Volatile gas exposure correlates with self-reported liver condition: insights from NHANES 2009–2018 and Mendelian randomization studies

Volatile gas exposure and self-reported liver conditions share pathophysiologic risk factors, but their exact association remains unclear. We used a weighted multivariable-adjusted logistic regression model, using data from the National Health and Nutrition Examination Survey (NHANES) 2009–2018. Integrative analyses of Non-alcoholic fatty liver disease (NAFLD), liver fibrosis, liver cirrhosis GWAS summaries and blood expression quantitative trait loci (eQTLs) were conducted via summary data-based MR (SMR) and colocalization analysis to prioritize putative blood smoking-related genes and their associations with each liver condition risk. Finally, we further verified these gene-disease causal links through MR and colocalization analysis. 12,099 NHANES participants were included. Male sex, 46–75 years, and smoke exposure correlated positively with LC; age and smoke exposure remained positively associated with LC incidence after adjustment, while non-Hispanic Black was a LC protective factor. SMR identified three blood-derived candidate genes: RGPD8 (Beta = −0.207), COX6B2 (Beta = −0.567), DNAJC27 (Beta = 0.859). MR and colocalization confirmed their associations with cirrhosis, fibrosis, and NAFLD, respectively. This study confirms a causal link between smoke exposure and increased LC risk, identifies novel gene-disease associations, and provides cross-disciplinary insights for targeted LC prevention and personalized research. This study confirms smoke exposure as a causal risk for self-reported liver conditions (LC). It reinforces smoking cessation as a critical clinical strategy for liver health, while the candidate genes offer potential targets for high-risk screening and personalized interventions, aiding clinical prevention and management of liver diseases.