The association between maternal smoking and the risk of kidney diseases in offspring: A Mendelian randomization analysis based on large-scale GWAS

Maternal smoking around birth (MSAB) has been associated with various adverse health outcomes in offspring, including an increased risk of kidney diseases. This study aims to investigate the potential causal relationship between MSAB and the risk of kidney diseases in descendants using Mendelian randomization (MR) methods, providing insights into the epidemiological background of kidney diseases and the application of MR in this context. We conducted a 2-sample MR analysis utilizing publicly available data from large-scale genome-wide association studies on MSAB (n = 397,732), breastfeeding (n = 352,094), and various kidney diseases, including acute kidney injury (AKI) (n = 482,266), chronic kidney injury (n = 482,858), glomerulonephritis (n = 500,348), renal malignancies (n = 463,010), and chronic kidney disease (n = 493,235). We employed multiple MR methods, including inverse variance weighted (IVW), weighted median, weighted mode, and MR Egger regression, to assess the causal effects. We used the odds ratio (OR) as our measure and conducted multivariable MR analysis to account for the confounding effect of breastfeeding. To ensure the reliability and stability of our results, we conducted sensitivity analyses, which included Cochran Q test, MR Egger, and leave-one-out analysis. The MR-IVW results indicated a strong positive causal association between MSAB and the risk of AKI (OR = 11.47, 95% confidence interval [CI]: 2.58-51.02, P-fdr = .008) and renal malignancies (OR = 1.02, 95% CI: 1.01-1.04, P-fdr = .01) in offspring. A potential causal relationship with glomerulonephritis was also observed (OR = 8.63, 95% CI: 1.13-65.88, P-fdr = .08). After adjusting for breastfeeding using multivariable MR, the associations between MSAB and AKI (OR: 13.43, 95% CI: 2.72-66.25, PIVW = .001) as well as renal malignancies (OR: 1.02, 95% CI: 1.01-1.04, PIVW = .005) remained statistically significant. This suggests that maternal smoking during pregnancy significantly increases the risk of AKI and renal malignancies in their children. Our study provides compelling evidence for a causal link between maternal smoking and an increased risk of kidney diseases in offspring, emphasizing the importance of addressing maternal smoking as a modifiable risk factor. Future research should focus on elucidating the underlying biological mechanisms and exploring interventions to mitigate the impact of maternal smoking on offspring health.