Causal links of human serum metabolites on the risk of prostate cancer: insights from genome-wide Mendelian randomization, single-cell RNA sequencing, and metabolic pathway analysis

Abstract

Background: Recently, serum metabolites have shown potential in predicting survival outcomes and may be related to the pathogenesis of prostate cancer. Nevertheless, the precise impact concerning the genetic effect of metabolites on prostate cancer risk remains obscure. In this context, we conducted a Mendelian randomization (MR) study aiming to explore the causality between genetically determined metabolites and the risk of prostate cancer.

Methods: We conducted a two-sample MR analysis aiming to identify the underlying metabolites associated with prostate cancer. Exposure information was obtained from the largest metabolome-based genome-wide association (GWAS) data containing 7,824 Europeans. Genome-wide association analysis was utilized to detect instrumental variables (IVs) for metabolites. We applied the inverse-variance weighted (IVW) approach as the primary method, and to augment the reliability and robustness of our findings, additional analysis methods encompassing weighted median, MR-Egger, and leave-one-out analysis were utilized. MR-Egger intercept test was implemented to explore the pleiotropy. Cochran's Q test was utilized to quantify the degree of heterogeneity. Additionally, we performed metabolic pathway analysis and single-cell RNA sequencing analysis.

Results: We found that three serum metabolites were causally associated with prostate cancer after utilizing rigorous screening standards. Utilizing single nucleotide polymorphisms as IVs, a 1-SD increase in fructose was associated with 77% higher risk of prostate cancer (OR:1.77, 95%CI: 1.05-2.97, P_IVW=0.031), a 1-SD increase in N1-methyl-3-pyridone-4-carboxamide was associated with 29% higher risk of prostate cancer (OR:1.29, 95%CI: 1.05-1.58, P_IVW=0.017), and a 1-SD increase in 12-hydroxyeicosatetraenoate (12-HETE) was associated with 18% higher risk of prostate cancer (OR:1.18, 95%CI: 1.07-1.31, P_IVW=0.0008). Metabolites that were causally linked to the risk of prostate cancer were mainly enriched in the valine, leucine and isoleucine biosynthesis pathway (P=0.026) and the nicotinate and nicotinamide metabolism pathway (P=0.048).

Conclusions: Our MR analysis provided suggestive evidence supporting the causal relationships between three identified serum metabolites and prostate cancer, necessitating further investigation to elucidate the underlying mechanisms through which these blood metabolites and metabolic pathways may impact the initiation and progression of prostate cancer.

Keywords: Mendelian randomization; metabolic pathways; prostate cancer; serum metabolites; single-cell RNA-seq.