ANGIOTENSINOGEN VARIANTS AND ADVERSE PREGNANCY OUTCOMES

在怀孕早期，母亲的血液容量通常会以未知的方式膨胀 机制；这种对怀孕的正常适应失败 与常见的不良妊娠结局有关，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体液中起着关键作用 体积和可能在这些严重并发症的病理生理学上 怀孕的迹象。我们最近发现了导致氨基的DNA变种 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 先兆子痫和其他相关疾病的病理生理学(如 胎儿宫内发育迟缓和早产) 将发生正常的体积膨胀。在这项提案中，我们制定了四个 不同的策略来扩展我们最初的发现。首先，我们将 对24,000名孕妇进行前瞻性流行病学调查，以 确定T235变异在常见妊娠疾病中的作用。 我们将从这些人中挑选150名无国界志愿者 T235变异为纯合子，替换为150纯合子 M235等位基因，用于母胎生理学和胎儿发育的纵向研究 生物化学，以确定当T235变异体如何行使其 不利的影响。利用年中平均大家庭人数的优势 犹他州，我们还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以获得额外的 血管紧张素原基因突变可能提供独特的 病理生理学洞察力。我们提出的四个相互关联的方法 将有助于更好地理解血管紧张素原在心脏疾病中的作用 妊娠和先兆子痫的病理生理学。不同于以往任何 在子痫前期患者中发现的基因改变 我们所描述的血管紧张素原是一种固有缺陷，尽管 它可能会被其他因素修改，不能是其他因素的次要 病理生理学变量。这一分子假说需要一个 对先兆子痫、胎儿生长的许多先前研究结果的重新解释 基于血管紧张素原基因的发育迟缓和早产。这个 为这项研究收集的DNA和血浆将是 在此之后对异常妊娠的未来分子研究 目前的建议。

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.