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. 2024 Apr 26;24(1):531.
doi: 10.1186/s12885-024-12301-x.

Associations of the circulating levels of cytokines with the risk of myeloproliferative neoplasms: a bidirectional mendelian-randomization study

Hao Xiong  1   2 , Huitao Zhang  2 , Jun Bai  1 , Yanhong Li  1 , Lijuan Li  3 , Liansheng Zhang  4
Affiliations

Associations of the circulating levels of cytokines with the risk of myeloproliferative neoplasms: a bidirectional mendelian-randomization study

Hao Xiong et al. BMC Cancer. .

Abstract

Objective: In the pathogenesis of myeloproliferative neoplasms (MPN), inflammation plays an important role. However, it is unclear whether there is a causal link between inflammation and MPNs. We used a bidirectional, two-sample Mendelian randomization (MR) approach to investigate the causal relationship between systemic inflammatory cytokines and myeloproliferative neoplasms.

Methods: A genome-wide association study (GWAS) of 8293 European participants identified genetic instrumental variables for circulating cytokines and growth factors. Summary statistics of MPN were obtained from a GWAS including 1086 cases and 407,155 controls of European ancestry. The inverse-variance-weighted method was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl).

Results: Our results showed that higher Interleukin-2 receptor, alpha subunit (IL-2rα) levels, and higher Interferon gamma-induced protein 10 (IP-10) levels were associated with an increased risk of MPN (OR = 1.36,95%CI = 1.03-1.81, P = 0.032; OR = 1.55,95%CI = 1.09-2.22, P = 0.015; respectively).In addition, Genetically predicted MPN promotes expression of the inflammatory cytokines interleukin-10 (IL-10) (BETA = 0.033, 95% CI = 0.003 ~ 0.064, P = 0.032) and monokine induced by interferon-gamma (MIG) (BETA = 0.052, 95% CI = 0.002-0.102, P = 0.043) and, on activation, normal T cells express and secrete RANTES (BETA = 0.055, 95% CI = 0.0090.1, P = 0.018).

Conclusion: Our findings suggest that cytokines are essential to the pathophysiology of MPN. More research is required if these biomarkers can be used to prevent and treat MPN.

Keywords: Cytokines; Inflammatory; Mendelian randomization; Myeloproliferative neoplasms.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study design overview and assumptions for MR Design. Assumption 1: IVs were not related to Confounders; Assumntion2: a strong correlation between iVs and exposure; Assumption 3: IVs can affect outcomes only through exposure and not through other pathways
Fig. 2
Fig. 2
Forest plot of Mendelian randomization analysis of the correlation between inflammatory cytokines and risk of myeloproliferative neoplasms (MR analysis method using IVW). A: Effects of 41 inflammatory cytokines on myeloproliferative tumors. B:Effects of myeloproliferative neoplasms on 41 inflammatory cytokines(*P < 0.05)
Fig. 3
Fig. 3
Leave-one-out analysis of bidirectional mendelian randomization in cytokines and MPN.The left side of the forest plot represents the SNPs for which the leave-one-out analysis was performed, and the short line parallel to the x-axis represents the 95% confidence interval for the OR/beta value of the MR analysis after excluding the corresponding SNPs. As shown in the figure, the overall error line does not change much after excluding each SNP, and all OR/beta values are on the 0 side, indicating that the results are reliable (A):Forest plots for the exposure of IL-2ra. B Forest plots for the exposure of IP-10. C Forest plots for the outcome of IL-10. D Forest plots for the outcome of MIG. E Forest plots for the outcome of RANTES
Fig. 4
Fig. 4
The GEO dataset analyses the expression of IP10 and IL2ra in each subtype of MPN and their diagnostic value.A: Expression of IP10 and IL2ra in ET and healthy donors; B: ROC curve of the prediction model based on IP10 and IL2ra to distinguish ET from healthy donors; C:IP10 and IL2ra expression in PV and healthy donors; D: ROC curve of the prediction model based on IP10 and IL2ra to distinguish PV from healthy donors; E:IP10 and IL2ra expression in MF and healthy donors; F: ROC curve of the prediction model based on IP10 and IL2ra to distinguish MF from healthy donors; ***P < 0.001, **P < 0.01,*P < 0.05,HC: Healthy donors
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