Intergenerational and individual effects of smoking exposure on non-alcoholic fatty liver disease: A Mendelian randomization study.

INTRODUCTION: Tobacco exposure has been linked to an increased risk of non-alcoholic fatty liver disease (NAFLD) in observational studies, yet evidence remains unclear due to confounding factors and reverse effect. This study aimed to explore the potential associations of maternal smoking around birth and age of smoking initiation with NAFLD risk. METHODS: Genome-wide association data for maternal smoking around birth, age of smoking initiation, and NAFLD were sourced from large-scale Genome-Wide Association Studies (GWAS) datasets. Qualified single nucleotide polymorphisms (SNPs) associated with the two exposures served as instrumental variables in two-sample Mendelian randomization analyses, which utilized the inverse-variance weighted (IVW) method, weighted median estimator, and MR-Egger regression to explore their potential associations with NAFLD. Sensitivity analyses confirmed no obvious directional pleiotropy, while significant heterogeneity was detected among included SNPs. RESULTS: Genetically predicted maternal smoking significantly elevated NAFLD susceptibility (IVW: OR=1.98; 95% CI: 1.16-3.39), validated by weighted median. No definitive link was found between smoking initiation age and NAFLD. No evidence supported a potential effect of NAFLD on maternal smoking around birth in reverse MR. CONCLUSIONS: This study supports a potential association between maternal smoking around birth and NAFLD, while smoking initiation age lacks sufficient genetic evidence.