Anuja Java, M.D.
Project Overview:
Preeclampsia (PE) is the leading cause of maternal and fetal morbidity and mortality. It is characterized by new-onset hypertension often associated with proteinuria after 20-weeks of gestation. Disease manifestations include HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets), kidney failure, seizures (eclampsia), stroke and cardiovascular complications. The only current treatment for PE is delivery, and labor is usually induced early to prevent systemic complications. The pathology of PE is primarily vascular, including endothelial injury and morphological alterations in uterine spiral arteries. This process is strikingly reminiscent of a thrombotic microangiopathy (TMA) in which endothelial injury results in hemolytic anemia, thrombocytopenia (low platelets), and kidney failure. Atypical hemolytic syndrome (aHUS) is a classic TMA caused by genetic variants in complement proteins that lead to overactivation of the complement system. Complement activity is an enzymatic cascade that is used to fight infections and dispose of cellular/tissue debris. The activation of the complement system needs to be tightly regulated in order to prevent damage to healthy host cells. In individuals with aHUS, the complement system activates inappropriately (due to genetic mutations) and damages the kidney and other organ systems.
Because of the similarity between PE and aHUS, we propose that PE may be caused by complement activation due to the presence of genetic variants. We will identify rare and common variants associated with PE in Aim 1 and functionally characterize the variants to determine their clinical significance in Aim 2. Establishing the role of complement in PE will identify high-risk patients who could be treated timely with anti-complement therapy to prevent short and long-term complications and open the door for development of novel complement therapeutics.
