Preeclampsia risk is influenced by both the mother’s genetic background and the genetics of her fetus; however, the specific genes responsible for conferring preeclampsia risk have largely remained elusive. Evidence that preeclampsia has a genetic predisposition was first detailed in the early 1960s, and overall preeclampsia heritability is estimated at ∼55%. Many traditional gene discovery approaches have been used to investigate the specific genes that contribute to preeclampsia risk, but these have largely not been successful or reproducible. Over the past decade, genome-wide association studies have allowed for significant advances in the understanding of the genetic basis of many common diseases. Genome-wide association studies are predicated on the idea that the genetic basis of many common diseases are complex and polygenic with many variants, each with modest effects that contribute to disease risk. Using this approach in preeclampsia, a large genome-wide association study recently identified and replicated the first robust fetal genomic region associated with excess risk. A screen of >7 million genetic variants in 2658 offspring from preeclamptic women and 308,292 population controls identified a single association signal close to the Fms-like tyrosine kinase 1 gene, on chromosome 13. Fms-like tyrosine kinase 1 encodes soluble Fms-like tyrosine kinase 1, a splice variant of the vascular endothelial growth factor receptor that exerts antiangiogenic activity by inhibiting signaling of proangiogenic factors. The Fms-like tyrosine kinase 1 pathway is central in preeclampsia pathogenesis because excess circulating soluble Fms-like tyrosine kinase 1 in the maternal plasma leads to the hallmark clinical features of preeclampsia, including hypertension and proteinuria. The success of this landmark fetal preeclampsia genome-wide association study suggests that well-powered, larger maternal and fetal genome-wide association study will be fruitful in identifying additional common variants that implicate causal preeclampsia genes and pathways. Such efforts will rely on the continued development of large preeclampsia consortia focused on preeclampsia genetics to obtain adequate sample sizes, detailed clinical phenotyping, and matched maternal-fetal samples. In summary, the fetal preeclampsia genome-wide association study represents an exciting advance in preeclampsia biology, suggesting that dysregulation at the Fms-like tyrosine kinase 1 locus in the fetal genome (likely in the placenta) is a fundamental molecular defect in preeclampsia.
Keywords: Fms-like tyrosine kinase 1; angiogenic imbalance; fetal genetics; genome-wide association study; heritability; hypertension; preeclampsia; vascular endothelial growth factor.