Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Divison of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
Genome Med. 2018 Aug 22;10(1):67. doi: 10.1186/s13073-018-0576-8.
The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control.
This is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome.
We show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype.
Our results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders.
免疫系统在妊娠和生命早期的发育中起着至关重要的作用。循环母体和新生儿免疫介质的改变与妊娠并发症以及以后发生自身免疫和神经发育疾病的易感性有关。有证据表明，成人的免疫系统不仅对环境刺激有反应，而且还受到强烈的遗传控制。
这是第一项对超过 700 对母婴进行的遗传研究，旨在分析母体妊娠中期血清衍生的 22 种和新生儿血斑衍生的 42 种免疫介质（细胞因子/趋化因子）在母体和胎儿基因型背景下的循环水平。我们首先估计了每种免疫分子的母体和胎儿全基因组 SNP 遗传率（h），然后进行全基因组关联研究（GWAS），以确定特定的基因座对个体免疫介质的贡献。最后，我们评估了遗传免疫决定因素与 ASD 结果之间的关系。
我们使用独立的方法显示了母体和新生儿细胞因子/趋化因子的遗传调节。我们证明了新的胎儿免疫功能基因座独立地影响母体免疫介质的生理水平，反之亦然。交叉相关的基因座与个体特异性免疫介质基因座位于不同的基因组区域。最后，我们观察到出生时白细胞介素 8（IL-8）水平升高、自闭症谱系障碍（ASD）状态和特定的母体基因型之间存在相互作用。
我们的研究结果表明，母体和胎儿遗传变异通过不同的机制影响妊娠和出生时的免疫系统，并且更好地了解早期发育中免疫因子的决定因素可能有助于揭示发育障碍的危险因素。
