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. 2023 Feb 20:14:1113804.
doi: 10.3389/fgene.2023.1113804. eCollection 2023.

Associations of circulation levels of cytokines with birthweight, preterm birth, spontaneous miscarriages, and stillbirth: A Mendelian randomization analysis

Honghong Wang  1   2   3   4 , Jinghang Jiang  1   5   6 , Tingwei Jin  1   5 , Yifu Wang  1   5 , Mingli Li  1   2 , Shengzhu Huang  1   2 , Juanjuan Xie  1   5 , Zhongyuan Chen  1   7 , Yi Guo  1   5 , Jie Zheng  1   5 , Yonghua Jiang  1   8   9 , Zengnan Mo  1   2   5
Affiliations

Associations of circulation levels of cytokines with birthweight, preterm birth, spontaneous miscarriages, and stillbirth: A Mendelian randomization analysis

Honghong Wang et al. Front Genet. .

Abstract

Background: The association between immune imbalances and adverse pregnancy outcomes has been extensive investigated by observational studies, but remain unclear. Thus, this study aimed to establish the causality of the circulation levels of cytokines on adverse pregnancy outcomes, such as offspring's birthweight (BW), preterm birth (PTB), spontaneous miscarriage (SM), and stillbirth (SB). Methods: Two-sample Mendelian randomization (MR) analysis was employed to investigate potential causal relations between 41 cytokines and pregnancy outcomes on the basis of previously published GWAS datasets. Multivariable MR (MVMR) analysis was implemented to investigate the effect of the composition of cytokine networks on the pregnancy outcomes. Potential risk factors were further estimated to explore the potential mediators. Results: Genetic correlation analysis based on large GWAS data sources revealed that genetically predicted MIP1b (β = -0.027, S.E. = 0.010, p = 0.009) and MCSF (β = -0.024, S.E. = 0.011, p = 0.029) were associated with reduced offspring's BW, MCP1 (OR: 0.90, 95% CI: 0.83-0.97, p = 0.007) was associated with reduced SM risk, SCF (β = -0.014, S.E. = 0.005, p = 0.012) associated with decreased number of SB in MVMR. The univariable MR showed that GROa (OR: 0.92, 95% CI: 0.87-0.97, p = 0.004) was associated with decreased PTB risk. Except for the MCSF-BW association, all above associations surpassed the Bonferroni corrected threshold. The MVMR results revealed that MIF, SDF1a, MIP1b, MCSF and IP10 composed cytokine networks, associated with offspring's BW. Risk factors analysis indicated that the above causal associations might be mediated by smoking behaviors. Conclusion: These findings suggest the causal associations of several cytokines with adverse pregnancy outcomes, which were potentially mediated by smoking and obesity. Some of the results did not been corrected through multiple tests and larger samples verification is required in further studies.

Keywords: Mendelian randomization; birthweight; cytokines; immune system; preterm birth; spontaneous miscarriages; stillbirth.

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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
Study design. Abbreviations: BW, birthweight; PTB, preterm birth; SM, spontaneous miscarriage; SB, stillbirth.
FIGURE 2
FIGURE 2
Analytical results from the MR study of the associations between the circulation levels of cytokines and offspring’s BW, PTB, SM, SB. Abbreviations: BW, birthweight; PTB, preterm birth; SM, spontaneous miscarriage; SB, stillbirth; OR, odds ratio; 95% CI: 95% confidence interval. The red lines represented p < 0.05.
FIGURE 3
FIGURE 3
MVMR analytical results of the associations between the circulation levels of cytokines and offspring’s BW, SB. Abbreviations: BW, birthweight; SB, stillbirth; 95% CI: 95% confidence interval. The blue line represented p < 0.05, the red lines represented surpassed the Bonferroni-corrected p-value threshold.
FIGURE 4
FIGURE 4
MVMR analytical results of the associations between the circulation levels of cytokines and SM. Abbreviations: SM, spontaneous miscarriage; 95% CI: 95% confidence interval. The red lines represented surpassed the Bonferroni-corrected p-value threshold.
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Grants and funding

This work was supported by the Natural Science Foundation of China (82060145, 81901538), Guangxi Key Research and Development Project (Grant No. Guike AB21196022), Guangxi Science and Technology Major Project (Grant No. Guike AA22412, Guike AA22398), the Natural Science Foundation of Guangxi Zhuang Autonomous Region (2021JJA140912, 2018JJB140051), Major project of Scientific Research and Technology Development Plan of Nanning (20221023), Advanced Innovation Teams and Xinghu Scholars Program of Guangxi Medical University, and Science and Technology Plan of Liuzhou (2019BJ10603).
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