Causal Effect of Tobacco Exposure on Acute Respiratory Distress Syndrome: A Mendelian Randomization Study

Abstract

Background: Previous studies have reported increased heterogeneity in acute respiratory distress syndrome (ARDS), but the causal relationship between ARDS and tobacco exposure is uncertain. Considering that tobacco exposure is relatively common, it can be used as an easily accessible indicator and is closely related to respiratory diseases. We examined the causal effect of tobacco exposure on ARDS-related phenotypes using a Mendelian randomization (MR) approach. Methods: In this investigation, we obtained tobacco exposure data from the most recent genome-wide association studies (GWASs) conducted by the GWAS and Sequencing Consortium of Alcohol and Nicotine Use (GSCAN). Moreover, summary statistics data for lifetime smoking behavior (SmkIndex) were obtained from the UK Biobank. Furthermore, the present study utilized ARDS GWAS data from the Finngen database. This study used two-sample MR (TSMR) to investigate the causal relationship between tobacco exposure and ARDS. We performed extensive sensitivity analyses to confirm the robustness, heterogeneity, and potential multibiological effects of the study results. Additionally, to control for false positive results during multiple hypothesis testing, we adopted a false discovery rate (FDR) to control for statistical bias due to multiple comparisons. Results: After FDR correction, tobacco exposure had no statistically significant effect on ARDS incidence. Several phenotypes with unadjusted low P values are worth mentioning, including cigarettes smoked daily (CigDay) (OR = 3.11, 95% CI 1.19-8.14, p = 0.020, FDR-p = 0.051) and age of initiation of regular smoking (AgeSmk) (OR = 0.01, 95% CI 0.00-0.45, p = 0.016, FDR-p= 0.051). In contrast, no causal links were identified for other measures of tobacco exposure with unadjusted p values, including smoking cessation (SmkCes) (OR = 1.33, 95% CI 0.19-9.43, p = 0.773), lifetime smoking behavior (SmkIndex) (OR = 3.02, 95% CI 0.59-15.30, p = 0.183), and smoking initiation (SmkInit) (OR = 1.86, 95% CI 0.74-4.70, p = 0.189). Conclusion: This study revealed a causal link between CigDay and AgeSmk and the risk of ARDS. However, no genetic associations were found between SmkCes, SmkInit, or SmkIndex and ARDS, suggesting heterogeneity in the impact of smoking exposure on the disease. Further research is required to clarify the causes of this heterogeneity.