A molecular variant of angiotensinogen associated with preeclampsia

Abstract

Pregnancy-induced hypertension (PIH) is a heterogeneous disorder which complicates 5-7% of all pregnancies and remains a leading cause of maternal, fetal and neonatal morbidity and mortality. Severe preeclampsia is the most distinctive and life-threatening form; a multi-system disorder more common in first pregnancies, it is characterized by high blood pressure and proteinuria. In a series of Caucasian women with pregnancy-induced hypertension, we have observed a significant association of preeclampsia with a molecular variant of angiotensinogen, T235, found previously to be associated with essential hypertension. This finding is corroborated in a sample ascertained in Japan. Together, these observations support a new pathophysiological interpretation of preeclampsia and of its relation to some forms of essential hypertension.

Interaction between the polymorphisms of the renin–angiotensin system in preeclampsia

“…We found a significant increased risk for preeclampsia in women carrying the C allele of the AT1R gene and the TT genotype of the AGT gene. Although the mechanism associating preeclampsia and RAS polymorphisms is still unclear, several studies have confirmed that particular RAS polymorphisms are positively associated with preeclampsia and that in addition to the classical circulating RAS, there are local de novo RAS that locally generate AngII [16,17]. It has also been reported [17] that the AGT gene may function as part of a spiral artery RAS that has a role in spiral artery remodeling and that the AGT 235T allele may be a marker of failed physiologic change, because the AGT expression may lead to elevated local AngII levels.…”

“…Human linkage and association genetic studies have revealed the presence of polymorphisms in genes encoding key components of the RAS that account for the proportion of the variance in activity of this system [13][14][15]. Studies of these polymorphisms reported both positive [16,17] and negative association with preeclampsia [18,19]. However, although the association of each of these polymorphisms with preeclampsia has been studied extensively, there are no available data of the possible synergistic effect of these variants.…”

Genomic Expression Systems on Hierarchy and Network Leading to Hypertension: Long on History, Short on Facts.

“…A single base change in codon 235 (235 Thr) results in the substitution of a threonine residue for methionine and is associated with increased plasma angiotensinogen concentrations in subjects with essential hypertension. A study of preeclamptic women from the United States and Japan reported that 235 Thr was associated with pre-eclampsia and that pre-eclamptic women possessing this variant had higher plasma angiotensinogen concentrations than did women homozygous for 235 Met (22). The maternal angiotensinogen gene was also implicated in a linkage study of pre-eclamptic pedigrees from Scotland and Iceland (23).…”

Genetics of arterial hypertension and hypotension

“…It is in linkage disequilibrium with a T174M polymorphism, also frequently addressed. Available evidence suggests that the T allele of the M235T variant is associated with higher circulating angiotensinogen levels (∼20% in homozygous carriers) and increased blood pressure and preeclampsia (Jeunemaitre et al 1992b;Ward et al 1992;Staessen et al 1999). Some animal models indicate that increased AGT gene expression results in hypertension (Takahashi and Smithies 1999).…”