Exploring causal associations between multiple smoke exposures and neuroblastoma suppressor NBL1 via Mendelian randomization.

INTRODUCTION: Neuroblastoma suppressor of tumorigenicity 1 (NBL1) is an established tumor suppressor and prognostic biomarker in neuroblastoma (NB). Although tobacco exposure is a well-known carcinogenic factor, its potential effect on NBL1 expression remains unclear. This two-sample Mendelian randomization (MR) study aimed to explore potential links between diverse smoking exposures, circulating NBL1 levels and NB risk. METHODS: This study performed a two-sample MR analysis to investigate the causal effects of maternal smoking around birth (66 single-nucleotide polymorphisms, SNPs), household smoking exposure (17 SNPs), and smoking initiation (37 SNPs) on circulating NBL1 levels using large-scale GWAS summary statistics. Causal estimates were obtained using IVW, weighted median, and MR-Egger methods, with sensitivity, reverse MR, and validation analyses conducted to assess robustness and directionality. RESULTS: No evidence of a causal association was observed between maternal smoking around birth or household smoking exposure and NBL1 levels. In contrast, genetically predicted smoking initiation was associated with lower NBL1 expression (IVW: OR=0.70; 95% CI: 0.50-0.99, p=0.04). The weighted median method failed to reach statistical significance (OR=0.642; 95% CI: 0.40-1.04, p=0.07), whereas MR-Egger regression yielded a non-significant estimate (OR=0.39; 95% CI: 0.06-2.56, p=0.34). Sensitivity analyses indicated no substantial pleiotropy or influential outliers. Reverse MR analysis provided no evidence that NBL1 influences smoking behavior. Additional validation analyses showed no causal association between smoking initiation and NB risk. CONCLUSIONS: Prenatal and household smoking exposures do not appear to affect NBL1 expression. Genetically predicted smoking initiation was associated with reduced NBL1 expression, but not with neuroblastoma risk.