High blood pressure complicates nearly 10% of all pregnancies and is a major factor in perinatal morbidity and mortality observed in developed countries. Hypertensive disorders of pregnancy are divided into three categories: 1) preeclampsia/eclampsia, 3) pregnancy-induced hypertension or transient hypertension and 3) preeclampsia/eclampsia superimposed on chronic hypertension. Despite extensive physiological research on preeclampsia, the etiology remains completely elusive. Furthermore, considerable disagreement over many of the proposed pathophysiologicaI mechanisms continues to exist. No clear treatment or preventive therapies are presenfly available. Yet, preeclampsia continues to be of central importance in modern obstetrics not only in terms of maternal and fetal morbidity and mortality but also in utilization of health care resources. Amidst the controversy and confusion, epidemiological studies have consistently provided compelling evidence for a strong genetic component to preeclampsia susceptibility. Surprisingly, little molecular genetic research on preeclampsia has been initiated and little is known concerning the importance of specific genes. The overall goal of the present study is to elucidate the genetic factor(s) that are involved in the pathogenesis of preeclampsia/eclampsia. We will capitalize on the availability of a large statewide network of patients with preeclampsia/eclampsia who have been cared for at our institution over the past three decades.
In Aim 1, we propose to elucidate the genetic importance of the angiotensinogen gene in the pathogenesis of preeclampsia. This will be accomplished through both association studies and the affected-pedigree-member (APM) method of linkage analysis.
In Aim 2, we will conduct a genome-wide search for chromosomal regions that may be linked to preeclampsia utilizing anonymous highly informative short tandem repeat polymorphisms (STRPs) spread throughout the genome. Linked chromosome regions will then be narrowed by fine mapping. All linkage analysis will be conducted utilizing the affected-pedigree-member method. Candidate genes within the linked regions (selected based on physiological and anatomical relevance) will then be evaluated by mutation analysis utilizing a combination of singe-strand conformational polymorphism (SSCP) and direct sequencing of genomic DNA. This proposal is built upon three strengths: l) The large statewide network of compliant patients, 2) A leading core human molecular genetics lab with capability for high throughput genotyping facilitating genome wide searches and with exceptional capability for mutation detection, and 3) The ability to conduct sophisticated genetic analysis of the data. With the studies outlined in the present proposal, the potential exists to dissect the important molecular genetic controllers involved in the pathogenesis of preeclampsia.
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