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Identification of pre-eclampsia - eclampsia susceptibility gene[s]

Prof Shaun Brennecke, Prof Christine East, Prof Eric Moses, Prof John Blangero

Pre-eclampsia (PE) is the most common serious medical disorder of human pregnancy. Particularly in their first pregnancy, pregnant women can suffer from high blood pressure, kidney dysfunction leading to leakage of protein into the urine, swelling of hands, feet and face, and, in severe cases, dizziness, headaches and difficulties with vision. This condition is called pre-eclampsia. If left untreated, it can lead to convulsions and other life-threatening problems for both mother and baby. Pre-eclampsia only occurs when a woman is pregnant, and currently, the only cure for it is to end the pregnancy, even if the baby is not yet ready for birth.

In Australia, mild pre-eclampsia occurs in 5-10% of pregnancies and severe pre-eclampsia in 1-2% of pregnancies. Pre-eclampsia and complications associated with this condition account for 15% of direct maternal mortality and 10% of perinatal mortality. Pre-eclampsia is the indication for 20% of labour inductions and 15% of Caesarean sections. It also accounts for 5-10% of preterm deliveries. Worlwide, pre-eclampsia and its complications kill many tens of thousands of women and their babies each year.

There is compelling evidence that in many cases pre-eclampsia has a genetic basis, albeit a complex one. With funding support from the National Institutes of Health in the USA, we are undertaking a comprehensive genetic analysis of Australian families affected by PE and have found evidence for a susceptibility' region on chromosome 2. We are now focussing our efforts on this chromosome 2 region to identify the gene(s) responsible.

The potential significance of this project is threefold. Firstly, when the gene is identified, the production of a clinical test both for the early (pre-pregnancy) detection of women at risk and for the actual diagnosis of pre-eclampsia in cases of clinical uncertainty would become feasible. Secondly, such a test, in turn, would facilitate early preventive treatment and thereby improve the outcome for mothers and babies. Thirdly, the knowledge gained would guide further studies on the causes of pre-eclampsia and aid in the development of new treatments for it.

Inherited thrombophilia and pre-eclamspsia

Prof Shaun Brennecke, Assoc Prof Joanne Said, Dr Amy Chui, Prof John Higgins, Assoc Prof Vera Ignjatovic, Prof Paul Monagle

Several disorders of the clotting system have been identified which predispose people to blood clots in their leg veins and other parts of the body. Collectively these disorders have been called thrombophilias. A relationship between thrombophilia and the pregnancy complication preeclampsia (toxaemia of pregnancy) has been suggested recently in a number of studies. The placentas of patients with pregnancy complications often contain blood clots so it is possible that patients who have a condition that predisposes them to blood clots may be more likely to get blood clots in the placenta and hence develop pregnancy complications. These pregnancy complications are major contributions to perinatal and maternal morbidity and mortality.

The role of placental proteins in the development of pre-eclampsia

Prof Shaun Brennecke, Ms Janet Stevenson, Dr Bill Kalionis

Pre-eclampsia is a common, serious pregnancy disorder that has a significant impact on the health and wellbeing of mothers and their babies. It involves maternal hypertension and protein in the urine; however, its cause is not well understood. The aim of this project is to clarify the cellular and molecular mechanisms that result in this pregnancy disorder. Evidence indicates that during pre-eclampsia the placenta experiences cellular stress and releases unknown factors into the maternal circulation that cause widespread inflammation. Some of these factors are likely to be proteins. This project is investigating the effects of a number of candidate placental proteins on the functions of endothelial cells that line the inside of maternal blood vessels. Placental proteins that are at increased concentration in maternal blood with pre-eclampsia, and that cause inflammation of maternal endothelial cells, may be targets for future therapeutic interventions to better manage pre-eclamptic pregnancies.

Early diagnosis of common pregnancy disorders

Clin Assoc Prof Fabricio da Silva Costa, Dr Bill Kalionis, Prof Shaun Brennecke

There is an important need in modern obstetric care for non-invasive blood-based tests for the accurate assessment of the risks early in pregnancy that patients will develop common pregnancy disorders. The aim of this project is to develop these types of tests for the pregnancy disorders pre-term labour, pregnancy-induced hypertension/pre-eclampsia, fetal growth restriction and gestational diabetes. Although these diseases affect between 15 and 25% of deliveries in Australia and have a significant impact on the health and wellbeing of mothers and their babies, diagnosis is made in the clinic only after they are well established. Available predictive tests provide relatively poor estimations of risks. The placenta plays a critical pathogenic role in the pregnancy disorders and altered placental protein expression and release into maternal blood are important features of the disease process in each case.

This project uses a proteomics approach to identify candidate placental proteins that may be suitable for development as predictive tests. Evaluation of the predictive/early diagnostic capacity of the protein biomarkers is made by measuring their concentrations in maternal blood prior to clinical manifestation of disease.

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