Genetically predicted phosphate and cardiovascular disease: A Mendelian randomization study

BACKGROUND: Extensive epidemiological studies have highlighted the correlation between serum phosphate and cardiovascular diseases. The present study aims to determine whether genetically predicted serum phosphate is causally associated with the distinct subtypes of cardiovascular events through the use of Mendelian randomization (MR) analysis. METHODS: Independent and strongly correlated single-nucleotide polymorphisms (SNPs) for serum phosphate were extracted from publicly available genome-wide association studies. Summary statistics of cardiovascular diseases were derived from large-scale consortiums, including HERMES and FinnGen biobank. MR-Egger, weighted median, inverse variance weighted, pleiotropy residual sum and outlier (MR-PRESSO) methods and MR using robust adjusted profile score (MR-RAPS) were employed to analyze causality. The sensitivity analyses comprised heterogeneity, horizontal pleiotropy, and leave-one-out approaches; these were used to ensure the stability of the results. RESULTS: Our study demonstrated that increased genetically predicted serum phosphate is causally associated with a higher risk of valvular heart disease (VHD) [For VHD including rheumatic fever: odds ratio (OR) = 2.45; 95% confidence interval (CI), 1.52–3.94; p = 0.0002; for non-rheumatic VHD: OR = 6.58; 95% CI, 2.50–17.32; p = 0.0001]. However, no causal association was detected between serum phosphate and other common cardiovascular diseases (including coronary heart disease, heart failure, atrial fibrillation, and essential hypertension). CONCLUSIONS: The results indicate strong causality between serum phosphate and valvular heart disease. Serum phosphate-lowering therapy within the physiological range may represent a novel therapeutic method for valvular heart disease.