Smoking behavior-related genetic variants and lung cancer risk in Japanese: an assessment by mediation analysis.

This article focuses on evaluating the association between five smoking behavior-related single nucleotide polymorphisms (SNPs) identified in a Japanese genome-wide association study and lung cancer risk, distinguishing direct genetic effects from those mediated by smoking behavior. Using mediation analysis in two independent Japanese studies—a case-control study (1,427 cases, 5,595 controls) and a prospective cohort study (128 incident cases among 10,520 subjects)—the researchers found that the SNP rs78277894 (EPHX2-CLU) exhibited a protective direct effect on lung cancer risk independent of smoking intensity, while rs56129017 (CYP2A6) showed carcinogenic direct and indirect effects, suggesting increased susceptibility to lung carcinogens beyond smoking behavior. These effects were specific to lung cancer and not observed in other smoking-related cancers. The findings contribute to understanding lung carcinogenesis pathways that operate independently of smoking behavior changes, particularly in East Asian populations.