Omega-6/Omega-3 Ratio as a Protective Factor in Lung Cancer: A Mendelian Randomization Study on Polyunsaturated Fatty Acids and Lung Adenocarcinoma Risk.

Background: While observational studies have reported conflicting associations between polyunsaturated fatty acids (PUFAs) and lung cancer risk, the causal role of specific PUFA subtypes remains unclear. Methods: Leveraging genome-wide association data from the UK Biobank and International Lung Cancer Consortium, we employed univariable, multivariable, and bidirectional Mendelian randomization (MR) analyses to investigate the causal effects of seven PUFA traits (including omega-3, DHA, EPA, omega-6, LA, AA, and the omega-6/omega-3 ratio) on lung cancer and its subtypes. Results: Our primary finding revealed a robust protective effect of a higher omega-6/omega-3 ratio against overall lung cancer (IVW: OR = 0.87; 95% CI: 0.78-0.96; P_value = 0.009) and lung adenocarcinoma (LUAD) (IVW: OR = 0.78; 95% CI: 0.67-0.89; P_value = 0.0005). Conversely, elevated omega-3 and DHA levels were associated with increased LUAD risk. These associations persisted after adjusting for BMI, smoking, and potential pleiotropy. Conclusion: This study provides the first causal evidence that a higher omega-6/omega-3 ratio reduces lung cancer risk, particularly LUAD, through multivariable and bidirectional Mendelian randomization analyses that account for BMI, smoking, and genetic pleiotropy. These findings highlight the ratio's potential as a novel and modifiable dietary target for prevention, offering actionable insights beyond prior studies focused on individual PUFA subtypes.