Renin Angiotensin System Polymorphisms and Pregnancy Complications

Field: Medicine (Health Sciences)

Introduction: The renin angiotensin system (RAS) plays an important role in blood pressure regulation and salt-water homeostasis. Aberrant maternal circulating and uteroplacental RAS profiles have been implicated in pregnancy complications, in particular preeclampsia. Our primary aims were to determine associations of polymorphisms in the RAS genes including renin, angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGT1R) and type 2 receptor (AGT2R) with pregnancy complications, including preeclampsia, small for gestational age (SGA) and spontaneous preterm birth (sPTB) and to identify potential gene-environment and gene-fetal sex interactions that may modify risks for these pregnancy complications. The secondary aims were to determine the association of RAS polymorphisms with maternal plasma RAS profile at 15 weeks’ gestation, maternal blood pressure at 15 weeks’ gestation and uterine and umbilical artery resistance at 20 weeks’ gestation. Methods: Healthy nulliparous women, their partners and babies (3234 trios) were recruited prospectively in Adelaide, Australia and Auckland, New Zealand. Data analyses were confined to 2121 Caucasian parent-infant trios, among which 123 had preeclampsia, 216 had SGA and 116 had sPTB. Uncomplicated pregnancies (n=1185) served as controls. DNA was genotyped by Sequenom MassARRAY. Maternal blood samples were taken at 15 weeks’ gestation and measured for plasma prorenin, ACE, angiotensin II (ANG II) and angiotensin 1-7 (ANG 1-7) concentrations. Maternal blood pressure was measured at 15 weeks’ gestation. Doppler sonography on the uterine and umbilical arteries was performed at 20 weeks’ gestation. Mean uterine or umbilical artery resistance indices (RI) above the 90th percentile were considered abnormal. Results: Maternal and neonatal ACE A11860G GG genotype was associated with elevated maternal plasma ACE concentration. Neonatal renin T/G and maternal AGT M235T were associated with maternal plasma ANG 1-7 concentration. In female-bearing pregnancies, maternal AGT1R A1166C CC genotype was associated with an increased risk for abnormal uterine artery RI, whereas in male-bearing pregnancies, the AGT M235T TT genotype in mothers and neonates was associated with an increased risk for abnormal umbilical artery RI. In the Australian SCOPE cohort, maternal ACE A11860G GG genotype was associated with an increased risk for SGA and a reduction in customized birth weight centile compared with the AA or AG genotype. Interestingly, these associations were only observed in female-bearing pregnancies and in women with socio-economic index<34 or pre-pregnancy green leafy vegetable intake<1 serve/day. Furthermore, maternal, neonatal and paternal AGT2R C4599A was associated with preeclampsia in women with BMI≥25kg/m². In the same subset of women, paternal AGT2R C4599A and paternal AGT2R A1675G were associated with uterine artery bilateral notching. Finally, no significant associations, gene-environment interactions or gene-fetal sex interactions were found for sPTB. Conclusion: The association of RAS polymorphisms with preeclampsia, SGA and abnormal uterine and umbilical artery RI indicates the involvement of the RAS in the pathogenesis of pregnancy complications, in particular preeclampsia and SGA. Furthermore, future genetic association studies into pregnancy complications should take account of fetal sex and appropriate environmental factors, otherwise genetic associations hidden by these factors may be left unrecognized.