A Mendelian randomization study on the causal association of circulating cytokines with colorectal cancer

by Youqian Kong, Xiaoyu Wang, Hongyun Xu, Shaoxuan Liu, Rui Qie

Background

Circulating cytokines have been associated with colorectal cancer (CRC). However, their causal correlation remains undetermined. This investigation uses genetic data to evaluate the mechanism that links circulating cytokines and CRC via Mendelian Randomization (MR).

Methods

A two-sample MR evaluation was carried out to investigate the mechanism associating circulating cytokines and CRC in individuals of European ancestry. The Genome-wide association studies statistics, which are publically accessible, were used. Eligible instrumental SNPs that were significantly related to the circulating cytokines were selected. Multiple MR analysis approaches were carried out, including Simple Mode, inverse variance weighted (IVW), MR-Egger, Weighted Mode, Weighted Median, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods.

Results

The evidence supporting the association of genetically predicted circulating levels with the increased risk of CRC was revealed; these included vascular endothelial growth factor (OR = 1.352, 95% CI: 1.019–1.315, P = 0.024), interleukin-12p70 (OR = 1.273, 95% CI: 1.133–1.430, P = 4.68×10⁻⁵), interleukin-13 (OR = 1.149, 95% CI: 1.012–1.299, P = 0.028), interleukin-10 (OR = 1.230, 95% CI: 1.013–1.493, P = 0.037), and interleukin-7 (OR = 1.191, 95% CI: 1.023–1.386 P = 0.024). Additionally, MR analysis negative causal association between macrophage colony stimulating factor and CRC (OR = 0.854, 95% CI: 0.764–0.955, P = 0.005). The data from Simple Mode, Weighted Median, MR-Egger, and Weighted Mode analyses were consistent with the IVW estimates. Furthermore, the sensitivity analysis indicated that the presence of no horizontal pleiotropy to bias the causal estimates.

Conclusion

This investigation identified a causal association between circulating cytokines levels risk of CRC and may provide a deeper understanding of the pathogenesis of CRC, as well as offer promising leads for the development of novel therapeutic targets for CRC.