Preeclampsia, the most common complication of pregnancy and a leading cause of maternal mortality world-wide, is an important cause of preterm delivery, fetal growth retardation and perinatal mortality. Pregnancies complicated by preeclampsia are associated with hyperlipidemia and several other endocrinological and immunological disturbances. Diffuse endothelial dysfunction associated with preeclampsia is thought to be caused by blood-borne products. For instance, it has been hypothesized that plasma lipids have direct adverse effects on endothelial function in pregnancy. Although approximately 50% of the inter-individual variation in plasma lipids are thought to be genetically determined, no one has systematically evaluated the extent to which pregnancy-associated hyper- triglyceridemia is mediated by genetic factors. No one has evaluated the relationship between preeclampsia and genetic markers known to be associated with dyslipidemia and cardiovascular disorders in non- pregnant individuals. Given 1) evidence of a genetic tendency towards susceptibility for preeclampsia; 2) the excess risk of preeclampsia in women with metabolic disorders known to have a strong genetic component; 3) available data suggesting that preeclamptics are at increased risk for developing hypertension or coronary heart disease later in life as compared to women with normotensive pregnancies; and 4) the emerging importance of genetic and environmental interactions in determining risk of complex phenotypes (e.g., circulating triglyceride levels) and predicting risk of complex metabolic disorders (e.g., hypertension, diabetes), we propose to conduct a hospital based, case- control study in Lima, Peru to examine the hypothesis that the apolipoprotein C (ApoE) polymorphism (an important determinant of variation in lipid levels) plays a role in determining risk of preeclampsia among Peruvian women. Risk associated with other candidate gene loci thought to be of importance in the etiology of preeclampsia including polymorphisms for the tumor necrosis factor-alpha (TNF-alpha) gene, the methylenetetrahydrofolate reductase (MTHFR) gene, and the angiotensinogen (AGT) gene will also be assessed. To accomplish these aims, we will conduct in-person interviews with, and collect blood specimens from 400 women with preeclampsia and 400 normotensive pregnant women. Blood specimens will be processed and stored at -70 degrees Centigrade until genotyping are performed in Seattle. Statistical analysis will focus on determining the risk of preeclampsia according to specific genotypes. In addition to addressing the primary aim, data collected for the proposed study (and archived DNA) will allow for an evaluation of the association between preeclampsia and other putative genetic and non-genetic risk factors among South American women. Clinical applications of study findings may result in early identification of high risk subjects and effective interventions. The development of preeclampsia screening and prevention strategies may be enhanced by conducting parallel studies involving participants form ethnically/racially, geographically and economically diverse backgrounds.
