Fibroblast growth factor 23 and outcomes of atrial fibrillation: from clinical association to genetic evidence

Fibroblast growth factor 23 (FGF23) has been implicated in the occurrence of atrial fibrillation (AF), but its prognostic value in AF patients remains unclear. A total of 35 197 AF patients with available follow-up data (3.56, 0.47-8.92 years) from the UK Biobank were included. Clinical association between serum FGF23 and AF-related outcomes including mortality, heart failure (HF), ischaemic stroke, and dementia were analysed using multivariable Cox regression. In those passed quality control for array sequencing, polygenic score for FGF23 (PGSFGF23) was calculated as genetic instrument, and the association between PGSFGF23 and the occurrence of endpoints after first AF diagnosis were further explored. In 886 patients who diagnosed AF at or prior to the enrolment, elevated serum FGF23 levels were significantly associated with an increased risk of all-cause (37% increase per standard deviation) and cardiovascular (40% increase per standard deviation) mortality and HF (43% increase per standard deviation). A total of 35 197 patients were available for genetic array sequencing data. Using polygenic score including seven independent SNPs reaching genome-wide significance threshold, genetic association analysis indicated that increased PGSFGF23 is associated with reduced risk of HF but increased risk of all-cause mortality and ischaemic stroke. Our findings suggest that FGF23 is a potential biomarker for accessing AF-related outcomes. The paradoxical association between genetic FGF23 and serum FGF23 level highlights the need for further investigation to elucidate the underlying mechanisms.