Proteome-wide Mendelian randomization identifies causal plasma proteins in prostate cancer development

Abstract

Background: The etiology of prostate cancer remained elusive, whether plasma protein levels are associated with prostate cancer is still unknown. Methods: We have performed Mendelian randomization analyses to calculate the causal effects of plasma proteins on the risk of prostate cancer in the PRACTICAL consortium dataset using cis-protein quantitative trait loci (cis-pQTL) variants as instrumental variables for plasma proteins, and cis-expression quantitative trait locus (cis-eQTL) for the circulating gene expression. We also replicated the findings in the FinnGen consortium. Results: Genetically proxied levels of 4 plasma proteins (CREB3L4, HDGF, SERPINA3, GNPNAT1) were identified as positively correlated with an increased risk of prostate cancer, while an increase in genetically proxied levels of 5 plasma proteins (TNFRSF6B, GSK3A, EIF4B, CLIC1, SMAD2) were significantly associated with a decreased risk of prostate cancer in the PRACTICAL consortium. Among the identified proteins, the causal effects of six proteins including CREB3L4, HDGF, SERPINA3, TNFRSF6B, EIF4B, and SMAD2 remained significant in the replication analyses in the FinnGen consortium and when combined with meta-analyses (SMAD2: OR 0.710, 95% CI 0.578–0.873, p-value = 0.001; CREB3L4: OR 1.260, 95% CI 1.164–1.364, p-value < 0.0001; HDGF: OR 1.072, 95% CI 1.021–1.125, p-value = 0.005; SERPINA3: OR 1.138, 95% CI 1.091–1.187, p-value < 0.0001; TNFRSF6B: OR 0.656, 95% CI 0.496–0.869, p-value = 0.003; EIF4B: OR 0.701, 95% CI 0.618–0.796, p-value < 0.0001). SMAD2 and CREB3L4 gene expressions proxied with cis-expression quantitative trait loci are also significantly associated with the risk of prostate cancer in both consortiums and when combined with meta-analyses (SMAD2: OR 0.787, 95% CI 0.719–0.861, p-value = 1.00 × 10–4; CREB3L4: OR 1.219, 95% CI 1.033–1.438, p-value = 0.019). Conclusions: Our consistent results highlighted the important roles of plasma SMAD2 and CREB3L4 in the risk of prostate cancer. Further investigations on these proteins may reveal their potential in the prevention and treatment of prostate cancer.