The association of maternal ACE A11860G with small for gestational age babies is modulated by the environment and by fetal sex: a multicentre prospective case-control study

Abstract

We aimed to determine whether the ACE A11860G genotype is associated with small for gestational age babies (SGA) and to determine whether the association is affected by environmental factors and fetal sex. Overall, 3234 healthy nulliparous women with singleton pregnancies, their partners and babies were prospectively recruited in Adelaide, Australia and Auckland, New Zealand. Data analyses were confined to 2121 Caucasian parent–infant trios, among which 216 were pregnancies with SGA infants and 1185 were uncomplicated pregnancies. Women with the ACE A11860G GG genotype in the combined and Adelaide cohorts had increased risk for SGA [odds ratios (OR) 1.5, 95% confidence interval (CI) 1.1–2.1 and OR 2.0, 95% CI 1.3–3.3, respectively) and delivered lighter babies (P = 0.02; P = 0.007, respectively) compared with those with AA/AG genotypes. The maternal ACE A11860G GG genotype was associated with higher maternal plasma ACE concentration at 15 weeks' gestation than AA/AG genotypes (P < 0.001). When the Adelaide cohort was stratified by maternal socio-economic index (SEI) and pre-pregnancy green leafy vegetable intake, the ACE A11860G GG genotype was only associated with an increased risk for SGA (OR 4.9, 95% CI 1.8–13.4 and OR 3.3, 95% CI 1.6–7.0, respectively) and a reduction in customized birthweight centile (P = 0.006 and P = 0.03) if superimposed on maternal SEI <34 or pre-pregnancy green leafy vegetable intake <1 serve/day. Furthermore, the associations of maternal ACE A11860G with customized birthweight centile observed among Adelaide women with SEI <34 or pre-pregnancy green leafy vegetable intake <1 serve/day were female specific. The current study identified a novel association of maternal ACE A11860G with SGA. More interestingly, this association was modified by environmental factors and fetal sex, suggesting ACE A11860G–environment–fetal sex interactions.Trial Registry Name: Screening nulliparous women to identify the combinations of clinical risk factors and/or biomarkers required to predict pre-eclampsia, SGA babies and spontaneous preterm birth.URL: .Registration number: ACTRN12607000551493.

Angiotensin Converting Enzyme 2 (ACE2) in Pregnancy: Preeclampsia and Small for Gestational Age

“…ACE concentrations are however, increased in women with PE (Merrill et al, 2002). Women who gave birth to SGA babies also had higher concentrations of plasma ACE at 15 weeks' gestation compared with women who delivered babies of normal birth weight (Zhou et al, 2013). To the best of our knowledge, there are no data on changes in maternal ACE2 and NEP levels in either normal pregnant women or women suffering from complicated pregnancies.…”

“…It is activated by estrogen-induced increases in angiotensinogen (AGT) and, subsequently, by the reduction in systemic vascular resistance caused by the ovarian hormone, relaxin (Lumbers and Pringle, 2014). It is perhaps not surprising then that alterations in the circulating and intrauterine RAS are associated with the development of preeclampsia (PE) and pregnancies in which the infant is born small for gestational age (SGA) (Irani and Xia, 2008;Zhou et al, 2013;Delforce et al, 2019).…”

The prevalence of unique SNPs in the renin‐angiotensin system highlights the need for pharmacogenetics in Indigenous Australians

“…18,19 It is non-functional but is in linkage disequilibrium with another SNP, A11860G (rs4343), which is associated with higher plasma ACE levels. 20,21 Interestingly, while the prevalence of the deletion polymorphism was no different in healthy Caucasians compared with Caucasian renal transplant patients, in Indigenous renal transplant patients it was more prevalent than in healthy Indigenous people (14% vs. 3% 14 ). These were, however, two different Indigenous populations; but the findings suggest that Indigenous people with the D deletion polymorphism become more susceptible to chronic renal disease.…”

“…The DD variant of the ACE gene is associated with hypertension, cardiovascular disease, and diabetic nephropathy . It is non‐functional but is in linkage disequilibrium with another SNP, A11860G (rs4343), which is associated with higher plasma ACE levels . Interestingly, while the prevalence of the deletion polymorphism was no different in healthy Caucasians compared with Caucasian renal transplant patients, in Indigenous renal transplant patients it was more prevalent than in healthy Indigenous people (14% vs .…”

Introduction: Celebrating Emeritus Scientia Professor Eugenie R Lumbers AM and Professor Caroline McMillen

“…Professor Lumbers' current research interests relate to the role(s) of the RAS in human placentation and in pregnancy-associated hypertension. 10 In addition, she is studying the fetal origins of human renal disease and the causes of low systemic blood flow in the preterm neonate. 11 She is also studying the potential therapeutic use of drugs that affect the activity of the RAS in the treatment of endometrial cancer.…”