Assessing the genetic estimates of the association between plasma caffeine and cancer risk through Mendelian randomization.

Background: Observational studies still cannot establish a causal relationship between plasma caffeine levels and cancer risk. This study aimed to investigate the genetic effects of plasma caffeine levels on cancer risk through Mendelian randomization (MR).

Methods: Plasma caffeine's genome-wide association study (GWAS) data were derived from a meta-analysis of 9,876 individuals of European ancestry. We selected 8 single nucleotide polymorphisms (SNPs) closely associated with plasma caffeine levels as instrumental variables (IVs). The GWAS data for cancer outcomes were obtained from genotype data in the Finnish Biobank and digital health record data from the Finnish National Institute for Health and Welfare, specifically the R10 version released on December 18, 2023. The risk effects of genetic variations were assessed using the inverse variance-weighted (IVW) method and the wald ratio method.

Results: After correction, genetically predicted higher levels of plasma caffeine were significantly associated with an increased risk of lung cancer (OR = 1.54, 95%CI: 1.33-1.78, P_FDR < 0.001). In cancer subtype analysis, genetically predicted higher levels of plasma caffeine were significantly associated with the risk of lung squamous cell carcinoma (OR = 1.60, 95%CI: 1.16-2.19, P_FDR = 0.037) and non-small cell lung cancer (OR = 1.51, 95%CI: 1.21-1.89, P_FDR = 0.003) after correction.

Conclusion: The current MR results indicate that long-term higher levels of plasma caffeine are associated with an increased risk of lung cancer. These findings merit further exploration to understand whether caffeine intake, supplementation, or cessation could have clinically relevant therapeutic or preventive effects.