Variants in the fetal genome near FLT1 are associated with risk of PREECLAMPSI

I’ve always found preeclampsia to be a fascinating clinical problem. Preeclampsia is a serious disorder during pregnancy in which: [a] systolic blood pressure (SBP) is >140 mm Hg and/or diastolic blood pressure (DBP) >90 mm Hg –– on two occasions at least 4 h apart in a previously normotensive patient; or [b] an SBP >160 mm Hg and/or DBP >110 mm Hg or higher on any one occasion. Patients also exhibit proteinuria (protein in the urine) of >0.3 grams of protein per 24-h sample. The disease can become serious with extensive liver and kidney damage, visual disturbances, fluid in the lung (pulmonary edema), and clotting disorders (inability to stop bleeding). Preeclampsia is the leading cause of maternal and perinatal death, and the disorder occurs in ~5% of pregnancies. Causes of preeclampsia remain unclear, but it represents complicated gene-environment interactions. There is evidence for inherited susceptibility; however, is the genetic risk derived from the mother? From the early developing embryo? Are father’s genes involved? Or some combination of all three genomes?

Authors [see attached article] report the first genome-wide association study (GWAS) of offspring from preeclamptic pregnancies, and they discovered genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10–11), comparing 4,380 cases with 310,238 controls. This locus is near the FLT1 gene (encoding FMS-like tyrosine kinase-1). This is a credible locus because, in previous studies the placental isoform of FLT1 has been implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth percentile. An additional nearby variant was found to be associated with preeclampsia independently of rs4769613.

Data presented herein imply that altered FLT1 expression by trophoblasts is not merely a secondary consequence of placental pathology in preeclampsia but is central to its etiology. [“The trophoblast” is the layer of trophoblast cells that form the outer layer of the embryonic blastocyst and that provide nutrients to the embryo and develop into a major portion of the placenta; trophoblasts are formed during the first stage of pregnancy and are among the the first cells to differentiate from the fertilized egg.] A role for fetal DNA sequence variants –– in susceptibility to preeclampsia –– is consistent with patterns of inheritance linking both maternal and paternal factors. The fetal FLT1 gene has previously been indirectly impli­cated in pregnancies with fetal Trisomy-13, which are accompanied with increased placental RLT1 expression and an increased incidence of preeclampsia. Placental FLT1 is a marker of placental malfunction, which is a hallmark of early-onset preeclampsia. The observation herein … that the FLT1 geno­type is associated even more strongly with late-onset preeclampsia … implies that placental pathology is also a feature of the late-onset form of the disease.

The DNA variants described herein by the authors can serve as tools for experimental testing of whether, how, when, and where they affect FLT1 expression, and how altered expression is related to the pathophysiology of preeclampsia and its subtypes. The discovery of sequence variants in the fetal genome, which increase the risk of disease in the mother, is a demonstration of the closeness between the mother and baby in the remarkable symbiotic process that we call pregnancy. 🙂

Nature Genetics Aug 2o17; 49: 1255–1260

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