Fine mapping of candidate effector genes for heart rate.

An elevated resting heart rate (RHR) is associated with increased cardiovascular mortality. Genome-wide association studies (GWAS) have identified > 350 loci. Uniquely, in this study we applied genetic fine-mapping leveraging tissue specific chromatin segmentation and colocalization analyses to identify causal variants and candidate effector genes for RHR. We used RHR GWAS summary statistics from 388,237 individuals of European ancestry from UK Biobank and performed fine mapping using publicly available genomic annotation datasets. High-confidence causal variants (accounting for > 75% posterior probability) were identified, and we collated candidate effector genes using a multi-omics approach that combined evidence from colocalisation with molecular quantitative trait loci (QTLs), and long-range chromatin interaction analyses. Finally, we performed druggability analyses to investigate drug repurposing opportunities. The fine mapping pipeline indicated 442 distinct RHR signals. For 90 signals, a single variant was identified as a high-confidence causal variant, of which 22 were annotated as missense. In trait-relevant tissues, 39 signals colocalised with cis-expression QTLs (eQTLs), 3 with cis-protein QTLs (pQTLs), and 75 had promoter interactions via Hi-C. In total, 262 candidate genes were highlighted (79% had promoter interactions, 15% had a colocalised eQTL, 8% had a missense variant and 1% had a colocalised pQTL), and, for the first time, enrichment in nervous system pathways. Druggability analyses highlighted ACHE, CALCRL, MYT1 and TDP1 as potential targets. Our genetic fine-mapping pipeline prioritised 262 candidate genes for RHR that warrant further investigation in functional studies, and we provide potential therapeutic targets to reduce RHR and cardiovascular mortality.

Associations of educational and marketing messages with beliefs about nicotine and reduced nicotine cigarettes.

INTRODUCTION: Widespread misperceptions about nicotine may have unintended effects on public health. We examined associations between existing messages about nicotine or tobacco and beliefs about nicotine and reduced nicotine cigarettes (RNC). METHODS: 2962 U.S. 18-45-year-olds were randomized in a May 2022 web-based survey to view one of 26 text-based messages about tobacco or nicotine from three sources: ongoing research (n = 8), messages authorized by FDA for VLN cigarettes (n = 6), and FDA's "From Plant to Product to Puff" campaign (n = 12); six messages from FDA's campaign did not reference nicotine and were treated as the reference source. Analyses examined associations between messages, grouped by source and individually, with beliefs about nicotine and RNC addictiveness and harms. RESULTS: Relative to FDA messages that did not reference nicotine, all message sources were associated with greater odds of a correct belief about nicotine (Odds Ratios [ORs] = 1.40-1.87, p's < 0.01); VLN messages were associated with greater correct beliefs about RNC addictiveness (b = 0.23, p < .05). No campaign produced greater correct beliefs about RNC harms. At the individual level, only five messages were associated with a correct belief about nicotine (ORs = 2.12-2.56, p-values < .01), and one with correct beliefs about RNC harms (b = 1.09, p < .05), vs. the reference message. CONCLUSIONS: Few existing messages improved understanding of the risks of nicotine separately from the risks of combustible products. Communication research is needed to promote greater public understanding of nicotine while minimizing unintended effects on nicotine and tobacco use.

Perceived relative harm and addictiveness compared with cigarettes and intentions to use modified risk tobacco products utilizing FDA-authorized marketing claims among adults in the United States.

INTRODUCTION: We assessed adults' perceived relative harm and addictiveness of products using FDA-authorized modified risk tobacco products (MRTP) claims and associations with intentions to use MRTPs. METHODS: Data were from the May 2022 Rutgers Omnibus study among US 18-45-year-old adults (n=2964), collected by the Rutgers Institute for Nicotine and Tobacco Studies (INTS). Outcomes were perceived relative harm and addictiveness versus a typical cigarette and intentions to use a product stating a reduced harm claim (General Snus) or a reduced exposure claim (VLN King). We conducted regression analyses of associations between perceived relative harm and addictiveness and intentions to use each product, stratified by smoking status. RESULTS: The minority of participants perceived products with a reduced harm claim as much less harmful vs. cigarettes (21 %, 19 %, 7 %, and 8 % among persons who smoked daily, smoked some days, formerly smoked, and never smoked respectively) and products with a reduced exposure claim as much less addictive vs. cigarettes (24 %, 26 %, 14 %, 20 % respectively). Perceived lower relative harm and addictiveness were significantly associated with higher intentions to use products stating reduced harm or reduced exposure claim across all smoking statuses with one exception (relative addictiveness was not associated with intention to use products stating the reduced harm claim among persons who formerly smoked). CONCLUSIONS: Two current FDA-authorized MRTP claims were not effective in conveying that MRTPs were less harmful or addictive than cigarettes to most participants. Perceiving products as less harmful or addictive were significantly associated with intentions to use MRTPs.

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Measurement of cigarette relighting: A common but understudied behavior.

OBJECTIVE: Relighting, i.e., extinguishing, saving, and later relighting and smoking unfinished cigarettes, appears prevalent, may be associated with nicotine dependence and negative health outcomes, yet is poorly understood. We estimate the prevalence, frequency, correlates of, and reasons for, cigarette relighting. METHODS: Survey respondents (n=676) were 18-45-year-old US-based Amazon Mechanical Turk (MTurk) participants who smoked cigarettes every/some days. Items assessed frequency of and reasons for relighting. Reported smoking sessions per day were compared to calculations based on reported cigarettes per day (CPD) and relighting frequency. RESULTS: Seventy-two percent of those who smoked reported relighting cigarettes. Reasons included not having time to finish (77%), not feeling like finishing (75%), saving money or avoiding wasting (70%), and making cigarettes last longer (59%). Nearly half (44%) relight to cut down and 34% to reduce harm. Hispanic (OR=1.73, CI:1.03-2.91) and non-Hispanic Black respondents (OR= 2.23, CI:1.20-4.10) had higher odds of relighting than others, as did those who smoke within 30minutes of waking (OR=2.45, CI:1.33-4.52) or wake up at night to smoke (OR=2.40, CI:1.68-3.44) (all ps <0.05). Respondents demonstrated low consistency in reporting the number of times they smoke (first-lit and relit) compared to calculations based on CPD and relighting frequency. CONCLUSIONS: Relighting is associated with race, ethnicity, nicotine dependence, and is often done to save money, cut down smoking, and reduce harm. Among those who relight, "smoking session" frequency seemed to be underestimated. Single item smoking frequency measures may not be ideal for individuals who smoke and relight.

T-wave morphology abnormalities in the STREAM stage 1 trial.

BACKGROUND: Shorter regimens for drug-resistant tuberculosis (DR-TB) have non-inferior efficacy compared with longer regimens, but QT prolongation is a concern. T-wave morphology abnormalities may be a predictor of QT prolongation. RESEARCH DESIGN AND METHODS: STREAM Stage 1 was a randomized controlled trial in rifampicin-resistant TB, comparing short and long regimens. All participants had regular ECGs. QT/QTcF prolongation (≥500 ms or increase in ≥60 ms from baseline) was more common on the short regimen which contained high-dose moxifloxacin and clofazimine. Blinded ECGs were selected from the baseline, early (weeks 1-4), and late (weeks 12-36) time points. T-wave morphology was categorized as normal or abnormal (notched, asymmetric, flat-wave, flat peak, or broad). Differences between groups were assessed using Chi-Square tests (paired/unpaired, as appropriate). RESULTS: Two-hundred participants with available ECGs at relevant times were analyzed (QT prolongation group n = 82; non-prolongation group n = 118). At baseline, 23% (45/200) of participants displayed abnormal T-waves, increasing to 45% (90/200, p < 0.001) at the late time point. Abnormalities were more common in participants allocated the Short regimen (75/117, 64%) than the Long (14/38, 36.8%, p = 0.003); these occurred prior to QT/QTcF ≥500 ms in 53% of the participants (Long 2/5; Short 14/25). CONCLUSIONS: T-wave abnormalities may help identify patients at risk of QT prolongation on DR-TB treatment. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02409290). Current Controlled Trial number, ISRCTN78372190.

The frequency of gene variant reclassification and its impact on clinical management in the inherited arrhythmia clinic.

BACKGROUND: Genetic testing in the inherited arrhythmia clinic informs risk stratification, clinical management, and family screening. Periodic review of variant classification is recommended as supporting evidence accrues over time. However, there is limited reporting of real-world data on the frequency and impact of variant reclassification. OBJECTIVE: The purpose of this study was to determine the burden of variant reclassification in our inherited arrhythmia clinic and the impact on clinical management. METHODS: Genetic testing reports for patients referred to our clinic from 2004-2020 were reviewed. Reported variants were reinvestigated using ClinVar, VarSome, and a literature review. Classification was updated using the American College of Medical Genetics and Genomics (ACMG) criteria and tested for association with arrhythmic events and modification of medical management. RESULTS: We identified 517 patients (median age 37 years) who underwent gene panel testing. A variant of uncertain significance (VUS) was reported for 94 patients (18.2%) and more commonly identified when using large gene panels (P <.001). A total of 28 of 87 unique VUSs (32.2%) were reclassified to pathogenic/likely pathogenic (n = 11) or benign/likely benign (n = 17). Of 138 originally reported pathogenic variants, 7 (5.1%) lacked support using ACMG criteria. Variant reclassification was not associated with arrhythmic events; however, it did impact genotype-specific counseling and future therapeutic options. CONCLUSION: In our large real-world patient cohort, we identify a clinically important proportion of both pathogenic variants and VUSs with evidence for reclassification. These findings highlight the need for informed pretest counseling, a regular structured review of variants reported in genetic testing, and the potential benefits to patients for supporting genotype-guided therapy.

Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement.

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

Long-term association of ultra-short heart rate variability with cardiovascular events.

Heart rate variability (HRV) is a cardiac autonomic marker with predictive value in cardiac patients. Ultra-short HRV (usHRV) can be measured at scale using standard and wearable ECGs, but its association with cardiovascular events in the general population is undetermined. We aimed to validate usHRV measured using ≤ 15-s ECGs (using RMSSD, SDSD and PHF indices) and investigate its association with atrial fibrillation, major adverse cardiac events, stroke and mortality in individuals without cardiovascular disease. In the National Survey for Health and Development (n = 1337 participants), agreement between 15-s and 6-min HRV, assessed with correlation analysis and Bland-Altman plots, was very good for RMSSD and SDSD and good for PHF. In the UK Biobank (n = 51,628 participants, 64% male, median age 58), after a median follow-up of 11.5 (11.4-11.7) years, incidence of outcomes ranged between 1.7% and 4.3%. Non-linear Cox regression analysis showed that reduced usHRV from 15-, 10- and 5-s ECGs was associated with all outcomes. Individuals with low usHRV (< 20th percentile) had hazard ratios for outcomes between 1.16 and 1.29, p < 0.05, with respect to the reference group. In conclusion, usHRV from ≤ 15-s ECGs correlates with standard short-term HRV and predicts increased risk of cardiovascular events in a large population-representative cohort.

Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension.

Genome-wide association studies of blood pressure (BP) have identified >1,000 loci, but the effector genes and biological pathways at these loci are mostly unknown. Using published association summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation and colocalization to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with ≥2 BP traits and 84 with all three. For >20% of signals, a single variant accounted for >75% posterior probability, 65 were missense variants in known (SLC39A8, ADRB2, and DBH) and previously unreported BP candidate genes (NRIP1 and MMP14). In disease-relevant tissues, we colocalized >80 and >400 distinct signals for each BP trait with cis-eQTLs and regulatory regions from promoter capture Hi-C, respectively. Integrating mouse, human disorder, gene expression and tissue abundance data, and literature review, we provide consolidated evidence for 436 BP candidate genes for future functional validation and discover several potential drug targets.

Right coronary artery compromise following radiofrequency catheter ablation for supraventricular tachycardia: cases reports.

Background: Coronary compromise is a serious potential complication following catheter ablation; however, procedural details in the literature are often lacking, preventing the identification of learning opportunities. Case summary: We report two cases of right coronary compromise following catheter ablation for symptomatic supraventricular tachycardia. After radiofrequency energy delivery at the coronary sinus ostium in both cases, inferior lead ST-elevation was observed. Diagnostic coronary angiography identified an occluded posterior left ventricular branch of the coronary artery, and optical coherence tomography demonstrated a high thrombus burden at this location. Electrocardiographic ST-segments settled with implantation of a drug-eluting stent. Discussion: Coronary compromise was likely secondary to energy delivery during catheter ablation. This case series highlights the need for electrophysiologist to understand coronary anatomy relative to anatomical landmarks, to anticipate the risk of vascular injury as physical distance from the site of ablation is likely important. Risk for coronary compromise, while a rare complication, needs to be discussed with patients during the consenting process. We also demonstrate the importance of an efficient multi-disciplinary team process for managing acute procedural complications.

Estimating Prevalence of Premium or Traditional Cigar Use and User Characteristics Based on Varying Definitions of Use.

BACKGROUND: Premium cigar use is infrequent compared with the use of other tobacco products, including other cigar types (eg, cigarillos), though current measurement methods for premium cigar use have limitations. Accordingly, prevalence estimates from existing surveillance studies likely underestimate the true prevalence of premium cigar use. AIMS AND METHODS: Using an online convenience sample of adults (ages 18-45 years) surveyed in February 2022, we examined premium or traditional cigar prevalence and characterized users based on four definitions of use: (1) past-year use, (2) past 30-day use, (3) use every day or some days, and (4) use every day, some days, or rarely, using a novel, one-item measure. We examined demographics, cigar use behaviors, and other tobacco product use for each definition and conducted sensitivity analyses using cigar brands. RESULTS: Prevalence estimates ranged from 1.8% using Definition 3 to 11.6% using Definition 1. Regardless of definition, premium or traditional cigar users were largely male, white, and aged 25-45 years. A large proportion of users based on Definition 3 were aged 25-34 years, had a regular premium cigar brand, smoked cigars on more than one day in the past month, used cannabis in the past month, and reported perceiving premium cigars as less harmful compared with cigarettes. DISCUSSION: Prevalence estimates of premium or traditional cigar use varied by more than fivefold based on the definition of use and user characteristics varied by definition. Existing national surveys are likely underestimating the prevalence and patterns of premium cigar use. IMPLICATIONS: Given that the negative health effects of premium cigars vary based on how the cigars are used (eg, frequency or duration), as well as co-use with other tobacco products and substances (eg, alcohol and cannabis), accurate measurement of these products is important for understanding patterns of use and their impact on public health.

Electronic Health Record Prompt to Improve Lung Cancer Screening in Primary Care.

INTRODUCTION: Lung cancer is the leading cause of cancer death in the U.S. Combusted tobacco use, the primary risk factor, accounts for 90% of all lung cancers. Early detection of lung cancer improves survival, yet lung cancer screening rates are much lower than those of other cancer screening tests. Electronic health record (EHR) systems are an underutilized tool that could improve screening rates. METHODS: This study was conducted in the Rutgers Robert Wood Johnson Medical Group, a university-affiliated network in New Brunswick, NJ. Two novel EHR workflow prompts were implemented on July 1, 2018. These prompts included fields to determine tobacco use and lung cancer screening eligibility and facilitated low-dose computed tomography ordering for eligible patients. The prompts were designed to improve tobacco use data entry, allowing for better lung cancer screening eligibility identification. Data were analyzed in 2022 retrospectively for the period July 1, 2017 to June 30, 2019. The analyses represented 48,704 total patient visits. RESULTS: The adjusted odds of patient record completeness to determine eligibility for low-dose computed tomography (AOR=1.19, 95% CI=1.15, 1.23), eligibility for low-dose computed tomography (AOR=1.59, 95% CI=1.38, 1.82), and whether low-dose computed tomography was ordered (AOR=1.04, 95% CI=1.01, 1.07) all significantly increased after the electronic medical record prompts were implemented. CONCLUSIONS: These findings show the utility and benefit of EHR prompts in primary care settings to increase identification for lung cancer screening eligibility as well as increased low-dose computed tomography ordering.

Premature atrial and ventricular contractions detected on wearable-format electrocardiograms and prediction of cardiovascular events.

Aims: Wearable devices are transforming the electrocardiogram (ECG) into a ubiquitous medical test. This study assesses the association between premature ventricular and atrial contractions (PVCs and PACs) detected on wearable-format ECGs (15 s single lead) and cardiovascular outcomes in individuals without cardiovascular disease (CVD). Methods and results: Premature atrial contractions and PVCs were identified in 15 s single-lead ECGs from N = 54 016 UK Biobank participants (median age, interquartile range, age 58, 50-63 years, 54% female). Cox regression models adjusted for traditional risk factors were used to determine associations with atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), stroke, life-threatening ventricular arrhythmias (LTVAs), and mortality over a period of 11.5 (11.4-11.7) years. The strongest associations were found between PVCs (prevalence 2.2%) and HF (hazard ratio, HR, 95% confidence interval = 2.09, 1.58-2.78) and between PACs (prevalence 1.9%) and AF (HR = 2.52, 2.11-3.01), with shorter prematurity further increasing risk. Premature ventricular contractions and PACs were also associated with LTVA (P < 0.05). Associations with MI, stroke, and mortality were significant only in unadjusted models. In a separate UK Biobank sub-study sample [UKB-2, N = 29,324, age 64, 58-60 years, 54% female, follow-up 3.5 (2.6-4.8) years] used for independent validation, after adjusting for risk factors, PACs were associated with AF (HR = 1.80, 1.12-2.89) and PVCs with HF (HR = 2.32, 1.28-4.22). Conclusion: In middle-aged individuals without CVD, premature contractions identified in 15 s single-lead ECGs are strongly associated with an increased risk of AF and HF. These data warrant further investigation to assess the role of wearable ECGs for early cardiovascular risk stratification.

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Tobacco Treatment Knowledge and Practices Among US Psychiatrists.

This study explores the extent to which psychiatrists are familiar with, and utilize, the USPHS guidelines for treating tobacco use and dependence (i.e., the 5A's), deliver cessation treatment, and the barriers they perceive to doing so. An original, national survey of 141 psychiatrists revealed that most Ask patients if they smoke (81.6%). Fewer Advise them to stop (78.7%) and Assess their willingness to quit (73.6%). A minority Assist with a quit plan (15.9%) and Arrange for follow-up (26.4%). Just 11.9% have used the USPHS guidelines in clinical practice; 37% have never heard of them. Even among those who say they have used the USPHS guidelines, implementation of the 5A's is quite low. Time-related factors were the most common barriers to cessation delivery (51.4%). Patient factors (30%) and financial/resource factors (25%) were less common. There is a strong need for increased implementation of clinical guidelines for evidence-based tobacco treatments among psychiatrists.

Impact of Mode Switching on Nonresponse and Bias in a Multimode Longitudinal Study of Young Adults.

Young adults are generally hard to survey, presenting researchers with numerous difficulties. They are hard to locate and contact due to high mobility. They are hard to persuade and exhibit high levels of resistance to survey participation. As a result, they pose a greater challenge for longitudinal surveys. This paper explores the role of mode of data collection in young adults' decisions to stay in a longitudinal panel. We draw on data from the National Young Adult Health Survey (NYAHS). NYAHS is a longitudinal study (three annual waves and 2 brief between-wave follow-up surveys) of adults aged 18-34 initially recruited in 2019 through RDD sampling of cell phone numbers nationwide. All sampled cell phone numbers were randomly assigned to one of three experimental conditions; the conditions differed in mode of data collection used in subsequent interviews once screened in. In the first condition, young adults continue all rounds of interviews by telephone ("telephone only" condition). The second group of young adults completed one round of interview by web and the rest by telephone ("telephone mostly" condition). The last third was asked to complete three interviews online and two interviews by telephone ("web mostly" condition). We examined the impact of mode switching on young adults' likelihood of participating in later surveys and on nonresponse bias in key survey outcomes. We found that switching young adults from telephone to web had an immediate negative effect on their likelihood of participating in that web survey, but it did not have a continued negative effect. Switching them from web to telephone increased response rates and reduced nonresponse bias. The findings have important practical implications on how to survey young adults.

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Prediction of Coronary Artery Disease and Major Adverse Cardiovascular Events Using Clinical and Genetic Risk Scores for Cardiovascular Risk Factors.

BACKGROUND: Coronary artery disease (CAD) and major adverse cardiovascular events (MACE) are the leading causes of death in the general population, but risk stratification remains suboptimal. CAD genetic risk scores (GRSs) predict risk independently from clinical tools, like QRISK3. We assessed the added value of GRSs for a variety of cardiovascular traits (CV GRSs) for predicting CAD and MACE and tested their early-life screening potential by comparing against the CAD GRS only. METHODS: We used data from 379 581 participants in the UK Biobank without known cardiovascular conditions (follow-up, 11.3 years; 3.3% CAD cases and 5.2% MACE cases). In a training subset (50%) we built 3 scores: QRISK3; QRISK3 and an established CAD GRS; and QRISK3, the CAD GRS and the CV GRSs. In an independent subset (50%), we evaluated each score's performance using the concordance index, odds ratio and net reclassification index. We then repeated the analyses without considering QRISK3. RESULTS: For CAD, the combination of QRISK3 and the CAD GRS had a better performance than QRISK3 alone (concordance index, 0.766 versus 0.753; odds ratio, 5.47 versus 4.82; net reclassification index, 7.7%). Adding the CV GRSs did not significantly improve risk stratification. When only looking at genetic information, the combination of CV GRSs and the CAD GRS had a better performance than the CAD GRS alone (concordance index, 0.637 versus 0.625; odds ratio, 2.17 versus 2.07; net reclassification index, 3.3%). Similar results were obtained for MACE. CONCLUSIONS: In individuals without known cardiovascular disease, the inclusion of CV GRSs to a clinical tool and an established CAD GRS does not improve CAD or MACE risk stratification. However, their combination only with the CAD GRS increases prediction performance indicating potential use in early-life screening before the advanced development of conventional cardiovascular risk factors.