Preeclampsia is a disease that affects up 10% of pregnancies globally and is the leading cause of maternal mortality and morbidity. There is not currently no effective therapy for this condition of vasospasm, endothelial damage and systemic inflammation. Data from mouse models of the targeted knock outs of complement components and regulators, a mouse model of antiphospholipid syndrome, and observational studies of human placentas supports involvement of complement activation in dysfunction of the placenta. In a histopathologically similar disease, aHUS, 50-60% of cases are associated with rare (heterozygous in <1% of the population) dysfunctional mutations. The functional deficits of the mutants have been characterized and the overwhelming majority, greater than 95%, have had a deficit that fits a model of increased or poorly regulated complement activation leading pathologic microthrombi. These findings led to the sequencing of membrane cofactor protein (MCP), complement factor I (FI), and complement factor H (FH) in a group of preeclamptic patients from the PROMISSE study (Predictors of pregnancy Outcome: biomarkers In antiphospholipid Syndrome and Systemic lupus Erythematosus). Rare variants were discovered in 7 of the 40 cases and in none of the 33 controls. Most of these had their functional deficit characterized and fit the existing model in aHUS of excessive complement activation causing the disease phenotype. Work done in this grant will use a two pronged approach of: targeted resequencing of cases and controls and experiments using primary placental samples, primary human trophoblast cells and trophoblast cell lines to further identify the role of the complement system in preeclampsia. Targeted resequencing of the initial population of PROMISSE patients will identify mutations in genes at loci implicated by linkage studies of families with preeclampsia and in the following pathways implicated by the literature: complement, thrombosis, cell cycle, apoptosis, angiogenesis, and endothelial cell activation. We will look at genes outside of the complement pathway as well as those in the pathway because the insult leading to complement activation is unknown and any predisposition to a prothrombotic state has the potential to increase the risk of preeclampsia. A second, larger targeted resequencing project will look at population of preeclamptic pregnancies, not just those with an autoimmune disease. Comparisons of healthy placentas with preeclamptic placentas will identify differences in complement activation between these two states. Studies in primary explants and primary human trophoblast cultures will allow the mechanisms of these changes to be studied and the effect on trophoblast cells to be followed over time. Finally, the effect of reperfusion injury in trophoblast cultures on complement activation and trophoblast state cell fate will be quantified and followed over time.

Public Health Relevance

Preeclampsia affects up to 10% of pregnancies and directly contributes to 76,000 maternal deaths and 500,000 fetal deaths annually. There is no therapy for this condition and it necessitates delivery of the infant, often preterm with immature organ development, which predisposes to morbidity in childhood and adult life. This research into the genetic risk factors and the mechanisms of disease will fill a gap in knowledge about the insults that cause the placental dysfunction characteristic of preeclampsia and the link between placental dysfunction and maternal decompensation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL103072-04
Application #
8502332
Study Section
Special Emphasis Panel (ZRG1-F06-E (20))
Program Officer
Meadows, Tawanna
Project Start
2010-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$47,232
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Yu, Yi; Triebwasser, Michael P; Wong, Edwin K S et al. (2014) Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum Mol Genet 23:5283-93
Seddon, Johanna M; Yu, Yi; Miller, Elizabeth C et al. (2013) Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet 45:1366-70
Salmon, Jane E; Heuser, Cara; Triebwasser, Michael et al. (2011) Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med 8:e1001013