Genetic support of a causal relationship between iron status and atrial fibrillation: a Mendelian randomization study

Atrial fibrillation is the most common arrhythmia disease. Animal and observational studies have found a link between iron status and atrial fibrillation. However, the causal relationship between iron status and AF remains unclear. The purpose of this investigation was to use Mendelian randomization (MR) analysis, which has been widely applied to estimate the causal effect, to reveal whether systemic iron status was causally related to atrial fibrillation.

Single nucleotide polymorphisms (SNPs) strongly associated (P < 5 × 10^-8) with four biomarkers of systemic iron status were obtained from a genome-wide association study involving 48,972 subjects conducted by the Genetics of Iron Status consortium. Summary-level data for the genetic associations with atrial fibrillation were acquired from the AFGen (Atrial Fibrillation Genetics) consortium study (including 65,446 atrial fibrillation cases and 522,744 controls). We used a two-sample MR analysis to obtain a causal estimate and further verified credibility through sensitivity analysis.

Genetically instrumented serum iron [OR 1.09; 95% confidence interval (CI) 1.02-1.16; p = 0.01], ferritin [OR 1.16; 95% CI 1.02-1.33; p = 0.02], and transferrin saturation [OR 1.05; 95% CI 1.01-1.11; p = 0.01] had positive effects on atrial fibrillation. Genetically instrumented transferrin levels [OR 0.90; 95% CI 0.86-0.97; p = 0.006] were inversely correlated with atrial fibrillation.

In conclusion, our results strongly elucidated a causal link between genetically determined higher iron status and increased risk of atrial fibrillation. This provided new ideas for the clinical prevention and treatment of atrial fibrillation.