Associations of risk factor burden and genetic predisposition with the 10-year risk of atrial fibrillation: observations from a large prospective study of 348,904 participants

BACKGROUND: Understanding the effects of risk factor burden and genetic predisposition on the long-term risk of atrial fibrillation (AF) is important to improve public health initiatives. However, the 10-year risk of AF considering risk factor burden and genetic predisposition is unknown. METHODS: A total of 348,904 genetically unrelated participants without AF at baseline from the UK were categorized into three groups: index ages 45 years (n = 84,206), 55 years (n=117,520), and 65 years (n=147,178). Optimal, borderline, or elevated risk factor burden was determined by body mass index, blood pressure, diabetes mellitus, alcohol consumption, smoking status, and history of myocardial infarction or heart failure. Genetic predisposition was estimated using the polygenic risk score (PRS), constructed using 165 predefined genetic risk variants. The combined effects of risk factor burden and PRS on the risk of incident AF in 10 years were estimated for each index age. Fine and Gray models were developed to predict the 10-year risk of AF. RESULTS: The overall 10-year risk of AF was 0.67% (95% CI: 0.61–0.73%) for index age 45 years, 2.05% (95% CI: 1.96–2.13%) for index age 55 years, and 6.34% (95% CI: 6.21–6.46%) for index age 65 years, respectively. An optimal risk factor burden was associated with later AF onset regardless of genetic predisposition and sex (P < 0.001). Significant synergistic interactions were observed for risk factor burden with PRS at each index age (P < 0.05). Participants with an elevated risk factor burden and high PRS had the highest 10-year risk of AF in reference to those who had both an optimal risk factor burden and a low PRS. At younger ages, optimal risk burden and high PRS might also lead to later onset of AF, compared to the joint effect of elevated risk burden and low/intermediate PRS. CONCLUSIONS: Risk factor burden together with a genetic predisposition is associated with the 10-year risk of AF. Our results may be helpful in selecting high-risk individuals for primary prevention of AF and facilitating subsequent health interventions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-023-02798-7.