Associations between genetically predicted concentrations of circulating inflammatory cytokines and the risk of ten pregnancy-related adverse outcomes: A two-sample Mendelian randomization study

Background: Evidence from increasing observational studies indicates that systemic inflammation plays a role in pregnancy-related adverse events. However, the causal associations between them are largely unclear. To investigate the potential causal effects of genetically regulated concentrations of inflammatory cytokines on the risk of adverse pregnancy outcomes, we performed a Mendelian randomization (MR) analysis.

Methods: The cis-protein quantitative trait loci for the 47 inflammatory cytokines derived from the latest genome-wide association studies (GWASs) consisting of 31,112 European individuals were used as the instrumental variables. The latest GWAS summary data for the ten adverse pregnancy events were obtained from the FinnGen project (samples ranging from 141,014 to 190,879). The inverse-variance weighted regression or Ward ratio was used as the primary MR analysis method. Sensitivity analyses based on the other five methods were performed to verify MR results. A replication MR analysis was conducted to further clarify the significant associations using data from the UK Biobank.

Results: Twenty-three of the 220 associations were nominally significant (P < 0.05). Among them, seven robust associations survived the Bonferroni correction and passed sensitivity analyses, including positive associations of soluble intercellular adhesion molecule (sICAM-1) with the risk of excessive vomiting in pregnancy, preeclampsia (PE), and pregnancy hypertension (PH), vascular endothelial growth factor with the risk of medical abortion, macrophage colony-stimulating factor (MCSF) with the risk of spontaneous abortion (SA), and an inverse association of macrophage inflammatory protein-1α with the risk of medical abortion. The associations of MCSF with SA, and sICAM-1 with both PE and PH were further confirmed in the replication analysis.

Conclusions: This study provides further evidence of the role of systemic inflammation, especially endothelial dysfunction in the pathology of adverse pregnancy events, and the identified cytokines warrant in-depth research to explore their underlying mechanisms of action and to evaluate their potential as targets for disease screening, prevention, and treatment in the future.