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. 2024 Oct 8:15:1405503.
doi: 10.3389/fphar.2024.1405503. eCollection 2024.

Causal links between circulatory inflammatory cytokines and risk of digestive polyps: a Mendelian randomization analysis

Ziqi Yan  1   2 , Hongming Zheng  1   2 , Jieni Feng  3 , Yiting Li  1   2 , Zhifan Hu  1   2 , Yuan Wu  1   2 , Guibin Liao  4 , Taosheng Miao  1   2 , Zexin Qiu  1   2 , Qiaolan Mo  1   2 , Jia Li  1   2 , Ailin Lai  1   2 , Yue Lu  4 , Bin Chen  1
Affiliations

Causal links between circulatory inflammatory cytokines and risk of digestive polyps: a Mendelian randomization analysis

Ziqi Yan et al. Front Pharmacol. .

Abstract

Background: There is a high morbidity of polyps in the digestive tract, and certain subtypes of polyps are thought to induce cancer progression and often recur, which may be associated with chronic inflammation. Mendelian randomization (MR) can help identify potential causative relationships and inform early treatment action.

Methods: We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and three types of polyps from European ancestry, respectively, including gastric polyp (6,155 cases vs. 341,871 controls), colonic polyp (22,049 cases vs. 332,368 controls) and gallbladder polyp (458 cases vs. 340,083 controls). Inverse-variance weighted (IVW), weight median (WM), and MR-Egger methods were used for calculating causal estimates. Furthermore, Bayesian model averaging MR (MR-BMA) method was employed to detect the dominant causal circulatory cytokines with adjustment for pleiotropy effects.

Results: Our univariable MR using inverse-variance weight method identified causal associations of IL-2ra (OR: 0.892, 95%CI: 0.828-0.961, p = 0.003), MIG (OR: 1.124, 95%CI: 1.046-1.207, p = 0.001) and IL-18 (OR: 0.912, 95%CI: 0.852-0.977, p = 0.008) with gastric polyp, MIP1b (OR: 0.956, 95%CI: 0.927-0.987, p = 0.005) and IL-6 (OR: 0.931, 95%CI: 0.870-0.995, p = 0.035) with colonic polyp and IL-9 (OR: 0.523, 95%CI: 0.345-0.794, p = 0.0007) with gallbladder polyp. Finally, our MR-BMA analysis prioritized MIG (MIP = 0.332, MACE = 0.022; PP: 0.264, MSCE = 0.059), IL-18 (MIP = 0.302, MACE = -0.020; PP: 0.243, MSCE = -0.059) and IL-2ra (MIP: 0.129; MACE: -0.005; PP: 0.112, MSCE: -0.031) for gastric polyp, and MIP1b (MIP = 0.752, MACE = -0.033; PP: 0.665, MSCE = -0.044) and IL-6 (MIP: 0.196; MACE: -0.012; PP: 0.140, MSCE: -0.064) for colonic polyp, and IL-9 (MIP = 0.936, MACE = -0.446; PP: 0.781, MSCE = -0.478) for gallbladder polyp as the top-ranked protective factors.

Conclusion: Our research advances the current understanding of the function of certain inflammatory biomarker pathways in the genesis and malignant mutation of polyps in the digestive tract. Deeper substantiation is necessary to assess the potential of these cytokines as pharmacological or lifestyle targets for digestive polyps prevention.

Keywords: Bayesian model averaging (BMA); GWAS -genome-wide association study; Mendelian randomization (MR); gallbladder polyp; gastric polyp; inflammation biomarkers; intestinal polyp.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Flow-chart on the overall study design. (MR, Mendelian randomization; MR-BMA, multivariable Mendelian randomization analysis using Bayesian model averaging; GWAS, Genome-wide association Study; bNGF, beta nerve growth factor; CTACK, cutaneous T cell-attracting chemokine; FGFBasic, basic fibroblast growth factor; GCSF, granulocyte colony-stimulating factor; GROa, growthregulated oncogene-a; HGF, hepatocyte growth factor; IFNg, interferon gamma; IL, interleukin; IP, interferon gamma-induced protein 10; MCP1, monocyte chemotactic protein 1; MCP3, monocyte-specific chemokine 3; MCSF, macrophage colony-stimulating factor; MIF, macrophage migration inhibitory factor; MIG, monokine induced by interferon gamma; MIP1a, macrophage inflammatory protein-1a; MIP1b, macrophage inflammatory protein-1b; PDGFbb, platelet-derived growth factor BB; RANTES, regulated upon activation normal T cell expressed and secreted factor; SCF, stem cell factor; SCGFb, stem cell growth factor beta; SDF1a, stromal cell derived factor-1 alpha; SNPs, single-nucleotide polymorphisms; TNFa, tumor necrosis factor alpha; TNFb, tumor necrosis factor beta; TRAIL, TNF-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor; IBD, inflammatory bowel disease; CRC, colorectal cancer; ICC, intrahepatic cholangiocarcinoma; 5-LO, 5-lipoxygenase; LTB4, Leukotriene B4).
FIGURE 2
FIGURE 2
Causal correlations of 41 inflammatory cytokines on gastric polyp, colonic polyp, and gallbladder polyp (the results from inverse variance weighted method were shown for all cytokines). The change in the odds ratio (OR) of risk of gastrointestinal system polyps per one-SD rise in the cytokine level is shown by OR and 95%confidence interval.
FIGURE 3
FIGURE 3
Scatter plots and funnel plots of Mendelian randomization (MR) analyses for significant cytokines in digestive polyp risk. (A–F) Individual inverse variance (IV) associations with cytokine risk are displayed versus individual IV associations with gastric polyp, colonic polyp, and gallbladder polyp in black dots, respectively. The 95%CI of odd ratio for each IV is shown by vertical and horizontal lines. The slope of the lines represents the estimated causal effect of the MR methods. (G–L) The funnel plots show the inverse variance weighted MR estimate of each cytokine single-nucleotide polymorphism with polyp versus 1/standard error (1/SEIV).
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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (NO. 82074197), Specialized Fields Program for Key Areas in Guangdong Province’s Ordinary Higher Education Institutions (NO. 2022ZDZX2012), and 2023 Guangzhou municipal key research and development plan agriculture and social development scientific and technological thematic project (NO. SL2022B03J00104).

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