Genetic risk, modifiable risk factors, and atrial fibrillation in the Danish diet, cancer, and health cohort

Abstract Background The etiology of AF is multifactorial. Genetic susceptibility and lifestyle contribute to atrial fibrillation (AF) risk.(1,2) However, the relationship between combined genetic predisposition and lifestyle risk factors on AF risk is unclear. Purpose We aimed to assess a possible interaction between modifiable risk factors and genetics on AF risk. Methods We included AF cases and a randomly drawn subcohort of 4,040 participants from the Danish Diet, Cancer, and Health study. Modifiable risk factors were assessed including smoking, body mass index, physical activity, diet, alcohol consumption, total cholesterol, and blood pressure. Based on cumulation of risk factors, a risk factor profile was determined for all participants and categorized as poor, intermediate, and ideal. Based on DNA sequence polymorphisms, we calculated a genetic risk score for AF, and categorized participants as having a low (quintile 1), intermediate (quintile 2-4) or high (quintile 5) genetic risk. Diagnoses of AF and/or atrial flutter were obtained from the Danish National Patient Register. We used weighted Cox proportional hazards regression to assess hazard ratios of AF. Results 3,094 AF cases occurred during a median follow-up of 12.9 years. Median age at baseline in the subcohort was 55 years (25th-75th percentile 52-60) and 2,092 (55%) were women. Participants at intermediate and high genetic risk had higher rates of AF compared with those at low genetic risk. Likewise, intermediate, and poor risk factor profiles were associated with higher rates of AF compared with those having ideal risk factor profiles. Weighted cumulative incidence proportions and hazard ratios of AF according to genetic risk and modifiable risk factors are shown in Figure 1. Within each category of genetic risk, incidence rates per 1,000 person-years were gradually higher with worse modifiable risk factor profiles. (Figure 2). For participants with high genetic risk, the incidence rates of AF per 1,000 person years were 5.0 (95% CI 3.4-7.3) for ideal, 6.6 (95% CI 5.4-8.1) for intermediate, and 10.4 (95% CI 9.2-11.8) for poor risk factor profiles. On an additive scale, there was a statistically significant interaction between genetic risk and modifiable risk factors (relative excess risk due to interaction=0.86 (95% 0.68-1.03, p<0.001). Conclusions A genetic risk score and modifiable risk factors were each associated with AF risk. The rates of AF increased gradually with cumulation of modifiable risk factors within each category of the genetic risk score, and we found an additive interaction between genetic risk and the modifiable risk factor profile. This underlines the importance of risk factor modification in primary AF prevention.Figure 1Figure 2