Genetic and other biological factors behind spontaneous preterm birth. Genetics, transcriptomics and proteomics of human spontaneous preterm delivery

Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Certain risk factors predispose infants to SPTB, but over half of SPTBs occur in pregnancies where there is no identifiable risk factor. Previous studies have suggested that SPTB has a genetic background and that both maternal and fetal genomes contribute to its likelihood. Other biological factors are also associated with SPTB, but knowledge about these factors is limited. One of the key tissues involved in parturition is the placenta.
In the first study we set out to identify fetal genetic variants that predispose infants to premature birth in a population of Finnish origin. Our results indicate that a gene variant of slit guidance ligand 2 (SLIT2) is associated with the risk of spontaneous preterm birth. Furthermore, SLIT2 and its receptor roundabout guidance receptor 1 (ROBO1) are expressed in placental cells, and their levels are higher in placentas from spontaneous preterm deliveries compared to term controls. Based on experiments SLIT2-ROBO1 signaling regulates expression of pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Thus, our results indicate that the fetal SLIT2 variant and expression of both SLIT2 and ROBO1 in placental cells are correlated with susceptibility to spontaneous preterm birth. We propose that this SLIT2-ROBO1 pair is a component of the signaling network that promotes spontaneous preterm birth.
In the second publication proteins for which particular levels in placenta are associated with SPTB were identified. The results showed that an abnormal amount of certain proteins in the placenta is connected to the risk of the fetus being born prematurely. This yielded a candidate, alpha-1 antitrypsin (AAT) as level of AAT was noted to be downregulated in SPTB placentas compared to term control placentas. AAT was localized in the placenta both inside the cells of the placenta and in structures outside the cells. These structures have an immunosuppressive function and lowers the immunological load between mother and fetus. We propose that loss of the effects of alpha-1 antitrypsin renders structures critical to maintaining pregnancy susceptible to inflammatory activation. This may lead to spontaneous premature birth.
In the third publication the association of heat shock proteins (HSPs) in SPTB was studied as it is known that some heat shock proteins (HSPs) are associated with pregnancy complications. Thus, datasets were used to identify SPTB-predisposing HSPs. In addition, the association of nuclear hormone receptors (NRs) with SPTB was studied, as HSPs regulate the activity of NRs. Multiple associations of HSPs and NRs with SPTB were found
Currently, there is no effective method for predicting or preventing SPTB. The aim of this study was to determine the biological factors behind predisposition to SPTB using hypothesis-free methods. New factors that affect the risk of SPTB susceptibility were identified. The results provide a starting point for further studies to develop ways to predict SPTB and prolong gestational age.