Genetic overlap and causal inferences between diet-derived antioxidants and small-cell lung cancer

Abstract

Several studies have reported that antioxidants exert both preventive and inhibitory effects against tumors. However, their causal effects on small-cell lung cancer (SCLC) remain controversial. Herein, we explored the causal effects of 6 antioxidants on SCLC by combining a genome-wide association study database and the Mendelian randomization (MR) approach. We obtained antioxidant genetic variance data for 6 exposure factors: carotene, vitamin A (retinol), selenium, zinc, vitamin C, and vitamin E, from the genome-wide association study database. The instrumental variables for exposure factors and SCLC outcomes were integrated by screening instrumental variables and merging data. Two-sample MR was used to analyze the causal relationship between exposure and outcomes. Finally, we examined the heterogeneity and horizontal pleiotropy of the MR analysis by performing multiple sensitivity analyses. We found a causal relationship between carotene and SCLC using two-sample MR analysis and sensitivity analysis (P = .02; odds ratio = 0.73; 95% confidence interval: 0.55-0.95). In contrast, there was no causal relationship between other examined antioxidants and SCLC. We found that diet-derived circulating antioxidants could afford protection against SCLC, and carotene is the causal protective factor against SCLC.

Figure 1.

Flow chart of the experimental design of this study.

Figure 2.

(A) Scatter plot of SNPs associated with diet-derived antioxidants and risk of SCLC. The plot shows the SNP effects on diet-derived antioxidants (x-axis, SD units) as well as SCLC (y-axis, OR) with 95% CI. The MR regression slopes of the lines represent the causal estimates using 5 approaches (IVW, MR-Egger, weighted median, simple mode, and weighted mode); (B) diagram of the leave-one-out method of SNPs associated with dietary antioxidants and SCLC. Each black point indicates the log OR for SCLC per standard deviation increase in dietary antioxidants, generated utilizing each dietary antioxidants -associated SNP as an instrument. The horizontal line denotes 95% CIs of the estimates. The red point shows the combined causal estimates utilizing all SNPs as an instrument based on leave-one-out method. IVW = inverse-variance weighted, MR = Mendelian randomization, OR = odds ratio, SCLC = small-cell lung cancer, SNPs = single nucleotide polymorphisms.