Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in
and early-onset AF.
...We sought to determine the contribution of rare and common genetic variation to AF risk in the general population.
The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome sequencing. In this case-control study, we included AF cases and controls of genetically determined white-European ancestry; analyses were performed using a logistic mixed-effects model adjusting for age, sex, the first 4 principal components of ancestry, empirical relationships, and case-control imbalance. An exome-wide, gene-based burden analysis was performed to examine the relationship between AF and rare, high-confidence LOF variants in genes with ≥10 LOF carriers. A polygenic risk score for AF was estimated using the LDpred algorithm. We then compared the contribution of AF polygenic risk score and LOF variants to AF risk.
The study included 1546 AF cases and 41 593 controls. In an analysis of 9099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene,
(odds ratio, 2.71,
=2.50×10
). The association with AF was more significant (odds ratio, 6.15,
=3.26×10
) when restricting to LOF variants located in exons highly expressed in cardiac tissue (
). Overall, 0.44% of individuals carried
variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF polygenic risk score only 9.3% had AF. In contrast, the AF polygenic risk score explained 4.7% of the variance in AF susceptibility, while
variants only accounted for 0.2%.
Both monogenic and polygenic factors contribute to AF risk in the general population. While rare
variants confer a substantial AF penetrance, the additive effect of many common variants explains a larger proportion of genetic susceptibility to AF.
Polygenic risk scores (PRS) for coronary artery disease (CAD) identify high-risk individuals more likely to benefit from primary prevention statin therapy. Whether polygenic CAD risk is captured by ...conventional paradigms for assessing clinical cardiovascular risk remains unclear.
This study sought to intersect polygenic risk with guideline-based recommendations and management patterns for CAD primary prevention.
A genome-wide CAD PRS was applied to 47,108 individuals across 3 U.S. health care systems. The authors then assessed whether primary prevention patients at high polygenic risk might be distinguished on the basis of greater guideline-recommended statin eligibility and higher rates of statin therapy.
Of 47,108 study participants, the mean age was 60 years, and 11,020 (23.4%) had CAD. The CAD PRS strongly associated with prevalent CAD (odds ratio: 1.4 per SD increase in PRS; p < 0.0001). High polygenic risk (top 20% of PRS) conferred 1.9-fold odds of developing CAD (p < 0.0001). However, among primary prevention patients (n = 33,251), high polygenic risk did not correspond with increased recommendations for statin therapy per the American College of Cardiology/American Heart Association (46.2% for those with high PRS vs. 46.8% for all others, p = 0.54) or U.S. Preventive Services Task Force (43.7% vs. 43.7%, p = 0.99) or higher rates of statin prescriptions (25.0% vs. 23.8%, p = 0.04). An additional 4.1% of primary prevention patients may be recommended for statin therapy if high CAD PRS were considered a guideline-based risk-enhancing factor.
Current paradigms for primary cardiovascular prevention incompletely capture a polygenic susceptibility to CAD. An opportunity may exist to improve CAD prevention efforts by integrating both genetic and clinical risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Aims
Physical activity may be an important modifiable risk factor for atrial fibrillation (AF), but associations have been variable and generally based on self-reported activity.
Methods and ...results
We analysed 93 669 participants of the UK Biobank prospective cohort study without prevalent AF who wore a wrist-based accelerometer for 1 week. We categorized whether measured activity met the standard recommendations of the European Society of Cardiology, American Heart Association, and World Health Organization moderate-to-vigorous physical activity (MVPA) ≥150 min/week. We tested associations between guideline-adherent activity and incident AF (primary) and stroke (secondary) using Cox proportional hazards models adjusted for age, sex, and each component of the Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) risk score. We also assessed correlation between accelerometer-derived and self-reported activity. The mean age was 62 ± 8 years and 57% were women. Over a median of 5.2 years, 2338 incident AF events occurred. In multivariable adjusted models, guideline-adherent activity was associated with lower risks of AF hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75–0.89; incidence 3.5/1000 person-years, 95% CI 3.3–3.8 vs. 6.5/1000 person-years, 95% CI 6.1–6.8 and stroke (HR 0.76, 95% CI 0.64–0.90; incidence 1.0/1000 person-years, 95% CI 0.9–1.1 vs. 1.8/1000 person-years, 95% CI 1.6–2.0). Correlation between accelerometer-derived and self-reported MVPA was weak (Spearman r = 0.16, 95% CI 0.16–0.17). Self-reported activity was not associated with incident AF or stroke.
Conclusions
Greater accelerometer-derived physical activity is associated with lower risks of AF and stroke. Future preventive efforts to reduce AF risk may be most effective when targeting adherence to objective activity thresholds.
Graphical Abstract
Wrist-worn accelerometer-derived moderate-to-vigorous physical activity levels meeting standard guideline recommendations is associated with lower risk of incident atrial fibrillation after adjustment for clinical risk factors. Wearable sensors may enable both objective assessment of physical activity and modification of AF risk through targeted feedback.
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
). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Oral anticoagulants reduce the risk of stroke in patients with atrial fibrillation. However, many patients with atrial fibrillation at elevated stroke risk are not treated with oral ...anticoagulants.
Objective
To test whether electronic notifications sent to primary care physicians increase the proportion of ambulatory patients prescribed oral anticoagulants.
Design
Randomized controlled trial conducted from February to May 2017 within 18 practices in an academic primary care network.
Participants
Primary care physicians (
n
= 175) and their patients with atrial fibrillation, at elevated stroke risk, and not prescribed oral anticoagulants.
Intervention
Patients of each physician were randomized to the notification or usual care arm. Physicians received baseline email notifications and up to three reminders with patient information, educational material and primary care guidelines for anticoagulation management, and surveys in the notification arm.
Main Measures
The primary outcome was the proportion of patients prescribed oral anticoagulants at 3 months in the notification (
n
= 972) vs. usual care (
n
= 1364) arms, compared using logistic regression with clustering by physician. Secondary measures included survey-based physician assessment of reasons why patients were not prescribed oral anticoagulants and how primary care physicians might be influenced by the notification.
Key Results
Over 3 months, a small proportion of patients were newly prescribed oral anticoagulants with no significant difference in the notification (3.9%, 95% CI 2.8–5.3%) and usual care (3.2%, 95% CI 2.4–4.2%) arms (
p
= 0.37). The most common, non-exclusive reasons why patients were not on oral anticoagulants included atrial fibrillation was transient (30%) or paroxysmal (12%), patient/family declined (22%), high bleeding risk (20%), fall risk (19%), and frailty (10%). For 95% of patients, physicians stated they would not change their management after reviewing the alert.
Conclusions
Electronic physician notification did not increase anticoagulation in patients with atrial fibrillation at elevated stroke risk. Primary care physicians did not prescribe anticoagulants because they perceived the bleeding risk was too high or stroke risk was too low.
Trial Registration
ClinicalTrials.gov
identifier NCT02950285
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Obesity is an important risk factor for hypertension. We aimed to investigate the association between different obesity patterns and hypertension risk in a large male population in the US. Male ...participants from the National Health and Nutrition Examination Survey (NHANES) (2007-2018) were enrolled in this cross-sectional study. Social demographic information, lifestyle factors, anthropometric measurements and biochemical measurements were collected. Three obesity patterns were classified according to the body mass index (BMI) and waist circumference (WC), including overweight and general obesity, abdominal obesity, and compound obesity. We adopted multivariate logistic regression to investigate the associations between hypertension and different obesity patterns after adjusting for cofounding factors. Subgroup analysis, stratified by age, smoking, drinking and estimated glomerular filtration rate (eGFR), was also conducted to explore the associations between obesity patterns and hypertension risk among different populations. Moreover, the association between WC and hypertension among male individuals was also explored using restricted cubic spline (RCS) analysis. Receiver operating characteristic (ROC) was used to evaluate the discriminatory power of WC for screening hypertension risk. 13,859 male participants from NHANES survey (2007-2018) were enrolled. Comparing with the normal-weight group, the odds ratios (ORs) 95% confidence interval (CI) for hypertension in individuals with overweight and general obesity, abdominal obesity and compound obesity were 1.41 1.17-1.70, 1.97 1.53-2.54 and 3.28 2.70-3.99, respectively. Subgroup analysis showed that the effect of different obesity patterns on hypertension risk was highly stable among individuals with different clinical conditions. In addition, WC had a positive correlation with the risk of hypertension (OR: 1.43; 95% CI 1.37-1.52; P < 0.001) in fully adjusted multivariate logistic regression model. RCS analysis showed that the association between WC and hypertension risk was in a nonlinear pattern, and WC had a good discriminatory power for hypertension in ROC analysis. Different patterns of obesity have a great impact on the risk of hypertension among male individuals. Increment of WC significantly increased the hypertension risk. More attention should be paid to the prevention of obesity, especially abdominal obesity and compound obesity in male individuals.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Laryngeal squamous cell carcinoma (LSCC) is one of the most common laryngeal tumors, and its incidence is increasing yearly; however, whether lymph node dissection should be performed during surgery ...remains unclear. We retrospectively analyzed the clinical and pathological data of 246 cases of LSCC and developed a nomogram for the prediction of lymph node metastasis (LNM) of LSCC. The predictive performance and consistency of the model were evaluated using the consistency coefficient (C-index) and calibration curve, respectively. Among 246 cases of LSCC, 52 cases had metastasis with a positivity rate of 21.14%. Multivariate analyses showed that dysphagia, clinical T stage, and pathological differentiation were independent risk factors for LNM in LSCC. The accuracy of the contour map used to predict the risk for LNM was 0.809. Overall, this nomogram model can be used to evaluate LNM in patients with LSCC before surgery to decide whether to conduct neck dissection and improve patient prognosis.
The most significantly associated genetic locus for atrial fibrillation (AF) is in chromosomal region 4q25, where four independent association signals have been identified. Although model-system ...studies suggest that altered PITX2c expression might underlie the association, the link between specific variants and the direction of effect on gene expression remains unknown for all four signals. In the present study, we analyzed the AF-associated region most proximal to PITX2 at 4q25. First, we identified candidate regulatory variants that might confer AF risk through a combination of mammalian conservation, DNase hypersensitivity, and histone modification from ENCODE and the Roadmap Epigenomics Project, as well as through in vivo analysis of enhancer activity in embryonic zebrafish. Within candidate regions, we then identified a single associated SNP, rs2595104, which displayed dramatically reduced enhancer activity with the AF risk allele. CRISPR-Cas9-mediated deletion of the rs2595104 region and editing of the rs2595104 risk allele in human stem-cell-derived cardiomyocytes resulted in diminished PITX2c expression in comparison to that of the non-risk allele. This differential activity was mediated by activating enhancer binding protein 2 alpha (TFAP2a), which bound robustly to the non-risk allele at rs2595104, but not to the risk allele, in cardiomyocytes. In sum, we found that the AF-associated SNP rs2595104 altered PITX2c expression via interaction with TFAP2a. Such a pathway could ultimately contribute to AF susceptibility at the PITX2 locus associated with AF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Oral anticoagulation (OAC) is effective yet reportedly underutilized for stroke prevention in atrial fibrillation (AF). Factors associated with delayed OAC after incident AF are unknown. Using a ...large electronic medical record, we identified incident episodes of AF diagnosed in 2006 to 2014 using a validated algorithm. Among patients with a Congestive heart failure, Hypertension, Age, Diabetes, and Stroke (CHADS2) score ≥1 started on OAC within 1 year, we examined baseline characteristics at AF diagnosis and their association with time to OAC using multivariable Cox proportional hazards modeling. Of 4,388 patients with incident AF and CHADS2 score ≥1 who were started on OAC within 1 year, the mean age was 72.6, and 41% were women. Median time to OAC was 5 days (interquartile range 1 to 43), and most patients received warfarin (86.3%). Among patients without prevalent stroke, 98 strokes (2.2% of the sample) occurred between AF diagnosis and OAC initiation. In multivariable analyses, several factors were associated with delayed OAC including female gender (hazard ratio HR 1.08, 95% confidence interval CI 1.01 to 1.15), absence of hypertension (HR 1.15, 95% CI 1.03 to 1.27), previous fall (HR 1.53, 95% CI 1.08 to 2.17), and chronic kidney disease (HR 1.12, 95% CI 1.04 to 1.21). Among women, OAC prescription at 1, 3, and 6 months was 70.0%, 81.7%, and 89.5%, respectively, whereas for men, OAC prescription was 73.4%, 84.0%, and 91.5%, respectively. Most patients with new AF and elevated stroke risk started on OAC receive it within 1 week, although the promptness of initiation varies. The stroke rate is substantial in the period between AF diagnosis and OAC initiation. Interventions targeting identified risk factors for delayed OAC may result in improved outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Genetic variants in LMNA may cause cardiac disease, but population-level contributions of variants to cardiac disease burden are not well-characterized.
We sought to determine the frequency and ...contribution of rare LMNA variants to cardiomyopathy and arrhythmia risk among ambulatory adults.
We included 185,990 UK Biobank participants with whole-exome sequencing. We annotated rare loss-of-function and missense LMNA variants for functional effect using 30 in silico prediction tools. We assigned a predicted functional effect weight to each variant and calculated a score for each carrier. We tested associations between the LMNA score and arrhythmia (atrial fibrillation, bradyarrhythmia, ventricular arrhythmia) or cardiomyopathy outcomes (dilated cardiomyopathy and heart failure). We also examined associations for variants located upstream vs downstream of the nuclear localization signal.
Overall, 1,167 (0.63%) participants carried an LMNA variant and 15,079 (8.11%) had an arrhythmia or cardiomyopathy event during a median follow-up of 10.9 years. The LMNA score was associated with arrhythmia or cardiomyopathy (OR: 2.21; P < 0.001) and the association was more significant when restricted to variants upstream of the nuclear localization signal (OR: 5.05; P < 0.001). The incidence rate of arrhythmia or cardiomyopathy was 8.43 per 1,000 person-years (95% CI: 6.73-10.12 per 1,000 person-years) among LMNA variant carriers and 6.38 per 1,000 person-years (95% CI: 6.27-6.50 per 1,000 person-years) among noncarriers. Only 3 (1.2%) of the variants were reported as pathogenic in ClinVar.
Middle-aged adult carriers of rare missense or loss-of-function LMNA variants are at increased risk for arrhythmia and cardiomyopathy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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