Circulating phosphorus level and risk of prostate cancer: a Mendelian randomization study.

BACKGROUND Recent observational studies have suggested that circulating phosphorus levels are positively associated with risk of prostate cancer. However, little is known about the causal direction of the association. OBJECTIVE To explore the potential causal relationship between circulating phosphorus and risk of prostate cancer, we conducted a Mendelian randomization (MR) study. DESIGN Summary statistics of prostate cancer were obtained from a meta-analysis of genome-wide association studies (GWAS) consisting of 79,148 cases and 61,106 controls. Single nucleotide polymorphisms (SNP) associated with serum phosphorus level were selected from a GWAS of 291,408 individuals from the UK Biobank. MR analysis was performed using the inverse-variance weighted (IVW) method, supplemented with simple-median, weighted-median, maximum likelihood-based, MR-Egger regression and MR-PRESSO test. We also performed a meta-analysis of observational studies to assess the associations of dietary phosphorus intake and serum phosphorus level with risk of prostate cancer. RESULTS In the MR analysis, a total of 125 independent SNPs associated with serum phosphorus levels were used as instrumental variables. Genetically predicted serum phosphorus levels were associated with a 19% increased risk of prostate cancer (95% confidence interval (CI): 9%, 31%) per one SD increment of serum phosphorus by IVW (P = 1.82 × 10-4). Sensitivity analyses using alternative MR methods produced similar positive associations, and no evidence of pleiotropy was detected by MR-Egger regression (P = 0.422). For meta-analysis, eight studies for dietary phosphorus intake and four for serum phosphorus levels were included involving a total of 669,080 participants. Consistently, high dietary phosphorus intake and serum phosphorus levels were associated with an 8% (95% CI: 4%, 12%) and 7% (95% CI: 1%, 14%) increase in prostate cancer risk, respectively. CONCLUSIONS Our study suggested a potential causal relationship between circulating phosphorus and risk of prostate cancer. Further studies are warranted to elucidate the underlying mechanism of phosphorus in the development of prostate cancer.