Variations in Discovery‐Based Preeclampsia Candidate Genes

Preeclampsia persists as a common and potentially lethal complication in 4–8% of all pregnancies. 1 Current consensus holds that pathology is evident at 10-18 weeks gestation with impaired trophoblast invasion. Shallow placentation and failure of complete physiologic remodeling of the myometrial spiral arteries set the stage for developing preeclampsia in the second half of gestation. 2 The unchanged spiral arteries retain vasoreactivity, leading to vasoconstriction, placental hypoperfusion, and associated systemic effects, such as increased inflammatory activation, endothelial dysfunction, and oxidative stress. 3,4 Life-threatening consequences may ensue-placental abruption, disseminated coagulopathy, pulmonary edema, renal failure, liver dysfunction, and eclampsia. 2 Infants in one third of preeclampsia pregnancies are growth restricted. 2,5 Because delivery of the placenta is the only cure, 6 about 10% of cases involve iatrogenic prematurity and the associated risk of neurological sequelae in the baby. 7 Further, mother and infant survivors of preeclampsia are at increased risk of later life cardiovascular disease. 8 Given the severe effects of preeclampsia, elucidating molecular factors involved in early aberrant placentation would have major impact. Mutations, gene regulatory mechanisms and other individual genomic variations are likely to interact with environmental influences to produce the phenotype, yet heritability estimates of 25-54% motivate the search for polymorphisms or other consistent factors that account for this complex disease in populations. 9,10 A panel of biomarkers, together with clinical and demographic factors and biophysical measures such as uterine artery pulsatility, is expected to constitute an effective screening modality for preeclampsia. 11-2 Our prior studies identified 36 candidate genes that were differentially expressed in first trimester placental samples in preeclampsia compared with uncomplicated pregnancies. 13 These discovery-based biomarkers from the tissues at the timing of known early pathogenesis were identified by Naive Bayes prediction modeling of global gene expression data and have been supported by further quantitative real time polymerase chain reaction studies, 13-4 and localization studies. 15-6 In addition, 40% of this set of genes are associated with chromosomal susceptibility regions found in large population linkage studies. 17 In this report, we present preliminary data on mechanisms by which gene expression may have been altered in first trimester preeclampsia placentas. Although there are numerous trans-acting gene regulatory mechanisms, we focused on common variations in DNA in a subset of the 36 candidate genes. We examined single nucleotide polymorphisms (SNPs), and methylation which occurs widely in the human placental genome. 18-20 Integrating gene expression and genetics data could elucidate common variations that control phenotype. 21 We explored whether biomarkers in maternal-fetal dyads could inform translation of the candidate genes towards prediction models for clinical use to identify those at risk for and eventually prevent preeclampsia.