Associations between maternal smoking around birth and hepatocellular carcinoma: A bidirectional two sample Mendelian randomization study in East Asian populations

INTRODUCTION: Maternal smoking around birth is known to cause a range of adverse fetal outcomes. This study aimed to investigate the potential relationship between maternal smoking around birth and the susceptibility of offspring to hepatocellular carcinoma (HCC) in East Asian populations. METHODS: Genome-wide association study (GWAS) summary statistics for maternal smoking around birth, which were obtained from the UK Biobank (ukb-e-1787EAS, data from 2020), and hepatocellular carcinoma, which were obtained from Biobank Japan (bbj-a-158, data from 2019) in East Asians, were obtained from the Mendelian randomization (MR) database platform. Single-nucleotide polymorphisms (SNPs) strongly associated with maternal smoking around birth were selected as instrumental variables (IVs) for two-sample MR analyses. Three complementary MR approaches were applied: inverse-variance weighting (IVW), weighted median estimation, and MR-Egger regression. RESULTS: A total of 113 SNPs significantly associated with maternal smoking around birth were identified after rigorous selection. Across all MR methods, consistent evidence supported a positive association between maternal smoking around birth and increased HCC risk in offspring (IVW: OR=1. 06; 95% CI: 1. 05-1. 07; weighted median: OR=1. 06; 95% CI: 1. 05-1. 08; MR-Egger: OR=1. 05; 95% CI: 1. 02-1. 08). Conversely, no evidence supported a potential effect of HCC on maternal smoking around birth in reverse MR, reinforcing the directionality of the observed association. CONCLUSIONS: This study provides genetic evidence supporting a possible link between increased maternal smoking around birth and elevated HCC risk in offspring among East Asians.