Abstract
Preterm birth (PTB) is the leading cause of newborn deaths around the world. Spontaneous preterm birth (sPTB) accounts for two-thirds of all PTBs; however, there remains an unmet need of detecting and preventing sPTB. Although the dysregulation of the immune system has been implicated in various studies, small sizes and irreproducibility of results have limited identification of its role. Here, we present a cross-study meta-analysis to evaluate genome-wide differential gene expression signals in sPTB. A comprehensive search of the NIH genomic database for studies related to sPTB with maternal whole blood samples resulted in data from three separate studies consisting of 339 samples. After aggregating and normalizing these transcriptomic datasets and performing a meta-analysis, we identified 210 genes that were differentially expressed in sPTB relative to term birth. These genes were enriched in immune-related pathways, showing upregulation of innate immunity and downregulation of adaptive immunity in women who delivered preterm. An additional analysis found several of these differentially expressed at mid-gestation, suggesting their potential to be clinically relevant biomarkers. Furthermore, a complementary analysis identified 473 genes differentially expressed in preterm cord blood samples. However, these genes demonstrated downregulation of the innate immune system, a stark contrast to findings using maternal blood samples. These immune-related findings were further confirmed by cell deconvolution as well as upstream transcription and cytokine regulation analyses. Overall, this study identified a strong immune signature related to sPTB as well as several potential biomarkers that could be translated to clinical use.
Highlights
Preterm birth (PTB), which is defined as giving birth before completion of 37 weeks of gestation, is the leading cause of newborn deaths worldwide
From the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database [23, 24], which were comprised of whole blood gene expression profiles from women who delivered preterm and term, respectively
In addition to whole blood samples, another study used in the meta-analysis (GSE73685) collected RNA samples from seven other different types of tissues including amnion, cord blood (CB), chorion, decidua, fundus, lower segment, and placenta (Table 1)
Summary
Preterm birth (PTB), which is defined as giving birth before completion of 37 weeks of gestation, is the leading cause of newborn deaths worldwide. In 2010, 14.9 million babies were born preterm, accounting for 11.1% of all births across 184 countries, with the highest PTB rates occurring in Africa and North America [1]. This high incidence of PTB is concerning since 29% of all neonatal deaths worldwide, approximately 1 million deaths total, are accounted to complications in PTB [2]. Numerous signs point to genetic factors as playing a role in birth timing including the observations that PTBs are likely to recur in mothers, women who are born preterm are more likely to deliver prematurely, and sisters of women who have delivered prematurely are at an increased risk of delivering preterm. The complexity and multiple etiologies of sPTB, along with the inconsistency in clinical phenotyping and non-uniform classification system, have limited the identification of genetic factors and clinically relevant biomarkers [11]
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