细胞因子在母体孕龄到后代眼病因果途径中的长期中介作用：生命过程网络孟德尔随机化。
The long-term mediation role of cytokines on the causal pathway from maternal gestational age to offspring eye diseases: Lifecourse-Network Mendelian randomization.
机构信息
Beijing International Center for Mathematical Research, Peking University, Beijing 100871, China.
Department of Neonatology, Jinan Children's Hospital, Jinan, Shandong 250022, China; Department of Neonatology, Children's Hospital Affiliated to Shandong University, Jinan, Shandong 250022, China.
出版信息
Int Immunopharmacol. 2023 Sep;122:110667. doi: 10.1016/j.intimp.2023.110667. Epub 2023 Jul 22.
BACKGROUND
Gestational duration has a significant impact on eye diseases. A large number of evidences suggest that cytokines are associated with gestational duration and eye diseases. However, the causal relationships among cytokines, maternal gestational impairment and offspring eye diseases remain unclear.
METHODS
We performed lifecourse-network Mendelian randomization (MR) to explore the causal relationships between maternal gestational duration (from the Early Growth Genetics (EGG) Consortium and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study, N = 84,689), neonatal/adult cytokines (from the NHGRI-EBI Catalog, N = 764/4,618), and adult eye diseases (from FinnGen consotium, N = 309,154) using summary-level data from large genome-wide association studies. Multiplicative random effects inverse variance weighted (IVW) and multivariable-IVW methods were the main analysis methods, and the other 15 pleiotropy-robust methods, weak IV-robust methods, and outliers-robust methods were used as auxiliary methods.
RESULTS
Maternal gestational age (early preterm birth, preterm birth, gestational duration, and post-term birth) had a causal relationship with 42 eye diseases. Four neonatal cytokines, Tumor Necrosis Factor-α(TNF-α), IL10, GROA, and CTACK, as well as four adult cytokines, CTACK, IL10, IL12p70 and IL6 are mediators in the causal relationships between early preterm birth and preterm birth in eight eye diseases. However, after adjusting for these mediators, a null direct causal effect of early preterm birth and preterm birth on eight eye diseases was found. In addition, there was no mediator in the causal relationship between gestational duration and post-term birth to eye diseases.
CONCLUSION
The effects of maternal gestational duration on offspring eye diseases through cytokines are long-term and life-course effects.
背景
妊娠持续时间对眼部疾病有重大影响。大量证据表明细胞因子与妊娠持续时间和眼部疾病有关。然而，细胞因子、母体妊娠损伤与后代眼部疾病之间的因果关系尚不清楚。
方法
我们进行了基于孟德尔随机化的生命历程网络分析，使用来自大型全基因组关联研究的汇总数据，探讨了母体妊娠持续时间（来自早期生长遗传学（EGG）联盟和拉伦贝克基金会综合精神病学研究倡议（iPSYCH）研究，N=84689）、新生儿/成人细胞因子（来自 NHGRI-EBI 目录，N=764/4618）与成人眼部疾病（来自 FinnGen 联盟，N=309154）之间的因果关系。主要分析方法为多效性稳健逆方差加权（IVW）和多变量-IVW 方法，其他 15 种易感性稳健方法、弱 IV 稳健方法和异常值稳健方法作为辅助方法。
结果
母体妊娠年龄（早产、早产、妊娠持续时间和过期妊娠）与 42 种眼部疾病有因果关系。4 种新生儿细胞因子（肿瘤坏死因子-α（TNF-α）、IL10、GROA 和 CTACK）和 4 种成人细胞因子（CTACK、IL10、IL12p70 和 IL6）是早产和早产与 8 种眼部疾病之间因果关系的中介物。然而，在调整这些中介物后，早产和早产对 8 种眼部疾病的直接因果效应为零。此外，妊娠持续时间和过期妊娠与眼部疾病之间没有因果关系的中介物。
结论
细胞因子介导的母体妊娠持续时间对后代眼部疾病的影响是长期的、贯穿生命历程的。
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