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Fetal Genetic Variants Implicated in Spontaneous Preterm Birth Risk

NEW YORK (GenomeWeb) – A team of researchers from Finland and the US has identified fetal genetic variants — including in a gene involved in axon guidance, neuronal migration, and inflammation — that appear to coincide with spontaneous preterm birth.

As they reported online today in PLOS Genetics, the researchers conducted a genome-wide association study involving almost 250 infants born by spontaneous preterm birth and more than 400 infants carried to term. After replication testing in hundreds more babies born particularly prematurely and thousands of control infants, they were left with a SNP in the SLIT2 gene that was significantly associated with spontaneous preterm birth, as well as suggestive associations for SNPs in other axon guidance genes.

The team's follow-up gene expression, localization, and functional experiments indicated that SLIT2 and ROBO1 — which encodes SLIT2's receptor protein — are expressed at higher-than-usual levels in certain parts of the placenta for infants experiencing spontaneous preterm birth.

"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 [spontaneous preterm birth]," senior and corresponding author Mika Rämet, a researcher affiliated with the University of Oulu and Tampere University, and his colleagues wrote.

Meanwhile, the researchers' small-interfering RNA knockdown experiments targeting ROBO1 indicated that downstream signaling through a SLIT2 and ROBO1 pathway appeared to influence everything from inflammatory gene regulation to pregnancy-specific beta-1-glycoprotein (PSG) gene expression and fetal growth.

Those and other findings hinted that the ROBO1 receptor and its SLIT2 ligand belong to a signaling network with ties to spontaneous preterm birth risk — a condition that can lead to lifelong health issues and increased mortality risk for affected infants.

"Complications caused by preterm birth are the most common cause of neonatal deaths and the largest direct cause of death of children [under five] years of age," the authors explained.

But while environmental factors, maternal genetics, and fetal genetics all seem to play a part in this process, "our understanding of the early molecular pathways leading to [spontaneous preterm birth] is incomplete and there are no effective means to prevent [spontaneous preterm birth]," they wrote.

For their GWAS, the researchers began by comparing array-based genotypes generated from umbilical cord blood, tissue, or saliva samples from 247 Finnish babies born before 36 weeks of gestation and 419 born-at-term control babies from the same population, searching for variants linked to either infants' gestational age at birth or to spontaneous preterm birth overall. They also did separate analyses focused on "very preterm" infants born earlier than 32 weeks of gestation and on mid-to-late preterm infants, comparing each group to control infants.

After repeatedly unearthing SLIT2 SNPs in the preterm birth analyses, the team took those and other suspicious variants forward for validation testing in a group of 260 more very preterm and 9,630 at-term control infants from Europe who had been profiled for a past study.

The most significant association with spontaneous birth involved a SNP called rs116461311 in SLIT2, prompting a series of immunohistochemistry, RT-qPCR, and gene silencing experiments on placental samples or cells that the researchers used to hammer out SLIT2-ROBO1 interactions and their consequences for birth timing.

"Based on the currently available evidence," the authors concluded, "we propose that activation of SLIT2-ROBO1 expression and signaling in [placental] trophoblast cells contributes to inflammatory and immune activation, which in turn leads to early labor and preterm birth."