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Fetal Variants Influence Maternal Preeclampsia Risk, New Study Finds

NEW YORK (GenomeWeb) – Variants within the fetal genome may influence whether the mother develops preeclampsia during her pregnancy, according to a new international study.

In a genome-wide association study of children whose mothers had preeclampsia while pregnant with them, researchers from the InterPregGen study searched for variants influencing disease risk. Preeclampsia, which occurs in about 5 percent of pregnancies and is marked by high blood pressure, can lead to seizures, stroke, and even death. It's also been linked to malformations of the placenta.

As the researchers — a team from the UK, Iceland, Finland, Norway, Kazakhstan, and Uzbekistan — reported today in Nature Genetics, they uncovered variants near the FLT1 gene that were associated with preeclampsia risk in the mothers. They further found that this association was strongest among children whose mothers developed preeclampsia late in pregnancy.

"We knew that faulty formation of the placenta is often found in preeclampsia. As it is the baby's genes that produce the placenta, we set out to see if we could find a link between the baby's DNA and the condition," the University of Nottingham's Linda Morgan, the senior author of the publication, said in a statement. "We found there were indeed some features in a baby's DNA that can increase the risk of preeclampsia."

The InterPregGen researchers examined nearly 7.5 million variants within 2,658 children of preeclamptic pregnancies and 208,292 population controls of European descent from three cohorts from Iceland and the UK. From this, they uncovered a single locus associated with genome-wide significance on chromosome 13, near the FLT1 gene.

They then genotyped that locus, rs4769613, and other signals that had suggestive associations in a further 1,722 cases and 1,946 controls from Norway. In this dataset, as well as in a joint analysis of the original and replication datasets, the locus was associated with preeclampsia.

This locus, though, only accounted for part of the association the region has with preeclampsia, suggesting that there might be other variants near the FLT1 gene that are independently linked to the condition. By genotyping 21 further variants from nine linkage disequilibrium blocks, they found that rs12050029 and rs149427560 also reached genome-wide significance.

The researchers also examined whether rs4769613 was more common among certain preeclampsia sub-classifications, such as gestational age at diagnosis. Late-onset preeclampsia, the researchers noted, has been thought to be due to maternal maladaptation to the physiological stress of pregnancy while early-onset preeclampsia has been thought to be due to insufficient placental implantation. The rs4769613 C allele was more common among late-onset preeclampsia cases, they reported.

The InterPregGen researchers noted that the signals near rs4769613 and rs12050029 are located in placental enhancer regions, which could reflect a mechanism for how they influence FLT1 expression.

FLT1 encodes a transmembrane tyrosine kinase receptor that is involved in angiogenesis. During pregnancy, it is expressed in fetal trophoblasts as the soluble sFlt-1 isoform, which enters maternal circulation. Excessive sFlt-1 levels are linked to widespread maternal endothelial dysfunction, including hypertension and proteinuria — hallmarks of preeclampsia.

Using the DeCode database of common diseases and traits, the researchers found that the rs4769613 and rs12050029 risk alleles — which are not in linkage disequilibrium — are both associated with decreased red blood cell count.

This suggested to the researchers that these variants lead to an increase of sFlt-1 in fetuses and to lower red blood cell levels in the general population, and indicates that they work through the nearby FLT1 gene.

"We believe the new insights from this study could form the basis for more effective prevention and treatment of preeclampsia in the future, and improve the outcome of pregnancy for mother and child," Morgan said.

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