Impact of maternal angiotensinogen M235T polymorphism and angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure, protein excretion and fetal outcome in pregnancy.

OBJECTIVE: To test the hypothesis that genetically determined alterations of the renin-angiotensin system are associated with hypertensive disorders in pregnancy. METHODS: A genetic association study was conducted at the obstetrics department of the Charité university hospital, Berlin, Germany. A total of 1068 Caucasian women were consecutively included after delivery and genotyped for the angiotensinogen M235T polymorphism and the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism. RESULTS: Women homozygous for the angiotensinogen T allele have significantly elevated mean systolic and diastolic blood pressures in the third trimester (118.4 +/- 1.1/71.5 +/- 0.7 versus 116.9 +/- 0.3/70.4 +/- 0.2 mmHg, n = 128 versus 940; P < 0.05). This finding is especially pronounced in the subgroup of primigravid women. The ACE polymorphism is not associated with blood pressure during pregnancy. None of the polymorphisms is associated with urinary protein excretion or oedema during pregnancy. Maternal polymorphisms do not influence fetal growth and birth weight. There is, however, an interesting trend towards an increased incidence of circulatory system malformations in newborns carrying alleles that are known to be associated with decreased intrinsic renin-angiotensin system activity. CONCLUSION: We demonstrate for the first time in a large Caucasian population that a common maternal polymorphism of the angiotensinogen gene is related to a blood pressure increase during pregnancy. The angiotensinogen M235T polymorphism might contribute to the multifactorial pathogenesis of gestational hypertension and pre-eclampsia.

New evidence for the fetal insulin hypothesis: fetal angiotensinogen M235T polymorphism is associated with birth weight and elevated fetal total glycated hemoglobin at birth.

BACKGROUND: Low birth weight is associated with an increased risk of cardiovascular events in later life. Insulin resistance is a key finding in adult patients with cardiovascular diseases. The neonatal phenotype of an individual with insulin resistance might be low birth weight, as insulin influences fetal growth. The renin-angiotensin-aldosterone system has been associated with cardiovascular disease and insulin resistance. We analyzed whether fetal polymorphisms of the angiotensinogen (AGT) and angiotensin-converting enzyme genes influence birth weight and/or fetal total glycated hemoglobin (fTGH), a surrogate parameter of fetal insulin resistance at birth. METHOD: In 1132 white women delivering singletons, neonatal umbilical blood samples and clinical data of the mothers and newborns were obtained. Newborns were genotyped with respect to the AGT M235T and angiotensin-converting enzyme insertion/deletion polymorphism. RESULTS: The AGT M235T TT polymorphism is associated with reduced birth weight (TT: 3288 g versus TM + MM: 3435 g, P < 0.05). Furthermore, newborns with a high percentage of fTGH (>6.5%) are more likely to have the TT genotype than those with normal fTGH (