Testing for Causal Association between Serum Urate, Gout, and Prostatic Cancer in European Males

Objective: To conduct a two-sample MR study including only men to test for a causal relationship between serum urate (SU) and gout and prostate cancer. Methods: We used GWAS for SU, gout, and prostate cancer to generate exposure instrumental variables (IV) associated with gout and urate. We used 20 single nucleotide polymorphisms (SNPs) associated with gout but not urate for an IV representing the non-hyperuricemia (inflammatory) compartment of gout and we used four SNPs from loci containing urate transporter genes for an IV representing urate levels. MR methods included inverse-variance-weighted (IVW), MR-Egger regression, and weighted median to test for causal relationships and horizontal pleiotropy. Results: The non-hyperuricemia compartment of gout IV showed a causal effect of gout on prostate cancer (Weighted median: P = 0.01). In contrast, the SU IV showed no evidence for a causal effect of SU on prostate cancer (IVW: P = 0.83; Weighted Median: P = 0.97). We found no evidence of horizontal pleiotropy from MR-Egger for either the urate or gout IV (non-hyperuricemia compartment of gout: P = 0.33; urate: P = 0.80). Loci contributing most strongly to the non-hyperuricemia causal effect included three genes: IL1R1, IL1RN, and SLC30A5. There was no evidence for a causal relationship of prostate cancer on gout or SU. Conclusion: MR analysis in a European male population found evidence for a causal effect between the non-hyperuricemia compartment of gout and prostate cancer. Implication of the IL1R1 and IL1RN genes directly implicates the gouty inflammation pathway in prostate cancer.