Risk for Heart Failure and Atrial Fibrillation Across the Lifespan for Carriers of the Amyloidogenic p.V142I Variant.

Background: To better define the importance of the amyloidogenic p.V142I allele across the life span of a carrier, we leveraged data from All of Us to provide a generalizable assessment of the population-level burden of cardiovascular risk and estimate the age at disease onset.

Methods: We included self-identifying Black participants in All of Us who provided genomic data (N=77 767). The exposure of interest was p.V142I carrier status (N=2213). Outcomes included incident heart failure (HF), atrial fibrillation, and carpal tunnel syndrome.

Results: The median (interquartile range) age at enrollment was 56 (42-64) years. For the subset with genetic ancestry data (N=50 516), the p.V142I carrier frequency was 3.5% (N=1771) among those with African ancestry. After adjustment for age and traditional risk factors, p.V142I carrier status was associated with a greater risk of HF (odds ratio, 1.56 [95% CI, 1.22-1.99]; =0.001), atrial fibrillation (odds ratio, 1.3 [95% CI, 1.08-1.90]; =0.013), and carpal tunnel syndrome (odds ratio, 1.94 [95% CI, 1.43-2.63]; <0.001).The risks increased in the sixth decade of life. In carriers, the attributable risk of the variant for HF, atrial fibrillation, and carpal tunnel syndrome was 27%, 26%, and 43%, respectively. While traditional HF risk factors did not modify the association of carrier status with HF (-interaction >0.05 for all), their presence substantially augmented the risk of HF over a lifetime.

Conclusions: p.V142I carriers are at an increased risk of HF and atrial fibrillation, beginning during the sixth decade of life. HF risk rises in a dose-dependent manner with other nonamyloid-related HF risk factors, highlighting the importance of aggressive treatment of HF risk factors among carriers. These observations also confirm the clinical relevance of the p.V142I variant for individuals of African ancestry and underscore the importance of efforts to increase diagnoses, implement TTR-targeted therapies, and evaluate screening strategies for variant transthyretin cardiac amyloidosis.