Abstract
BACKGROUND: The current understanding of the relationship between circulating metabolites and neuroblastoma (NB) risk is insufficient. Herein, bidirectional Mendelian randomization (MR) studies were utilized to examine the potential causal associations of metabolites and the risk of NB. METHODS: Significant single-nucleotide polymorphisms (SNPs) associated with circulating metabolites were obtained from the genome-wide association study (GWAS) in the European population (N = 7824). Summary statistics for NB were aggregated from prior GWAS studies encompassing 1,627 patients and 3,254 cancer-free children. The causality was assessed primarily by inverse-variance weighted (IVW), along with MR-Egger regression, weighted median estimator, and weighted mode method. RESULTS: Among the 486 metabolites analyzed, a genetically determined elevation in blood butyrylcarnitine concentration (log(10)) was significantly correlated with a 51.5% decrease in NB risk [IVW odds ratio (OR) = 0.485, 95% confidence interval (CI): 0.285-0.826, P = 0.008]. In the reverse MR analyses, an increase in log odds of NB risk demonstrated a significant correlation with a decrease in guanosine [IVW Beta ± SE: -0.042 ± 0.015 log(10) change, P = 0.004] and an elevation in 3-methyl-2-oxobutyrate [IVW Beta ± SE: 0.010 ± 0.004 log(10) change, P = 0.011] levels. Besides, no significant causal effect of NB on butyrylcarnitine was observed. CONCLUSIONS: This research identifies bidirectional causal relationships between circulating metabolites and NB. Increased levels of blood butyrylcarnitine are associated with a reduced risk of NB, whereas lower levels of guanosine and higher levels of 3-methyl-2-oxobutyrate are indicative of NB patients. Further investigation is required for the mechanisms.