Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2

Abstract

Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) and 419 term controls (GA 38–41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 ( SLIT2 ; rs116461311, minor allele frequency 0.05, p = 1.6×10 −6 ). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2 . In 172 very preterm-born infants (GA <32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10 −7 ). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein ( PSG ) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB.

Role of galectin-glycan circuits in reproduction: from healthy pregnancy to preterm birth (PTB)

“…A genome-wide association study (GWAS) has found that slit guidance ligand 2-roundabout guidance receptor 1 (SLIT2-ROBO1) signaling in trophoblasts is associated with PTB and that higher mRNA levels of SLIT2 and ROBO1 are detected in the basal plate of placentas from PTB samples [148]. Interestingly, knockdown of ROBO1 in trophoblast- derived cells upregulated 6 of 10 pregnancy-specific glycoproteins (PSGs).…”

Functional Genomics of Healthy and Pathological Fetal Membranes

“…A similar approach was also used in a genome wide association study of early preterm and term infants. Several significant variants near the gene SLIT2 were identified that overlaps regions of DNase hypersensitivity, suggesting regulatory activity, in several fetal tissues including the amnion (Tiensuu et al, 2019).…”

Mutations in Gene Coding for SLIT2 Linked to Preterm Birth: SLIT2 and its receptor ROBO1 are components of the signaling network that promotes spontaneous preterm birth

“…In one new study, mutations in the gene that codes for SLIT2, a protein expressed in fetal cells in placentas and involved in directing the growth of the fetal nervous system, are shown to be associated with the risk of SPTB (Tiensuu et al, 2019). In addition, both SLIT2 and its receptor roundabout guidance receptor 1 (ROBO1) were expressed in placental cells, and mRNA levels were higher in placentas from spontaneous preterm deliveries than those in a control group of infants born at full term.…”