Genetically predicted lower FLT3L levels increase the risk of hypertrophic cardiomyopathy partly mediated by phosphate: Evidence from a 2-step Mendelian randomization analysis

We performed a 2-step Mendelian randomization (MR) study to investigate the associations of Fms-related tyrosine kinase 3 ligand (FLT3L) and phosphate levels with the risk of hypertrophic cardiomyopathy (HCM). Genetic instruments for 75 circulating inflammatory factors were obtained from the NHGRI-EBI GWAS Catalog, while summary statistics for circulating phosphate and HCM were derived from the UK Biobank and FinnGen, respectively. Univariable MR analysis using the inverse-variance weighted method indicated that genetically predicted higher phosphate levels were associated with an increased risk of HCM (OR = 1.36, P  = 4.82 × 10 ⁻² ). Among the inflammatory markers, FLT3L emerged as a significant candidate and showed inverse associations with phosphate levels (β = -0.05, P  = 1.70 × 10 ⁻⁹ ) and HCM (OR = 0.79, P  = 4.10 × 10 ⁻² ). Bidirectional MR analyses did not support a causal effect of phosphate on FLT3L. Mediation analysis suggested that phosphate levels accounted for an estimated 12.05% of the total effect of FLT3L on HCM. Genetic liability to lower FLT3L levels is associated with a higher risk of HCM, and this relationship may be partially mediated through circulating phosphate levels.