Male sex, polygenic risk score predict outcomes in Brugada syndrome

Nonmodifiable factors such as male sex, type of SCN5A mutation, and polygenic risk score are independently associated with outcomes in patients with Brugada syndrome (BrS), a study has shown.

This study included 2,182 unrelated Italian patients with BrS (median age at diagnosis 41.6 years, 81 percent male), whose clinical and genetic data were analysed using multivariable Cox proportional hazards model.

Male sex (hazard ratio [HR], 3.6, 95 percent confidence interval [CI], 1.9‒6.9; p=0.0001), missense SCN5A mutations in BrS-enriched domains (HR, 2.3, 95 percent CI, 1.2‒4.3; p=0.008), nonmissense SCN5A mutations (HR, 3.2, 95 percent CI, 1.8‒5.7; p<0.001), and polygenic risk score for BrS (HR, 1.3, 95 percent CI, 1.0‒1.6; p=0.041) each correlated with a significantly increased risk of a first life-threatening arrhythmic event (LAE) since birth.

“Based on these results, we derived the nonmodifiable risk of each patient with BrS, and the division of nonmodifiable risk into tertiles identified three distinct risk profiles,” the researchers said.

Follow-up analysis revealed that nonmodifiable risk showed independent associations with LAE (HR, 1.8, 95 percent CI, 1.1‒2.7; p=0.014), together with classical predictors such as history of LAE prior to diagnosis (HR, 13.8, 95 percent CI, 8.1‒23.7; p<0.0001), history of unexplained syncope before diagnosis (HR, 4.1, 95 percent CI, 2.4‒6.8; p<0.0001), and spontaneous type 1 pattern at diagnosis (HR, 2.1, 95 percent CI, 1.2‒3.8; p=0.010).

“The model was internally validated, and we derived the equation permitting to calculate the granular 5-year risk of experiencing an LAE at follow-up for each patient with BrS, which may be used to facilitate clinical decision-making,” the researchers said.