Serum total folate, 5‐methyltetrahydrofolate and vitamin B12 concentrations on incident risk of lung cancer

Tobacco smoking is a major known risk factor for lung cancer. While micronutrients, especially those involved in maintaining DNA integrity and regulating gene expression, may be protective, research on this association is limited. This report aimed to investigate associations of total folate, 5-methyltetrahydrofolate (5-mTHF) and vitamin B12 with incident risk of lung cancer, and whether the associations vary by smoking status. A nested case-control study with 490 incident lung cancer cases and 490 controls matched by age (±1 year), sex, residence, and center, drawn from a community-based prospective study in China, was conducted from 2016 to 2019. 5-mTHF accounted for the majority of total folate. Only 4.4% had detectable unmetabolized folic acid. Lung cancer cases had lower levels of 5-mTHF compared to controls. There was an inverse, nonlinear association between 5-mTHF and lung cancer, which persisted after adjustment for covariables (P for trend = .001). Compared to the lowest 5-mTHF quartile, those in higher quartiles had lower risks of lung cancer: second quartile OR = 0.65; 95% CI: 0.45-0.93; third quartile OR = 0.50; 95% CI: 0.34-0.74; fourth quartile OR = 0.56; 95% CI: 0.38-0.83. This inverse association was more pronounced among ever smokers; consistently, the highest risk of lung cancer (OR = 3.21, 95% CI: 1.97-5.24) was observed among ever smokers with low 5-mTHF levels compared to participants who never smoked and had higher 5-mTHF levels. Vitamin B12 was not associated with lung cancer risk. In this sample of Chinese adults without confounding by unmetabolized folic acid, higher levels of 5-mTHF were associated with lower risk of incident lung cancer.