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Cardiomyopathy Gene Variants and Polygenic Risk Scores in Atrial Fibrillation: Evidence for an Atrial-First Phenotype
Guilherme L da Rocha1, James Feiner2, Julieta Lazarte3
1Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
Insights
Genetic variants causing cardiomyopathy increase atrial fibrillation (AF) risk, even without heart failure. Combining genetic risk scores with these variants helps predict atrial versus ventricular disease development.
Area of Science:
- Cardiovascular Genetics
- Genomics
- Medical Genetics
Background:
- Atrial fibrillation (AF) is a heritable condition with a complex genetic basis.
- Understanding the genetic links between AF and cardiomyopathies is crucial for risk stratification.
Purpose of the Study:
- To investigate the impact of cardiomyopathy-causing variants on AF risk.
- To assess the utility of polygenic risk scores (PRS) in differentiating atrial and ventricular disease risks.
Main Methods:
- Cox regression analysis was used to assess associations between cardiomyopathy variants and AF.
- Disease-specific PRSs for AF, dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM) were utilized.
- Meta-analysis and Kaplan-Meier methods were employed to evaluate cumulative incidence.
Main Results:
- Disease-causing variants were associated with a 1.73-fold increased hazard of AF (P < 0.001).
- This association persisted after adjusting for ventricular cardiomyopathy or heart failure (adjusted HR: 1.55).
- Individuals with high-risk variants and PRS showed significantly higher cumulative AF and cardiomyopathy risks.
Conclusions:
- Cardiomyopathy-associated genetic variants elevate AF risk, independent of overt ventricular disease or heart failure.
- Integrating disease-specific PRSs with these variants aids in predicting the likelihood of developing atrial or ventricular disease.
- Genes causing cardiomyopathy may have a substantial, often equal or greater, impact on AF risk.
Background:
Atrial fibrillation (AF) is heritable and its complex underlying genetic substrate is gradually being unraveled.
Objectives:
We sought to explore the impact of disease-causing cardiomyopathy variants on the risk of AF after adjustment for incident ventricular cardiomyopathy and clinical heart failure in 2 cohort studies (UK Biobank [UKB] and All of Us [AoU]) and evaluate the utility of polygenic risk scores (PRS) to further discern the risk of atrial and ventricular phenotypes in carriers.
Methods:
Cox regression was used to evaluate for associations between disease-causing variants within genes for 3 cardiomyopathies (dilated cardiomyopathy [DCM], hypertrophic cardiomyopathy [HCM], and arrhythmogenic right ventricular cardiomyopathy) and AF. Disease-specific PRSs for AF, DCM, and HCM stratified study participants into quintiles. A HR random-effects meta-analysis was performed using the DerSimonian-Laird method. The Kaplan-Meier method was used to ascertain cumulative incidence from birth to 75 years of age.
Results:
Among 655,796 individuals from UKB and AoU, presence of a disease-causing variant was associated with an increased AF hazard (HR: 1.73; 95% CI: 1.59-1.89; P < 0.001), including after adjustment for incident ventricular cardiomyopathy or clinical heart failure (adjusted to HR: 1.55; 95% CI: 1.46-1.64, P < 0.001). The cumulative AF risk for study participants with a putative disease-causing rare variant and a PRSAF within the top-risk quintile ranged from 32.5% (UKB) to 32.4% (AoU) relative to 9.8% (UKB) and 11.0% (AoU) for individuals without a putative disease-causing variant and a PRSAF within the lowest-risk quintile. The absolute cumulative cardiomyopathy risk among study participants with both a putative disease-causing variant and a disease-specific PRS within the top-risk quintile ranged from 5.9% (UKB) to 15.2% (AoU) for DCM and from 11.7% (UKB) to 19.1% (AoU) for HCM.
Conclusions:
Genetic variants that cause cardiomyopathy also increase the risk of AF, even in individuals without heart failure or overt ventricular disease. Combining disease-specific PRSs with these variants helps identify whether a person is more likely to develop atrial or ventricular disease. Although discovered as causes of cardiomyopathy, these genes often have an equal or greater impact on the risk of AF.
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