Publications by authors named "Patrick T Ellinor"

327 Publications

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.

JAMA Cardiol 2021 Sep 8. Epub 2021 Sep 8.

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome.

Objective: To examine the results of genetic testing for early-onset AF.

Design, Setting, And Participants: This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021.

Exposures: Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories.

Main Outcomes And Measures: Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders.

Results: Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8).

Conclusions And Relevance: In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.
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http://dx.doi.org/10.1001/jamacardio.2021.3370DOI Listing
September 2021

The genomics of heart failure: design and rationale of the HERMES consortium.

ESC Heart Fail 2021 Sep 3. Epub 2021 Sep 3.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

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 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.
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http://dx.doi.org/10.1002/ehf2.13517DOI Listing
September 2021

Comparative Clinical Effectiveness of Population-Based Atrial Fibrillation Screening Using Contemporary Modalities: A Decision-Analytic Model.

J Am Heart Assoc 2021 Sep 3;10(18):e020330. Epub 2021 Sep 3.

Cardiovascular Research Center and Cardiac Arrhythmia Service Division of Cardiology Massachusetts General Hospital Boston MA.

Background Atrial fibrillation (AF) screening is endorsed by certain guidelines for individuals aged ≥65 years. Yet many AF screening strategies exist, including the use of wrist-worn wearable devices, and their comparative effectiveness is not well-understood. Methods and Results We developed a decision-analytic model simulating 50 million individuals with an age, sex, and comorbidity profile matching the United States population aged ≥65 years (ie, with a guideline-based AF screening indication). We modeled no screening, in addition to 45 distinct AF screening strategies (comprising different modalities and screening intervals), each initiated at a clinical encounter. The primary effectiveness measure was quality-adjusted life-years, with incident stroke and major bleeding as secondary measures. We defined continuous or nearly continuous modalities as those capable of monitoring beyond a single time-point (eg, patch monitor), and discrete modalities as those capable of only instantaneous AF detection (eg, 12-lead ECG). In total, 10 AF screening strategies were effective compared with no screening (300-1500 quality-adjusted life-years gained/100 000 individuals screened). Nine (90%) effective strategies involved use of a continuous or nearly continuous modality such as patch monitor or wrist-worn wearable device, whereas 1 (10%) relied on discrete modalities alone. Effective strategies reduced stroke incidence (number needed to screen to prevent a stroke: 3087-4445) but increased major bleeding (number needed to screen to cause a major bleed: 1815-4049) and intracranial hemorrhage (number needed to screen to cause intracranial hemorrhage: 7693-16 950). The test specificity was a highly influential model parameter on screening effectiveness. Conclusions When modeled from a clinician-directed perspective, the comparative effectiveness of population-based AF screening varies substantially upon the specific strategy used. Future screening interventions and guidelines should consider the relative effectiveness of specific AF screening strategies.
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http://dx.doi.org/10.1161/JAHA.120.020330DOI Listing
September 2021

Predictive Accuracy of a Clinical and Genetic Risk Model for Atrial Fibrillation.

Circ Genom Precis Med 2021 Aug 31:CIRCGEN121003355. Epub 2021 Aug 31.

Cardiovascular Research Center, Massachusetts General Hospital, Boston. (S.K., L.-C.W., P.T.E., S.A.L.).

Background: Atrial fibrillation (AF) risk estimation using clinical factors with or without genetic information may identify AF screening candidates more accurately than the guideline-based age threshold of ≥65 years.

Methods: We analyzed 4 samples across the United States and Europe (derivation: UK Biobank; validation: FINRISK, Geisinger MyCode Initiative, and Framingham Heart Study). We estimated AF risk using the CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology AF) score and a combination of CHARGE-AF and a 1168-variant polygenic score (Predict-AF). We compared the utility of age, CHARGE-AF, and Predict-AF for predicting 5-year AF by quantifying discrimination and calibration.

Results: Among 543 093 individuals, 8940 developed AF within 5 years. In the validation sets, CHARGE-AF (C index range, 0.720-0.824) and Predict-AF (0.749-0.831) had largely comparable discrimination, both favorable to continuous age (0.675-0.801). Calibration was similar using CHARGE-AF (slope range, 0.67-0.87) and Predict-AF (0.65-0.83). Net reclassification improvement using Predict-AF versus CHARGE-AF was modest (net reclassification improvement range, 0.024-0.057) but more favorable among individuals aged <65 years (0.062-0.11). Using Predict-AF among 99 530 individuals aged ≥65 across each sample, 70 849 had AF risk <5%, of whom 69 067 (97.5%) did not develop AF, whereas 28 681 had AF risk ≥5%, of whom 2264 (7.9%) developed AF. Of 11 379 individuals aged <65 years with AF risk ≥5%, 435 (3.8%) developed AF before age 65 years, with roughly half (46.9%) meeting anticoagulation criteria.

Conclusions: AF risk estimation using clinical factors may prioritize individuals for AF screening more precisely than the age threshold endorsed in current guidelines. The additional value of genetic predisposition is modest but greatest among younger individuals.
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http://dx.doi.org/10.1161/CIRCGEN.121.003355DOI Listing
August 2021

Population sequencing data reveal a compendium of mutational processes in the human germ line.

Science 2021 08 12;373(6558):1030-1035. Epub 2021 Aug 12.

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.
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http://dx.doi.org/10.1126/science.aba7408DOI Listing
August 2021

Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.

Circ Genom Precis Med 2021 Aug 28;14(4):e003300. Epub 2021 Jul 28.

Regeneron Genetics Center, Tarrytown, NY. Departments of Medicine, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.R.).

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 (, , and ), a controversial monogenic SCD gene (), and novel genes ( and ) involved in cardiac conduction. Loss-of-function and pathogenic variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (=8.4×10). Similar variants in and (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (=4×10), 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.
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http://dx.doi.org/10.1161/CIRCGEN.120.003300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373440PMC
August 2021

Coronary Disease Association With ADAMTS7 Is Due to Protease Activity.

Circ Res 2021 Aug 28;129(4):458-470. Epub 2021 Jun 28.

Cardiovascular Disease Initiative (T.M., B.T.M., B.B., N.R.P., A.A., D.L., Q.M.Z., S.K., P.T.E.), Broad Institute of MIT and Harvard, Cambridge, MA.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349873PMC
August 2021

Deep Learning to Predict Cardiac Magnetic Resonance-Derived Left Ventricular Mass and Hypertrophy From 12-Lead ECGs.

Circ Cardiovasc Imaging 2021 06 15;14(6):e012281. Epub 2021 Jun 15.

Cardiovascular Disease Initiative (S.K., J.P.P., C.D.A., P.T.E., J.E.H., S.A.L.), Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge.

Background: Classical methods for detecting left ventricular (LV) hypertrophy (LVH) using 12-lead ECGs are insensitive. Deep learning models using ECG to infer cardiac magnetic resonance (CMR)-derived LV mass may improve LVH detection.

Methods: Within 32 239 individuals of the UK Biobank prospective cohort who underwent CMR and 12-lead ECG, we trained a convolutional neural network to predict CMR-derived LV mass using 12-lead ECGs (left ventricular mass-artificial intelligence [LVM-AI]). In independent test sets (UK Biobank [n=4903] and Mass General Brigham [MGB, n=1371]), we assessed correlation between LVM-AI predicted and CMR-derived LV mass and compared LVH discrimination using LVM-AI versus traditional ECG-based rules (ie, Sokolow-Lyon, Cornell, lead aVL rule, or any ECG rule). In the UK Biobank and an ambulatory MGB cohort (MGB outcomes, n=28 612), we assessed associations between LVM-AI predicted LVH and incident cardiovascular outcomes using age- and sex-adjusted Cox regression.

Results: LVM-AI predicted LV mass correlated with CMR-derived LV mass in both test sets, although correlation was greater in the UK Biobank (r=0.79) versus MGB (r=0.60, P<0.001 for both). When compared with any ECG rule, LVM-AI demonstrated similar LVH discrimination in the UK Biobank (LVM-AI c-statistic 0.653 [95% CI, 0.608 -0.698] versus any ECG rule c-statistic 0.618 [95% CI, 0.574 -0.663], P=0.11) and superior discrimination in MGB (0.621; 95% CI, 0.592 -0.649 versus 0.588; 95% CI, 0.564 -0.611, P=0.02). LVM-AI-predicted LVH was associated with incident atrial fibrillation, myocardial infarction, heart failure, and ventricular arrhythmias.

Conclusions: Deep learning-inferred LV mass estimates from 12-lead ECGs correlate with CMR-derived LV mass, associate with incident cardiovascular disease, and may improve LVH discrimination compared to traditional ECG rules.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.012281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217289PMC
June 2021

Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

Nat Med 2021 06 7;27(6):1012-1024. Epub 2021 Jun 7.

Institute for Molecular Medicine Finland, Helsinki, Finland.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
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http://dx.doi.org/10.1038/s41591-021-01371-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245201PMC
June 2021

Accelerometer-derived physical activity and risk of atrial fibrillation.

Eur Heart J 2021 07;42(25):2472-2483

Cardiovascular Disease Initiative, Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA, USA.

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.
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http://dx.doi.org/10.1093/eurheartj/ehab250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291334PMC
July 2021

COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets.

Nature 2021 07 29;595(7865):107-113. Epub 2021 Apr 29.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure, but little is known about its pathophysiology. Here we generated single-cell atlases of 24 lung, 16 kidney, 16 liver and 19 heart autopsy tissue samples and spatial atlases of 14 lung samples from donors who died of COVID-19. Integrated computational analysis uncovered substantial remodelling in the lung epithelial, immune and stromal compartments, with evidence of multiple paths of failed tissue regeneration, including defective alveolar type 2 differentiation and expansion of fibroblasts and putative TP63 intrapulmonary basal-like progenitor cells. Viral RNAs were enriched in mononuclear phagocytic and endothelial lung cells, which induced specific host programs. Spatial analysis in lung distinguished inflammatory host responses in lung regions with and without viral RNA. Analysis of the other tissue atlases showed transcriptional alterations in multiple cell types in heart tissue from donors with COVID-19, and mapped cell types and genes implicated with disease severity based on COVID-19 genome-wide association studies. Our foundational dataset elucidates the biological effect of severe SARS-CoV-2 infection across the body, a key step towards new treatments.
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http://dx.doi.org/10.1038/s41586-021-03570-8DOI Listing
July 2021

A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.

Am J Epidemiol 2021 Apr 16. Epub 2021 Apr 16.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
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http://dx.doi.org/10.1093/aje/kwab115DOI Listing
April 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

Role of genetics in atrial fibrillation management.

Europace 2021 04;23(23 Suppl 2):ii4-ii8

Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Atrial fibrillation (AF) management has significantly improved during the career of professor Crijns. Research was implemented into guidelines and clinical practice. However, despite advances in AF management, large differences between individual treatment responses still exist and the mechanisms underlying initiation and perpetuation of AF are not completely understood. International collaborations have revealed the genetic contribution to AF and steps towards improving AF management are being made. In this short review, the most important paradigms shifts in the field of AF genetics are recognized and the future role of genetics in personalized management of AF is discussed.
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http://dx.doi.org/10.1093/europace/euaa366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035706PMC
April 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 May;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
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http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

Usefulness of Rhythm Monitoring Following Acute Ischemic Stroke.

Am J Cardiol 2021 05 20;147:44-51. Epub 2021 Feb 20.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

We characterized monitor utilization in stroke survivors and assessed associations with underlying clinical atrial fibrillation (AF) risk. We retrospectively analyzed consecutive patients with acute ischemic stroke 10/2018-6/2019 without prevalent AF and assessed the 6-month incidence of monitor utilization (Holter/ECG, event/patch, implantable loop recorder [ILR]) using Fine-Gray models accounting for the competing risk of death. We assessed for predictors of monitor utilization using cause-specific hazards regression adjusted for the Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) score, stroke subtype, and discharge disposition. Of 493 patients with acute ischemic stroke (age 65±16; 47% women), the 6-month incidence of monitor utilization was 36.5% (95% CI 31.7, 41.3), and 6-month mortality was 13.6% (10.4, 16.8). Monitoring was performed with Holter/event (n = 107; 72.3%), ILR (n = 34; 23.0%) or both (n = 7; 4.7%). Monitoring was more likely after cryptogenic (hazard ratio [HR] 4.53 [3.22, 6.39]; 6-month monitor incidence 70.6%) and cardioembolic (HR 2.43 [1.28, 4.62]; incidence 47.7%) stroke, versus other/undocumented (incidence 22.7%). Among patients with cryptogenic stroke, the 6-month incidence of ILR was 27.5% [18.5, 36.5]. Monitoring was more likely after discharge home (HR 1.80 [1.29, 2.52]; incidence 46.1%) versus facility (incidence 24.9%). Monitoring was not associated with CHARGE-AF score (HR 1.08 per 1-SD increase [0.91, 1.27]), even though CHARGE-AF was associated with incident AF (HR 1.56 [1.03, 2.35]). In conclusion, rhythm monitors are utilized after one-third of ischemic strokes. Monitoring is more frequent after cryptogenic strokes, though ILR use is low. Monitor utilization is not associated with AF risk.
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http://dx.doi.org/10.1016/j.amjcard.2021.01.038DOI Listing
May 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Non-Vitamin K Antagonist Oral Anticoagulant vs Warfarin for Post Cardiac Surgery Atrial Fibrillation.

Ann Thorac Surg 2021 Jan 10. Epub 2021 Jan 10.

Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: Treatment guidelines for nonvalvular atrial fibrillation (AF) recommend use of non-vitamin K antagonist oral anticoagulants (NOACs) over warfarin, yet clinical trials excluded individuals with post cardiac surgery AF. We sought to compare outcomes with NOACs vs warfarin for new onset post cardiac surgery AF.

Methods: We examined 26,522 patients from The Society of Thoracic Surgeons' database with post cardiac surgery AF who were discharged on oral anticoagulation from July 2017-December 2018. Three primary outcomes were evaluated: 30-day mortality, major bleeding complications, and stroke/transient ischemic attack. Secondary outcomes included postoperative length of stay, 30-day myocardial infarction, venous thromboembolism, and pericardial effusion/tamponade.

Results: A total of 9769 (36.8%) participants were prescribed NOACs and 16,753 (63.2%) warfarin. In multivariable analysis, there was no association between type of anticoagulant and 30-day major bleeding complications (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.49-1.18), stroke/transient ischemic attack (OR 0.94, 95% CI 0.53-1.67) or mortality (OR 1.08, 95% CI 0.80-1.45). After stratification by renal function or isolated coronary bypass vs valve surgery, there remained no difference in the primary outcomes. Additionally, there was no difference in 30-day myocardial infarction (OR 1.17, 95% CI 0.62-2.22), venous thromboembolism (OR 0.91, 95% CI 0.47-1.78), or pericardial effusion/tamponade (OR 1.09, 95% CI 0.80-1.47) between the 2 groups. NOAC therapy was associated with a half-day reduction in postoperative length of stay (β -0.47, 95% CI -0.62 to -0.33).

Conclusions: NOACs are associated with a reduction in postoperative length of stay, without excess bleeding or other short-term complications, compared with warfarin. These findings support the broader use of NOACs as a safe alternative to warfarin in patients with post cardiac surgery AF at elevated stroke risk and acceptable bleeding risk.
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http://dx.doi.org/10.1016/j.athoracsur.2020.12.031DOI Listing
January 2021

Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease.

Circ Genom Precis Med 2021 02 12;14(1):e003006. Epub 2021 Jan 12.

TIMI Study Group, Division of Cardiovascular Medicine, Department of Medicine (N.A.M., G.E.M.M., Y.G., F.K.K., R.P.G., B.M.S., E.B., M.S.S., C.T.R.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease.

Methods: We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations.

Results: A total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles (-trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI, 1.23-2.89; =0.004) and 2.70-fold (95% CI, 1.81-4.06; <0.0001) higher risk of VTE compared with patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the genetic risk score was associated with a 47% (95% CI, 29-68) increased risk of VTE (<0.0001).

Conclusions: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.
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http://dx.doi.org/10.1161/CIRCGEN.120.003006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887088PMC
February 2021

Identification of two preclinical canine models of atrial fibrillation to facilitate drug discovery.

Heart Rhythm 2021 04 17;18(4):632-640. Epub 2020 Dec 17.

Cardiac Arrhythmia Service & Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts.

Background: Atrial fibrillation (AF) is the most common arrhythmia occurring in humans, and new treatment strategies are critically needed. The lack of reliable preclinical animal models of AF is a major limitation to drug development of novel antiarrhythmic compounds.

Objective: The purpose of this study was to provide a comprehensive head-to-head assessment of 5 canine AF models.

Methods: Five canine models were evaluated for the efficacy of AF induction and AF duration. We tested 2 acute models: short-term atrial tachypacing (AT) for 6 hours with analysis of AF at hourly increments, and carbachol injection into a cardiac fat pad followed by short-term AT. We also tested 3 chronic models: pacemaker implantation followed by either 4 weeks of AT and subsequent atrial burst pacing or intermittent long-term AT for up to 4-5 months to generate AF ≥4.5 hours, and finally ventricular tachypacing to induce heart failure followed by atrial burst pacing to induce AF.

Results: Careful evaluation showed that acute AT, AT for 4 weeks, and the heart failure model all were unsuccessful in generating reproducible AF episodes of sufficient duration to study antiarrhythmic drugs. In contrast, intermittent long-term AT generated AF lasting ≥4.5 hours in ∼30% of animals. The acute model using carbachol and short-term AT resulted in AF induction of ≥15 minutes in ≥75% of animals, thus enabling testing of antiarrhythmic drugs.

Conclusion: Intermittent long-term AT and the combination of local carbachol injection with successive short-term AT may contribute to future drug development efforts for AF treatment.
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http://dx.doi.org/10.1016/j.hrthm.2020.12.015DOI Listing
April 2021

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

Performance of Atrial Fibrillation Risk Prediction Models in Over 4 Million Individuals.

Circ Arrhythm Electrophysiol 2021 01 9;14(1):e008997. Epub 2020 Dec 9.

Cardiovascular Disease Initiative, Broad Institute of the Massachusetts Institute of Technology & Harvard University, Cambridge (S.K., J.M.A., A.P., A.V.K., P.T.E., S.A.L.).

Background: Atrial fibrillation (AF) is associated with increased risks of stroke and heart failure. Electronic health record (EHR)-based AF risk prediction may facilitate efficient deployment of interventions to diagnose or prevent AF altogether.

Methods: We externally validated an electronic health record AF (EHR-AF) score in IBM Explorys Life Sciences, a multi-institutional dataset containing statistically deidentified EHR data for over 21 million individuals (Explorys Dataset). We included individuals with complete AF risk data, ≥2 office visits within 2 years, and no prevalent AF. We compared EHR-AF to existing scores including CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation), CHEST (coronary artery disease or chronic obstructive pulmonary disease, hypertension, elderly, systolic heart failure, thyroid disease), and CHADS-VASc. We assessed association between AF risk scores and 5-year incident AF, stroke, and heart failure using Cox proportional hazards modeling, 5-year AF discrimination using C indices, and calibration of predicted AF risk to observed AF incidence.

Results: Of 21 825 853 individuals in the Explorys Dataset, 4 508 180 comprised the analysis (age 62.5, 56.3% female). AF risk scores were strongly associated with 5-year incident AF (hazard ratio per SD increase 1.85 using CHADS-VASc to 2.88 using EHR-AF), stroke (1.61 using CHEST to 1.92 using CHARGE-AF), and heart failure (1.91 using CHADS-VASc to 2.58 using EHR-AF). EHR-AF (C index, 0.808 [95% CI, 0.807-0.809]) demonstrated favorable AF discrimination compared to CHARGE-AF (0.806 [95% CI, 0.805-0.807]), CHEST (0.683 [95% CI, 0.682-0.684]), and CHADS-VASc (0.720 [95% CI, 0.719-0.722]). Of the scores, EHR-AF demonstrated the best calibration to incident AF (calibration slope, 1.002 [95% CI, 0.997-1.007]). In subgroup analyses, AF discrimination using EHR-AF was lower in individuals with stroke (C index, 0.696 [95% CI, 0.692-0.700]) and heart failure (0.621 [95% CI, 0.617-0.625]).

Conclusions: EHR-AF demonstrates predictive accuracy for incident AF using readily ascertained EHR data. AF risk is associated with incident stroke and heart failure. Use of such risk scores may facilitate decision support and population health management efforts focused on minimizing AF-related morbidity.
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http://dx.doi.org/10.1161/CIRCEP.120.008997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856013PMC
January 2021

Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer.

medRxiv 2020 Nov 16. Epub 2020 Nov 16.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood . Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality . Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.
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http://dx.doi.org/10.1101/2020.11.12.20230821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685330PMC
November 2020

Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.

Circulation 2021 Feb 13;143(5):470-478. Epub 2020 Nov 13.

TIMI Study Group, Boston, MA (N.A.M., F.K.K., F.N., G.M.M., R.P.G., B.M.S., M.L.O'D., E.M.A., E.B., M.S.S., C.T.R.).

Background: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease.

Methods: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors.

Results: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke ( trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHADS-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHADS-VASc score of 3.

Conclusions: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHADS-VASc scores, the GRS identified patients with risk comparable to those with higher CHADS-VASc scores.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856243PMC
February 2021

Associations Between Alcohol Intake and Genetic Predisposition With Atrial Fibrillation Risk in a National Biobank.

Circ Genom Precis Med 2020 12 6;13(6):e003111. Epub 2020 Nov 6.

Cardiovascular Disease Initiative, The Broad Institute of MIT & Harvard, Cambridge (J.L.H., L.-C.W., S.H.C., S.J.J., V.N.M., S.K., P.T.E., S.A.L.).

Background: Excess alcohol intake and inherited predisposition may increase risk of atrial fibrillation (AF). We assessed the association between alcohol intake, polygenic predisposition to AF, and incident AF in the UK Biobank, a prospective cohort study.

Methods: In 376 776 UK Biobank participants enrolled between 2006 and 2010, we tested alcohol consumption (stratified by the Centers of Disease Control and Prevention acceptable range of ≤98 g/wk for women or ≤196 g/wk for men; and as a continuous variable) and an AF polygenic risk score for association with incident AF.

Results: Among participants (47.5% male, mean age 56.9 years), 6293 developed AF during a median of 6.9 years of follow-up. Alcohol consumption was associated with AF (hazard ratio, 1.10 [95% CI, 1.05-1.16] for intake above an acceptable range; hazard ratio, 1.04 per 100 g/wk [95% CI, 1.02-1.06]). An AF polygenic risk score was associated with AF (hazard ratio, 1.38 per SD [95% CI, 1.35-1.41]). In models including both alcohol and the AF polygenic risk score, each remained associated with AF. The 5-year cumulative risk of AF for individuals with alcohol intake above an acceptable range and in the highest decile of polygenic risk was 2.33% (95% CI, 2.07-2.59), compared with 0.69% (95% CI, 0.58-0.80) for those with alcohol intake within an acceptable range and in the lowest decile of polygenic risk.

Conclusions: Alcohol consumption is associated with increased risk of AF across a range of polygenic predisposition to AF and adds to inherited and clinical predisposition to increase AF susceptibility. Preventive efforts focused on minimizing alcohol intake may be broadly applicable.
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http://dx.doi.org/10.1161/CIRCGEN.120.003111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738370PMC
December 2020

Epigenetic Analyses of Human Left Atrial Tissue Identifies Gene Networks Underlying Atrial Fibrillation.

Circ Genom Precis Med 2020 12 6;13(6):e003085. Epub 2020 Nov 6.

Cardiovascular Research Center, Massachusetts General Hospital, Boston (A.W.H., S.A.L., N.R.T., P.T.E.).

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), binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions (<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 (<2×10). Chromatin states were differentially methylated, promoters were less methylated than repressed regions (<2×10). 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 , , , and .

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.
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http://dx.doi.org/10.1161/CIRCGEN.120.003085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240092PMC
December 2020

Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank.

Arterioscler Thromb Vasc Biol 2021 01 29;41(1):465-474. Epub 2020 Oct 29.

Center for Genomic Medicine (A.P.P., J.P.P., P.T.E., A.V.K.), Massachusetts General Hospital, Boston.

Objective: Lp(a) (lipoprotein[a]) concentrations are associated with atherosclerotic cardiovascular disease (ASCVD), and new therapies that enable potent and specific reduction are in development. In the largest study conducted to date, we address 3 areas of uncertainty: (1) the magnitude and shape of ASCVD risk conferred across the distribution of lipoprotein(a) concentrations; (2) variation of risk across racial and clinical subgroups; (3) clinical importance of a high lipoprotein(a) threshold to guide therapy. Approach and Results: Relationship of lipoprotein(a) to incident ASCVD was studied in 460 506 middle-aged UK Biobank participants. Over a median follow-up of 11.2 years, incident ASCVD occurred in 22 401 (4.9%) participants. Median lipoprotein(a) concentration was 19.6 nmol/L (25th-75th percentile 7.6-74.8). The relationship between lipoprotein(a) and ASCVD appeared linear across the distribution, with a hazard ratio of 1.11 (95% CI, 1.10-1.12) per 50 nmol/L increment. Substantial differences in concentrations were noted according to race-median values for white, South Asian, black, and Chinese individuals were 19, 31, 75, and 16 nmol/L, respectively. However, risk per 50 nmol/L appeared similar-hazard ratios of 1.11, 1.10, and 1.07 for white, South Asian, and black individuals, respectively. A high lipoprotein(a) concentration defined as ≥150 nmol/L was present in 12.2% of those without and 20.3% of those with preexisting ASCVD and associated with hazard ratios of 1.50 (95% CI, 1.44-1.56) and 1.16 (95% CI, 1.05-1.27), respectively.

Conclusions: Lipoprotein(a) concentrations predict incident ASCVD among middle-aged adults within primary and secondary prevention contexts, with a linear risk gradient across the distribution. Concentrations are variable across racial subgroups, but the associated risk appears similar.
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http://dx.doi.org/10.1161/ATVBAHA.120.315291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769893PMC
January 2021

Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase.

Circulation 2020 Dec 23;142(25):2443-2455. Epub 2020 Oct 23.

Cardiovascular Research Center (L.X., S.C., A.H., A.B., J.T., M.N., P.T.E., D.J.M.), Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood.

Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.

Results: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; <0.0001).

Conclusions: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049210DOI Listing
December 2020
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