High-proportion spliced-in titin truncating variants in African and European ancestry in the All of Us Research Program.

High-proportion spliced-in titin truncating variants (hiPSI TTNtvs) have been associated with an increased risk of atrial fibrillation, dilated cardiomyopathy (DCM) and heart failure in individuals of European ancestry. However, similar data in individuals of African ancestry are lacking. Here we examined the association of hiPSI TTNtvs with atrial fibrillation, DCM and heart failure in individuals of African ancestry using data from the All of Us Research Program. Among 38,154 individuals of African ancestry, 169 (0.4%) individuals carried a hiPSI TTNtv. hiPSI TTNtv carriers were at a higher risk of developing atrial fibrillation (adjusted hazard ratio (HR) 2.42, 95% confidence interval (CI) 1.52-3.85), DCM (HR 2.82, 95% CI 1.81-4.39) and heart failure (HR 2.07, 95% CI 1.43-3.00) compared with noncarriers. The association of hiPSI TTNtvs with atrial fibrillation, DCM and heart failure was similar in individuals of African ancestry and those of European ancestry. Therefore, genetic testing for hiPSI TTNtvs may permit early identification of carriers and support preventive measures to reduce the likelihood of heart failure development both in individuals of European ancestry and in individuals of African ancestry.