Presence of a disease-causing cardiomyopathy variant increased the hazard of atrial fibrillation (adjusted HR 1.55; 95% CI 1.46-1.64; P<0.001), even after adjustment for incident heart failure.
Cohort (n=655,796)
Yes
Does the presence of disease-causing cardiomyopathy variants increase the risk of atrial fibrillation in individuals from the UK Biobank and All of Us cohorts?
Genetic variants that cause cardiomyopathy significantly increase the risk of atrial fibrillation, even in the absence of overt heart failure or ventricular disease, and combining these with polygenic risk scores helps stratify atrial versus ventricular disease risk.
Effect estimate: adjusted HR 1.55 (95% CI 1.46-1.64)
p-value: p=<0.001
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.
Rocha et al. (Wed,) conducted a cohort in Atrial fibrillation (n=655,796). Disease-causing cardiomyopathy variants vs. Absence of disease-causing variants was evaluated on Atrial fibrillation (adjusted HR 1.55, 95% CI 1.46-1.64, p=<0.001). Presence of a disease-causing cardiomyopathy variant increased the hazard of atrial fibrillation (adjusted HR 1.55; 95% CI 1.46-1.64; P<0.001), even after adjustment for incident heart failure.