The role of PHLDA2 as a biomarker for intrauterine growth restriction

Babies that do not grow well in the womb and are born weighing less than 2500g are termed growth restricted. Intrauterine growth restriction (IUGR) affects thousands of babies born in the UK each year, many die and others are left with serious medical problems including brain damage. Each year in South East England alone 120 babies will die as a consequence of IUGR. We do not fully understand why certain otherwise normal babies in normal pregnancies stop growing properly. We know that the environment and the genetically inherited parts called ?genes? both have a role. Understanding the biology of growth in the womb will lead to diagnosis, treatment and maybe even one day, prevention of IUGR. There are a group of genes called ?imprinted genes? that play an important role in fetal growth and are only active when they are inherited from the mother or the father. Unlike most pairs of genes they are not active from both. We have shown that the imprinted gene, PHLDA2, a growth suppressor, which is active from the mother, is significantly higher in the placenta of small babies. This gene could be developed as a biomarker to use to diagnose IUGR during pregnancy. If this marker is found to be at high levels during the pregnancy of an IUGR baby it will allow the doctors to keep a closer eye on the baby that is at risk. Most importantly by understanding exactly how this gene works and affects the growth of the baby we should also be able to help very small babies to grow better in the womb.

IUGR is one of the three major causes of perinatal and childhood mortality and morbidity, the other two being prematurity and major congenital malformations. Prematurity outranks IUGR numerically as a causative factor for perinatal mortality and morbidity, although IUGR is a major contributor to the number of premature births (www.marchofdimes.com/peristats). Antenatally, the definition of IUGR is a fetus with ultrasound evidence of slowed growth. IUGR fetuses are at an increased risk of intrauterine hypoxia, acidosis and death and demonstrate signs of fetal distress both before and during labour. Growth restricted babies can have many medical problems and are at considerably increased risk of neurological developmental delay. In later life they are also at an increased risk of developing hypertension, heart disease and glucose intolerance. Growth restricted babies can also demonstrate catch-up growth during the first four years of life and it is these individuals who appear to be at increased risk of certain adult diseases such as diabetes. Our current understanding of the underlying pathogenesis of IUGR is limited. The aetiology is multifactorial, with genetic, environmental and maternal factors (e.g. smoking and nutrition) playing important roles. The role of genes in the aetiology of IUGR can be studied and may lead to diagnostic and therapeutic advances in reducing the incidence of IUGR.
Imprinted genes have been shown to be very important in placental development and may be critical in nutrient transfer and fetal growth in utero. The proposed study aims to analyze in depth the maternally imprinted PHLDA2 gene that is known to be important in fetal growth. We have shown that PHLDA2 is at a significantly higher level in term placenta of small babies (p=0.0001). Its imprinted status is conserved and we have identified a deletion in its promoter region that correlates with birth weight in two separate well-characterised but small (350 each) cohorts. Further analysis of PHLDA2 deletion frequency in the ASLSPAC normal birth weight cohort (7,000 children and parents) will lead to a better understanding of these important genetic pathways in fetal growth. Investigations of the control of regulation of PHLDA2 expression and its protein function in the placenta will also aid in understanding the aetiology and mechanism of IUGR. This evaluation and development of the role of PHLDA2 in human intrauterine growth will allow its further clinical development and characterisation as a biomarker for IUGR during pregnancy.