Daily smoking intensity increases lung cancer risk through sphingomyelin and phosphatidylcholine: An in-silico using European population and Mendelian randomization

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Abstract
Lung cancer is a leading cause of morbidity and mortality worldwide, with smoking as a major risk factor. This study investigated the causal relationship between smoking intensity, plasma lipid phenotypes, and lung cancer risk using Mendelian randomization (MR) analysis. Bidirectional MR analysis examined daily cigarette consumption’s impact on non-small cell carcinoma, not otherwise specified (NOS), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and small cell lung cancer (SCLC). Associations between smoking and 179 plasma lipid phenotypes were explored, followed by analysis of lipid groups’ causal links to lung cancer subtypes. Mediation MR estimated the mediation proportion. Smoking intensity showed a significant positive correlation with all lung cancer subtypes (non-small cell carcinoma, not otherwise specified (NOS) [NSCLC-NOS]: odds ratio [OR] = 2.31, 95% confidence interval [CI] = 1.30–4.10; LUAD: OR = 2.99, 95% CI = 1.47–6.10; LUSC: OR = 3.69, 95% CI = 1.39–9.80; SCLC: OR = 3.66, 95% CI = 1.06–12.56). Increased smoking was linked to lower levels of 3 phosphatidylcholine (PC) and higher levels of 2 sphingomyelin (SM) molecules. Bayesian weighted MR revealed 41 plasma lipid phenotypes significantly affected lung cancer risk. PC (16:0_0:0) and SM (d36:2) mediated 1.79% and 3.27% of the risk for NSCLC-NOS, respectively, while SM (d42:2) mediated 2.72% of the risk for SCLC. The study established a causal relationship between daily smoking intensity and the risk of both NSCLC and SCLC, mediated by changes in specific plasma lipid phenotypes. This highlights the critical role of lipid metabolism in smoking-related lung cancer. Understanding the lipid metabolic pathways involved in smoking-induced lung cancer could aid in the development of targeted interventions, potentially reducing the elevated cancer risk associated with increased smoking intensity.

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