Document resource
Background The interplay between genetic susceptibility and clinical risk for incident atrial fibrillation (AF) is unclear.Methods We used a case-cohort study design and included AF cases and a randomly drawn subcohort of 4040 participants from the Danish Diet, Cancer and Health cohort. The simplified version of the Future Innovations in Novel Detection of Atrial Fibrillation (FIND-AF) risk score was used to quantify individual participant clinical risk of incident AF as low (0–3 points), high (4–6 points) and very high risk (7–14 points). We calculated individual participant Genetic Risk Scores (GRS) from 142 variants to categorise participants as low (quintile 1), intermediate (quintile 2–4) or high (quintile 5) genetic risk of AF. We used weighted Cox proportional hazards regression to quantify risk of incident AF according to FIND-AF risk and GRS and assessed the relative excess risk due to interaction (RERI) for interaction on an additive scale.Results During a median follow-up of 12.9 years, 3094 participants developed AF. Compared with individuals with low FIND-AF risk score and low GRS, the multivariable-adjusted HR for AF was 3.47 (95% CI 2.64 to 4.55) for those with high FIND-AF risk score and high GRS and 12.76 (95% CI 5.07 to 32.11) for those with very high FIND-AF risk score and high GRS. The RERI was 0.56 (95% CI 0.43 to 0.70), indicating a positive additive interaction between GRS and FIND-AF risk score.Conclusions Genetic susceptibility and clinical risk interacted on an additive scale to elevate AF risk. These results highlight the need for future research on prevention and screening among individuals with both high genetic and clinical risk for AF.