Abstract / Summary
Abstract Background The causal effect of maternal smoking around birth (MSAB) on offspring gastroesophageal reflux disease (GERD) remains uncertain. We aimed to investigate the causal relationship between MSAB and GERD, to determine the modifying effect of breastfeeding, and to assess whether inflammatory proteins act as mediators. Methods We obtained MSAB and breastfeeding data from the UK Biobank, and GERD data from the FinnGen consortium, based on large-scale genome-wide association studies (GWAS) summary data. We employed two-sample Mendelian randomization (MR) to investigate the causal relationships of MSAB and breastfeeding on inflammatory proteins and GERD. We also examined the associations between inflammatory proteins and GERD. Multivariate MR was applied to assess the effect of MSAB on GERD while adjusting for breastfeeding. Two-step MR was performed to explore whether inflammatory proteins mediated the pathway from exposure to outcome. Sensitivity analyses were conducted to ensure the reliability and stability of the results. Results Genetically predicted MSAB was associated with increased GERD risk (OR = 2.544, 95% CI: 1.189-5.446, P = 0.016), whereas breastfeeding was associated with decreased GERD risk (OR = 0.238, 95% CI: 0.058-0.971, P = 0.045). The association between MSAB and GERD was attenuated when adjusting for breastfeeding. MSAB showed suggestive associations with several inflammatory proteins ( P < 0.05), but none remained significant after multiple-testing adjustment and did not act as mediators. Conclusion Our MR study supports potential causal roles of MSAB and breastfeeding in offspring GERD development. Breastfeeding may reduce the MSAB-associated GERD risk, highlighting the importance of promoting breastfeeding as a modifiable protective intervention.