Prevalence and implications of cardiomyopathy-associated genetic variants in early-onset atrial fibrillation
Authors: Wijdeveld L F J M , Jurgens S J , Ajufo E , Challa S P , Ramo J T , Kany S , Weng L C , Choi S H , Van Tintelen J P , Brundel B J J M , Ellinor P T 
Published: October 2024

Abstract

Background
Atrial fibrillation (AF) is a common and morbid arrhythmia. Despite a substantial heritable component, genetics does not currently play a role in personalized medicine for AF. Rare genetic variants in genes associated with inherited cardiomyopathies (CMP) are enriched in AF patients. However, prior studies on rare variants in AF mainly relied on hospital-based populations, and knowledge on clinical outcomes remains limited.

Purpose
We aimed to evaluate the potential diagnostic yield and prognostic implication of pathogenic or likely pathogenic (PLP) genetic variants for CMP in persons with AF, using large population-based cohorts.

Methods
This study utilized sequencing data and electronic health records (EHR) from the All of Us Researh Program (AllofUs) and UK Biobank (UKB). Using ClinVar, we curated a set of PLP variants in 36 CMP-associated genes and assessed the carrier prevalence overall, in participants with AF, and in participants with early-onset AF (below 65, 55 and 45 years). Next, we used Cox proportional hazards models to evaluate the association between variant carrier status and incident risk of heart failure or CMP, after AF diagnosis. In all time-to-event analyses, individuals with prevalent heart failure or CMP at AF diagnosis were excluded and models were adjusted for age, sex, and principal components of ancestry. Sensitivity analyses were performed requiring a minimum period from AF to HF or CMP, of 1, 3 and 6 months.

Results
After excluding related individuals, we identified 32,281 (8.19%) and 9,666 (6.06%) AF cases in UKB and AllofUs, respectively. Compared to the overall populations (UKB: 1.15%; AllofUs: 1.36%), PLP variants for CMP were about ~5 times more prevalent in AF with onset before 45 (UKB: 4.98%; AllofUs: 5.26%), ~3 times more prevalent in AF with onset before 55 (UKB: 3.41%; AllofUs: 4.34%) and ~2 times more prevalent in all AF patients (UKB: 2.03%; AllofUs: 2.67%). In turn, AF patients carrying PLP variants had increased risk of developing heart failure or CMP, after AF diagnosis (AllofUs HR 1.81, 1.44-2.29, p&lt;1e10-6, UKB:HR=1.39 1.08-1.78, p&lt;0.01), which remained present when requiring a minimum of 6 months after AF diagnosis (AllofUs:HR 1.70, 1.29-2.25, p&lt;0.001; UKB:HR=1.59, 1.21-2.07, p&lt;0.001). Effect sizes were greater when limiting analysis to AF patients with onset before 65 (cases=1021, HR 1.91, 1.35-2.68, p&lt;0.0001) and before 55 years (cases=384, HR 2.53, 1.55-4.1, p &lt;0.001) in AllofUs. UK Biobank did not reflect this increase (cases&lt;65=513, HR&lt;65=1.27, 0.63-2.39, p&lt;65&gt;0.05). Considering only HF events in AllofUs, the effect remained present (HR 1.70, 1.32-2.19, p&lt;0.0001).

Conclusion
The yield of CMP-associated PLP variants is substantial among persons with early-onset AF, even when considering a 55 year cutoff. AF patients with PLP variants have an increased risk of future heart failure or CMP. Our results further support the clinical relevance of genetic testing in early-onset AF.Prevalence of CMP variants in AF by age