Pre-eclampsia/eclampsia (PE/E) is the most common and serious disorder of human pregnancy and is associated with substantial maternal and perinatal morbidity and mortality. There is currently no known prevention or cure for PE/E with the only effective treatment being Caesarean section, irrespective of gestation. Worldwide, the condition occurs in all major ethnic groups and eclampsia alone is responsible for over 70,000 maternal deaths annually. An assessment of its global economic importance is difficult, if not impossible. In the U.S. a conservative cost estimate in relation to caring for mothers and neonates born of mothers suffering from PE runs into several billions of dollars per annum. Like many other common human diseases there is a large genetic component underlying susceptibility to developing PE/E but the genetics are complex and not yet understood. Several groups, including ours, have provided strong evidence for PE/E susceptibility loci on chromosome 2. In the proposed next phase of the study, we will test hypotheses about the specific genes at the chromosome 2 locus we have identified to be responsible for susceptibility. The overall goal of the research is to identify the specific genes responsible for susceptibility to PE/E and to characterize the functional variants within these genes. Molecular advances in DNA sequencing and quantitative assessments of gene expression, combined with recent development of novel statistical genetic analysis make this a time of unprecedented opportunity for finding the most likely functional variants influencing susceptibility to PE/E. In this project, we will use an innovative combination of state of the science molecular and statistical genetic approaches to identify genetic determinants of susceptibility to this pregnancy disorder that persists as a major global health concern.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Reddy, Uma M
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Texas Biomedical Research Institute
San Antonio
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Yong, Hannah E J; Melton, Phillip E; Johnson, Matthew P et al. (2015) Genome-wide transcriptome directed pathway analysis of maternal pre-eclampsia susceptibility genes. PLoS One 10:e0128230
Yong, H E J; Murthi, P; Borg, A et al. (2014) Increased decidual mRNA expression levels of candidate maternal pre-eclampsia susceptibility genes are associated with clinical severity. Placenta 35:117-24
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Fenstad, Mona H; Johnson, Matthew P; Roten, Linda T et al. (2010) Genetic and molecular functional characterization of variants within TNFSF13B, a positional candidate preeclampsia susceptibility gene on 13q. PLoS One 5:
Fenstad, M H; Johnson, M P; Loset, M et al. (2010) STOX2 but not STOX1 is differentially expressed in decidua from pre-eclamptic women: data from the Second Nord-Trondelag Health Study. Mol Hum Reprod 16:960-8
Roten, Linda T; Johnson, Matthew P; Forsmo, Siri et al. (2009) Association between the candidate susceptibility gene ACVR2A on chromosome 2q22 and pre-eclampsia in a large Norwegian population-based study (the HUNT study). Eur J Hum Genet 17:250-7

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