ANGIOTENSINOGEN VARIANTS AND ADVERSE PREGNANCY OUTCOMES

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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.