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Babies' DNA affects mothers' risk for pre-eclampsia
These results from the InterPregGen study are published in Nature Genetics. The work was carried out by genetics experts from the United Kingdom (UK), Nordic countries and Central Asia and is the first to show an effect of DNA from the fetus on the health of its mother.
Pre-eclampsia affects up to 5% of pregnancies and is first suspected when a woman is found to have high blood pressure, usually in the second half of pregnancy after 20 week of pregnancy.
It is diagnosed when a significant amount of protein is found in a woman's urine. In severe cases red blood cells breakdown which can lead to impaired liver and kidney function, including swelling and shortness of breath from fluid in the lungs. Left untreated, it may result in seizures. Severe pre-eclampsia increases the risk of death for both mother and baby.
A mother's risk factors include obesity, a prior history of hypertension, older age, or diabetes mellitus. It is frequently diagnosed in a woman's first pregnancy and when carrying twins.
Underlying mechanisms involve an abnormal formation of blood vessels in the placenta. A mother's blood pressure is seen as high if greater than 140 mmHg systolic or 90 mmHg diastolic on two separate readings, more than four hours apart after twenty weeks of pregnancy. Pre-eclampsia is routinely screened for in prenatal visits.
The 5-year study involved teams from the UK, Iceland, Finland, Norway, Kazakhstan and Uzbekistan. They studied the genetic make-up of 4,380 babies born from pre-eclamptic pregnancies and compared their DNA with over 300,000 healthy individuals.
Dr Linda Morgan, from the University of Nottingham's School of Life Sciences, coordinated the 5-year study, which included DNA samples contributed from Iceland, Norway and Finland as well as from over 20 universities and maternity units in the UK.
"For many years midwives and obstetricians have known that a woman is more likely to develop pre-eclampsia if her mother or sister had the disorder. More recently research has shown that the condition also runs in families of men who father pre-eclamptic pregnancies.
Laboratory and statistical analysis performed at the Wellcome Trust Sanger Institute (UK) and deCODE Genetics (Iceland) pinpointed the location in the baby's DNA that increases risk of pre-eclampsia. This location was confirmed by other InterPregGen members to fit hand-in-glove with other medical information about pre-eclampsia.
Dr Ralph McGinnis, who led the analysis at the Sanger Institute: "Pre-eclampsia has been recognized since ancient Egypt and Greece as being a danger to the lives of mothers and babies. This first piece of the genetic jigsaw holds substantial promise for unlocking some of the mystery of how pre-eclampsia is caused. Our finding may also enable better prediction of mothers who will become pre-eclamptic when combined with clinical information and with other pieces of the genetic jigsaw that will also surely be discovered in the next few years."
The baby's DNA comes from both its mother's and its father's genes - in keeping with the inherited risk of pre-eclampsia. The DNA changes associated with pre-eclampsia are common — over 50% of people carry this sequence in their DNA so the inherited changes are not sufficient in themselves to cause disease, but they do increase the risk of pre-eclampsia.
The research found DNA variations close to the gene that makes a protein called sFlt-1 with significant differences between babies born from pre-eclamptic pregnancies and the control group.
Morgan concludes: "We believe the new insights from this study could form the basis for more effective prevention and treatment of pre-eclampsia in the future, and improve the outcome of pregnancy for mother and child."
DNA from a further 4,220 babies from pre-eclamptic pregnancies in Kazakhstan and Uzbekistan is currently being analysed in an extended study to see if the same variations occur near sFlt-1.
Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death1. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility2. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets3, 4. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia5. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.
Subject terms: Genetic association study Reproductive disorders
The research was funded by a 6 million Euro grant from the European Commission.
Competing financial interests V.S., G.T., L.S., J.K.S., U.T. and K.S. are employees of the biotechnology firm deCODE Genetics, a subsidiary of Amgen. D.A.L. has received industry funding for biomarker research unrelated to this paper from Medtronic, Roche Diagnostics and Ferring Pharmaceuticals.
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Pre-eclampsia can become a life threatening condition for mom and baby.
Image Credit: public domain