Dataset Information

Polygenic Risk Score Predicts Sudden Death in Patients With Coronary Disease and Preserved Systolic Function.

ABSTRACT:

Background

A familial predisposition to sudden and/or arrhythmic death (SAD) in the setting of coronary artery disease (CAD) exists; however, the genetic basis is poorly understood.

Objectives

The purpose of this study was to determine whether a genome-wide polygenic score for coronary artery disease (GPS_CAD) might have utility in SAD risk stratification in CAD patients without severe systolic dysfunction.

Methods

A previously validated GPS_CAD was generated utilizing genome-wide genotyping in 4,698 PRE-DETERMINE participants of European ancestry with CAD and left ventricular ejection fraction >30%-35%. The population was dichotomized according to top GPS_CAD decile as defined by the general population, and absolute, proportional, and relative risks for SAD and non-SAD were estimated using competing risk analyses.

Results

Over a median follow-up of 8.0 years, participants in the top GPS_CAD decile were at elevated absolute SAD risk (8.0%; 95% CI: 5.1%-12.4% vs 4.8%; 95% CI: 3.3%-7.0%; P = 0.005) and proportional SAD risk (29% vs 16%; P = 0.0003) compared with the remainder. After controlling for left ventricular ejection fraction, clinical factors, and electrocardiogram parameters, the top GPS_CAD decile was associated with SAD (subdistribution HR: 1.77; 95% CI: 1.23-2.54; P = 0.002) but not non-SAD (subdistribution HR: 1.00; 95% CI: 0.80-1.25; P = 0.98) (P for Δ = 0.003). The addition of the top GPS_CAD decile to the multivariable model significantly improved net reclassification indexes (NRIs) (continuous NRI: 14.0%; P = 0.024; and categorical NRI: 6.6%; P = 0.005) but not the C-index (difference in C-index: 0.007; P = 0.143).

Conclusions

Among CAD patients without severe systolic dysfunction, high GPS_CAD specifically predicted SAD and enriched for both absolute and proportional SAD risk, identifying a population who might benefit from defibrillator therapy.

SUBMITTER: Sandhu RK

PROVIDER: S-EPMC10460525 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Polygenic Risk Score Predicts Sudden Death in Patients With Coronary Disease and Preserved Systolic Function.

Sandhu Roopinder K RK Dron Jacqueline S JS Liu Yunxian Y Moorthy M Vinayaga MV Chatterjee Neal A NA Ellinor Patrick T PT Chasman Daniel I DI Cook Nancy R NR Khera Amit V AV Albert Christine M CM

Journal of the American College of Cardiology 20220801 9

<h4>Background</h4>A familial predisposition to sudden and/or arrhythmic death (SAD) in the setting of coronary artery disease (CAD) exists; however, the genetic basis is poorly understood.<h4>Objectives</h4>The purpose of this study was to determine whether a genome-wide polygenic score for coronary artery disease (GPS<sub>CAD</sub>) might have utility in SAD risk stratification in CAD patients without severe systolic dysfunction.<h4>Methods</h4>A previously validated GPS<sub>CAD</sub> was gene ...[more]

PMID: 36007985

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Project description:ImportanceThe majority of sudden and/or arrhythmic deaths (SAD) in patients with coronary heart disease occur in those without severe systolic dysfunction, for whom strategies for sudden death prevention are lacking.ObjectiveTo provide contemporary estimates of SAD vs other competing causes of death in patients with coronary heart disease without severe systolic dysfunction to search for high-risk subgroups that might be targeted in future trials of SAD prevention.Design, setting, and participantsThis prospective observational cohort study included 135 clinical sites in the United States and Canada. A total of 5761 participants with coronary heart disease who did not qualify for primary prevention implantable cardioverter defibrillator therapy based on left ventricular ejection fraction (LVEF) of more than 35% or New York Heart Association (NYHA) heart failure class (LVEF >30%, NYHA I).ExposuresClinical risk factors measured at baseline including age, LVEF, and NYHA heart failure class.Main outcomes and measuresPrimary outcome of SAD, which is a composite of SAD and resuscitated ventricular fibrillation arrest.ResultsThe mean (SD) age of the cohort was 64 (11) years. During a median of 3.9 years, the cumulative incidence of SAD and non-SAD was 2.1% and 7.7%, respectively. Sudden and/or arrhythmic death was the most common mode of cardiovascular death accounting for 114 of 202 cardiac deaths (56%), although noncardiac death was the primary mode of death in this population. The 4-year cumulative incidence of SAD was lowest in those with an LVEF of more than 60% (1.0%) and highest among those with LVEF of 30% to 40% (4.9%) and class III/IV heart failure (5.1%); however, the cumulative incidence of non-SAD was similarly elevated in these latter high-risk subgroups. Patients with a moderately reduced LVEF (40%-49%) were more likely to die of SAD, whereas those with class II heart failure and advancing age were more likely to die of non-SAD. The proportion of deaths due to SAD varied widely, from 14% (18 of 131 deaths) in patients with NYHA II to 49% (37 of 76 deaths) in those younger than 60 years.Conclusions and relevanceIn a contemporary population of patients with coronary heart disease without severe systolic dysfunction, SAD accounts for a significant proportion of overall mortality. Moderately reduced LVEF, age, and NYHA class distinguished SAD and non-SAD, whereas other markers were equally associated with both modes of death. Absolute and proportional risk of SAD varied significantly across clinical subgroups, and both will need to be maximized in future risk stratification efforts.

Project description:The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.

Project description:BackgroundThe value of polygenic risk scores (PRSs) towards improving guideline-recommended clinical risk models for coronary artery disease (CAD) prediction is controversial. Here we examine whether an integrated polygenic risk score improves the prediction of CAD beyond pooled cohort equations. METHODS: An observation study of 291,305 unrelated White British UK Biobank participants enrolled from 2006 to 2010 was conducted. A case-control sample of 9499 prevalent CAD cases and an equal number of randomly selected controls was used for tuning and integrating of the polygenic risk scores. A separate cohort of 272,307 individuals (with follow-up to 2020) was used to examine the risk prediction performance of pooled cohort equations, integrated polygenic risk score, and PRS-enhanced pooled cohort equation for incident CAD cases. The performance of each model was analyzed by discrimination and risk reclassification using a 7.5% threshold.ResultsIn the cohort of 272,307 individuals (mean age, 56.7 years) used to analyze predictive accuracy, there were 7036 incident CAD cases over a 12-year follow-up period. Model discrimination was tested for integrated polygenic risk score, pooled cohort equation, and PRS-enhanced pooled cohort equation with reported C-statistics of 0.640 (95% CI, 0.634-0.646), 0.718 (95% CI, 0.713-0.723), and 0.753 (95% CI, 0.748-0.758), respectively. Risk reclassification for the addition of the integrated polygenic risk score to the pooled cohort equation at a 7.5% risk threshold resulted in a net reclassification improvement of 0.117 (95% CI, 0.102 to 0.129) for cases and - 0.023 (95% CI, - 0.025 to - 0.022) for noncases [overall: 0.093 (95% CI, 0.08 to 0.104)]. For incident CAD cases, this represented 14.2% correctly reclassified to the higher-risk category and 2.6% incorrectly reclassified to the lower-risk category.ConclusionsAddition of the integrated polygenic risk score for CAD to the pooled cohort questions improves the predictive accuracy for incident CAD and clinical risk classification in the White British from the UK Biobank. These findings suggest that an integrated polygenic risk score may enhance CAD risk prediction and screening in the White British population.

Project description:BackgroundAlthough sudden cardiac death is a leading cause of death in the United States, most victims of sudden cardiac death are not identified as at risk prior to death. We sought to derive and validate a population-based risk score that predicts sudden cardiac death.MethodsThe Atherosclerosis Risk in Communities (ARIC) Study recorded clinical measures from men and women aged 45-64 years at baseline; 11,335 white and 3780 black participants were included in this analysis. Participants were followed over 10 years and sudden cardiac death was physician adjudicated. Cox proportional hazards models were used to derive race-specific equations to estimate the 10-year sudden cardiac death risk. Covariates for the risk score were selected from available demographic and clinical variables. Utility was assessed by calculating discrimination (Harrell's C-index) and calibration (Hosmer-Lemeshow chi-squared test). The white-specific equation was validated among 5626 Framingham Heart Study participants.ResultsDuring 10 years' follow-up among ARIC participants (mean age 54.4 years, 52.4% women), 145 participants experienced sudden cardiac death; the majority occurred in the highest quintile of predicted risk. Model covariates included age, sex, total cholesterol, lipid-lowering and hypertension medication use, blood pressure, smoking status, diabetes, and body mass index. The score yielded very good internal discrimination (white-specific C-index 0.82; 95% confidence interval [CI], 0.78-0.85; black-specific C-index 0.75; 95% CI, 0.68-0.82) and very good external discrimination among Framingham participants (C-index 0.82; 95% CI, 0.79-0.86). Calibration plots indicated excellent calibration in ARIC (white-specific chi-squared 5.3, P = .82; black-specific chi-squared 4.1, P = .77), and a simple recalibration led to excellent fit within Framingham (chi-squared 2.1, P = 0.99).ConclusionsThe proposed risk scores may be used to identify those at risk for sudden cardiac death within 10 years and particularly classify those at highest risk who may merit further screening.

Dataset Information

Polygenic Risk Score Predicts Sudden Death in Patients With Coronary Disease and Preserved Systolic Function.

Background

Objectives

Methods

Results

Conclusions

Publications

Polygenic Risk Score Predicts Sudden Death in Patients With Coronary Disease and Preserved Systolic Function.

Similar Datasets

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