ANGIOTENSINOGEN VARIANTS AND ADVERSE PREGNANCY OUTCOMES

在妊娠早期，母体血容量通常会以未知的方式增加 机制;这种正常的适应怀孕失败， 与常见的不良妊娠结局相关，包括先兆子痫， 胎儿宫内发育迟缓和早产。 肾素- 血管紧张素系统在控制母体液体中具有关键作用 这些严重并发症的病理生理学 怀孕。 我们最近发现了DNA变异， 血管紧张素原（肾素底物）中的酸取代，其中之一 （T235）与先兆子痫密切相关。 我们假设 功能不同的血管紧张素原蛋白可能是 先兆子痫和其它相关病症（例如 胎儿宫内发育迟缓和早产）， 正常的体积膨胀。 在这份提案中，我们列出了四个 不同的策略来扩展我们的初步发现。 一是 对24,000名孕妇进行前瞻性流行病学调查， 确定T235变异体在常见妊娠疾病中的作用。 从这些人群中，我们将选择150名未孕志愿者， T235变异纯合子和150名替代纯合子 M235等位基因，用于母胎生理学的纵向研究， 生物化学，以确定T235变体何时发挥其作用 不利影响。 利用大的平均家庭规模， 犹他州，我们也将研究先兆子痫妇女的女性亲属 以确定重要的血管紧张素原变异体的遗传学。 最后，我们将检查先兆子痫患者的DNA， 血管紧张素原基因的突变可能提供独特的 病理生理学洞察力 我们提出的四种相互关联的方法 将有助于更好地了解血管紧张素原在 妊娠和先兆子痫的病理生理学。 与以往任何 在先兆子痫患者中发现， 血管紧张素原是一种内在缺陷，尽管 它可能被其他因素所改变，不能“次要”于其他因素， 病理生理变量。 这个分子假说需要一个 重新解释先兆子痫、胎儿生长 发育迟缓和早产。 的 为这项研究收集的DNA和血浆将是宝贵的资源， 未来的异常妊娠的分子研究 目前的提案。

Early in gestation maternal blood volume normally expands by an unknown mechanism; failure of this normal adaptation to pregnancy has been associated with common adverse pregnancy outcomes including preeclampsia, intrauterine growth retardation, and premature labor. The renin- angiotensin system has a critical role in controlling maternal fluid volume and probably in the pathophysiology of these serious complications of pregnancy. We have recently discovered DNA variants which cause amino acid substitutions in angiotensinogen (renin substrate), one of which (T235) is strongly associated with preeclampsia. We hypothesize that functionally different angiotensinogen proteins may underlie the pathophysiology of preeclampsia and other related disorders (such as intrauterine growth retardation and premature labor) by not allowing normal volume expansion to occur. In this proposal, we map out four different strategies to extend our initial findings. First, we will conduct a prospective, epidemiologic survey of 24,000 pregnancies to determine the role of the T235 variant in common disorders of pregnancy. From this population, we will select nulligravida volunteers, 150 who are homozygous for T235 variant and 150 who are homozygous for the alternative M235 allele, for a longitudinal study of maternal-fetal physiology and biochemistry in order to determine how when the T235 variant exerts its adverse effect. Taking advantage of the large average family size in Utah, we will also study the female relatives of women with preeclampsia in order to define the genetics of important angiotensinogen variants. Finally, we will examine DNA from preeclamptic patients for additional mutations in the angiotensinogen gene which may offer unique pathophysiologic insight. The four interrelated approaches we propose will lead to a better understanding of the role of angiotensinogen in pregnancy and of the pathophysiology of preeclampsia. Unlike any previous finding in preeclamptic patients, the genetic alteration in angiotensinogen we have described is an intrinsic defect which, although it may be modified by other factors, cannot be "secondary" to other pathophysiologic variables. This molecular hypothesis will demand a reinterpretation of many prior findings in preeclampsia, fetal growth retardation, and premature labor based on angiotensinogen genotypes. The DNA and plasma collected for this study will be invaluable resources for future molecular investigations of abnormal pregnancies beyond this current proposal.