in stroke (hazards ratio HR 3·77, 95% CI 1·98–7·20 in 1958–1967 compared with 1998–2007; ptrend =0·0001) and a 25% (95% CI −3–46%) decrease in mortality (HR 1·34, 95% CI 0·97–1·86 in 1958–1967 compared with 1998–2007; ptrend =0·003) in 20 years following atrial fibrillation onset. Interpretation Trends of increased incidence and prevalence of atrial fibrillation in the community were probably partly due to enhanced surveillance. Measures are needed to enhance early detection of atrial fibrillation, through increased awareness coupled with targeted screening programmes and risk factor-specific prevention. Funding NIH, NHLBI, NINDS, Deutsche Forschungsgemeinschaft.
Abstract
Aims
There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol ...consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts.
Methods and results
In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11–1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF.
Conclusions
In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention.
Graphical Abstract
Hazard ratio for incident atrial fibrillation for alcohol consumption in gram per day by non-linear Cox regression plotted on the log-scale (N = 92 452). The model uses age as time scale and is sex and cohort stratified. The reference value is 0 g/day.
Stratification for subsequent coronary events among patients with coronary artery disease (CAD) is of considerable interest because of the potential to guide secondary preventive therapies. Recently, ...we identified eight microRNAs (miRNAs), which facilitated acute coronary syndrome (ACS) diagnosis. In this study, we aimed to evaluate their potential role as prognostic biomarkers for cardiovascular disease.
The serum concentrations of eight candidate miRNAs -miR-19a, miR-19b, miR-132, miR-140-3p, miR-142-5p, miR-150, miR-186, and miR-210 were measured in a cohort of 1112 patients with documented CAD-including 430 patients with ACS and 682 patients with stable angina pectoris. Cardiovascular death was the main outcome measure.
During a median follow-up of 4.0 years, most miRNAs reliably predicted cardiovascular death in ACS patients. Cox regression analyses indicated that in particular miR-132 (HR 2.85 per 1 SD increase, P = 0.022), miR-140-3p (HR 2.88 per 1 SD increase, P = 0.022), and miR-210 (HR 3.10 per 1 SD increase, P = 0.039) were able to precisely predict cardiovascular death. Circulating miR-132, miR-140-3p, and miR-210 clearly improved various model performance measures, including C-statistics (AUC area under the receiver-operating characteristic curve for miR-132: 0.737; AUC for miR-140-3p: 0.756; AUC for miR-210: 0.754).
This is the largest study so far evaluating the prognostic value of circulating miRNAs in cardiovascular disease. Our study shows that single miRNAs derived from peripheral blood predict mortality in secondary prevention settings, and thereby represent valuable biomarkers for risk estimation in CAD.
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