Genetic association of circulating interleukins and risk of colorectal cancer: A bidirectional Mendelian randomization study

Previous studies have reported that inflammation, especially interleukin family members, plays an important role in the development of colorectal cancer (CRC). However, because of various confounders and the lack of clinical randomized controlled trial, the causal relationship between genetically predicted level of interleukin family and CRC risk has not been fully explained.

Bi-directional Mendelian randomization (MR) was conducted to investigate the causal association between interleukin family members and CRC.

Several genetic variables were extracted as instrumental variables (IVs) from summary data of genome-wide association studies (GWAS) for interleukin and CRC. IVs of interleukin family were obtained from recently published GWAS studies and the summary data of CRC was from FinnGen Biobank. After a series of quality control measures and strict screening, six models were used to evaluate the causal relationship. Pleiotropy, heterogeneity test, and a variety of sensitivity analysis were also used to estimate the robustness of the model results.

Genetically predicted higher circulating levels of IL-2 (odds ratio [OR]: 0.76; 95% confidence interval [CI]: 0.63-0.92; p = .0043), IL-17F(OR: 0.78; 95% CI: 0.62-1.00; p = .015), and IL-31 (OR: 0.88; 95% CI: 0.79-0.98; p = .023) were suggestively associated with decreased CRC risk. However, higher level of IL-10 (OR: 1.40; 95% CI: 1.18-1.65; p = .000094) was causally associated with increased risk of CRC. Reverse MR results indicated that the exposure of CRC was suggestively associated with higher levels of IL-36α (OR: 1.23; 95% CI: 1.01-1.49; p = .040) and IL-17RD (OR: 1.22; 95% CI, 1.00-1.48; p = .048) and lower level of IL-13 (OR: 0.78; 95% CI: 0.65-0.95; p = .013). The overall MR results did not provide evidence for causal relationships between other interleukins and CRC (p > .05).

We offer suggestive evidence supporting a potential causal relationship between circulating interleukins and CRC, underscoring the significance of targeting circulating interleukins as a strategy to mitigate the incidence of CRC.