GENETIC RISK FACTORS OF PREECLAMPSIA AMONG PERUVIAN WOME

子痫前期是妊娠最常见的并发症，也是世界范围内孕产妇死亡的主要原因，是早产、胎儿发育迟缓和围产儿死亡的重要原因。妊娠合并先兆子痫与高脂血症和其他几种内分泌和免疫紊乱有关。与子痫前期相关的弥漫性内皮功能障碍被认为是由血液传播的产品引起的。例如，有人假设，血浆脂类对怀孕期间的内皮功能有直接的不利影响。尽管大约50%的个体间血脂差异被认为是遗传决定的，但还没有人系统地评估遗传因素在多大程度上调节了妊娠相关的高甘油三酯血症。还没有人评估先兆子痫与已知与非妊娠个体的血脂异常和心血管疾病相关的遗传标记之间的关系。给出了1)遗传倾向易患先兆子痫的证据；2)有代谢紊乱的妇女患先兆子痫的额外风险，已知有很强的遗传成分；3)现有数据表明，与正常血压怀孕的妇女相比，先兆子痫患者在以后的生活中患高血压或冠心病的风险更高；4)遗传和环境交互作用在确定复杂表型风险(如循环甘油三酯水平)和预测复杂代谢疾病风险(如高血压、糖尿病)方面的重要性，我们建议在秘鲁利马进行一项以医院为基础的病例对照研究，以检验载脂蛋白C(ApoE)基因多态(血脂水平变化的重要决定因素)在确定秘鲁妇女先兆子痫风险中发挥作用的假设。还将评估与其他被认为在子痫前期病因学中具有重要作用的候选基因座相关的风险，包括肿瘤坏死因子-α(TNF-α)基因、亚甲基四氢叶酸还原酶(MTHFR)基因和血管紧张素原(AGT)基因的多态。为了实现这些目标，我们将对400名先兆子痫妇女和400名血压正常的孕妇进行面谈，并收集血液样本。血液样本将在零下70摄氏度进行处理和存储，直到西雅图进行基因分型。统计分析将侧重于根据特定的基因类型确定先兆子痫的风险。除了解决主要目标外，为拟议的研究收集的数据(和存档的DNA)将允许评估先兆子痫与南美妇女中其他假定的遗传和非遗传风险因素之间的联系。研究结果的临床应用可能导致早期识别高危对象和有效的干预措施。通过开展涉及不同民族/种族、地理和经济背景的参与者的平行研究，可以加强先兆子痫筛查和预防战略的制定。

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.