The association of AGTR2 polymorphisms with preeclampsia and uterine artery bilateral notching is modulated by maternal BMI
Introduction
Preeclampsia affects up to 7% of nulliparous pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide [1], [2]. To date, the exact cause of preeclampsia is still unknown. Since hypertension is both a risk factor and a symptom of preeclampsia, the renin angiotensin system (RAS), which plays an important role in blood pressure regulation, electrolyte and volume homeostasis [3], has been studied intensively for its contribution to the development of the disorder.
In third trimester preeclamptic women are reported to have reduced plasma renin activity [4], increased serum angiotensin converting enzyme (ACE) activity [4], reduced angiotensin II (ANG II) concentration [4] and increased responsiveness to ANG II [5], [6] compared to women with normal pregnancy. The aberrant RAS levels/activities observed in preeclamptic pregnancies may indicate the involvement of RAS in the pathogenesis of preeclampsia. Therefore, genetic polymorphisms in the RAS components, which modulate RAS levels/activities, may potentially predispose women to preeclampsia.
Over the past decade, several polymorphisms in the AGTR1 and AGTR2 genes have been identified. AGTR1 A1166C (rs5186) is located in the 3′ UTR of AGTR1 on the chromosome 3. The AGTR1A1166C CC genotype is associated with greater ANG II responsiveness [7] and increases risk for coronary artery disease and myocardial infarction [8] compared with the AA genotype. AGTR2 C4599A (rs11091046), AGTR2 A1675G (rs1403543) and AGTR2 T1134C (rs12710567) are located in the 3′ UTR of exon 3, intron 1 and the promoter region of the AGTR2 gene on the X chromosome, respectively. The AGTR2 A1675G G allele is associated with higher AGTR2 expression compared with the A allele [9]. The functional effects of AGTR2 C4599A and AGTR2 T1334C on AGTR2 have not been investigated previously. AGTR2 A1675G and AGTR2 C4599A have been shown to be in linkage disequilibrium in a Japanese population [10]. In a Chinese cohort, the AGTR2 T1334C C allele is associated with an increased risk for essential hypertension compared with the T allele [11].
In the current study, our primary aim was to determine if the aforementioned AGTR1 and AGTR2 polymorphisms in mothers, fathers and babies were associated with preeclampsia. Since assessing gene–environment interactions is becoming an increasingly important aspect of genetic association studies [12], [13], our secondary aim was to determine whether the association of AGTR1 and AGTR2 polymorphisms with preeclampsia is affected by risk factors for preeclampsia, including maternal age [14], [15], BMI [16], green leafy vegetable intake [17], fruit intake [18], socio-economic status [19] and smoking [20]. In addition, since RAS components are sexually dimorphic in adults [21], we explored our primary and secondary aims in pregnancies bearing female and male infants separately.
Section snippets
Ethics approval
In Australia, ethical approval was obtained from the Central Northern Adelaide Health Service Ethics of Human Research Committee (study number: REC 1714/5/2008). In New Zealand, ethical approval was given by the Northern Region Ethics Committee (study number: AKX/02/00/364). All participants provided written informed consent. Australian clinical trial registry number: ACTRN 12607000551493.
Participants
The current study is a nested case control study embedded in a large prospective multicentre study,
Study population
Of the 3234 recruited women, 1113 (34%) women were excluded due to one of the reasons shown in Fig. 1. The final analyses were conducted on 2121 Caucasian women, consisting of 1185 (55.9%) women with uncomplicated pregnancies, 123 (5.8%) preeclamptic women and 813 (38.3%) women with other complications.
For the 2121 Caucasian parent-infant trios, genotype data of up to 199 (9.4%) women, 470 (22.2%) partners and 578 (27.3%) infants could not be analysed for one of the following reasons: non
Discussion
In the current study, in women with BMI ≥ 25 kg/m2, maternal, paternal and neonatal AGTR2 C4599A was associated with preeclampsia. In the same subset of women, a similar non-significant trend was also observed for maternal, paternal and neonatal AGTR2 A1675G, which has previously been shown to be in linkage disequilibrium with AGTR2 C4599A [10]. Furthermore, in women with BMI ≥ 25 kg/m2, paternal AGTR2 C4599A A allele and paternal AGTR2 A1675G G allele were associated with an increased risk for
Conflict of interest
None of the authors have any conflicts of interest to declare.
Funding
The Australian SCOPE study was funded by the Premier's Science and Research Fund, Government of South Australia. The New Zealand SCOPE study was funded by New Enterprise Research Fund, Foundation for Research Science and Technology; Health Research Council; Evelyn Bond Fund, Auckland District Health Board Charitable Trust. Genotyping and data analyses were funded by the National Health and Medical Research Council Australia (NHMRC) Project Grant 565320 awarded to CTR and GAD and by the
Acknowledgements
The authors would like to thank the families who participated in the SCOPE study. We would also like to thank Denise Healy and Rennae Taylor for coordinating the Adelaide and Auckland cohorts, respectively. We thank MedSciNet (Sweden), Eliza Chan and SCOPE midwives for support with the database.
References (39)
- et al.
Pre-eclampsia
Lancet
(2005) - et al.
Primary, secondary, and tertiary prevention of pre-eclampsia
Lancet
(2001) - et al.
Epidemiology of preeclampsia and eclampsia in the United States, 1979–1986
Am J Obstet Gynecol
(1990) - et al.
Pregnancy outcome at age 40 and older
Obstet Gynecol
(1996) - et al.
Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions?
Am J Obstet Gynecol
(2006) - et al.
A dietary pattern characterized by high intake of vegetables, fruits, and vegetable oils is associated with reduced risk of preeclampsia in nulliparous pregnant Norwegian women
J Nutr
(2009) - et al.
Cigarette smoking during pregnancy and risk of preeclampsia: a systematic review
Am J Obstet Gynecol
(1999) - et al.
Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway
Blood
(1998) - et al.
Expression of AT1R, AT2R and AT4R and their roles in extravillous trophoblast invasion in the human
Placenta
(2010) - et al.
Molecular characterization of renin-angiotensin system components in human intrauterine tissues and fetal membranes from vaginal delivery and cesarean section
Placenta
(2011)
Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis
J Biol Chem
The risk of preeclampsia rises with increasing prepregnancy body mass index
Ann Epidemiol
IFPA award in placentology lecture: complicated interactions between genes and the environment in placentation, pregnancy outcome and long term health
Placenta
Angiotensin-(1-7) in normal and preeclamptic pregnancy
Endocrine
A study of angiotensin II pressor response throughout primigravid pregnancy
J Clin Invest
Prediction of pregnancy-induced hypertensive disorders by angiotensin II sensitivity and supine pressor test
Br J Obstet Gynaecol
Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries
Hypertension
Searching for a better assessment of the individual coronary risk profile. The role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms
Eur Heart J
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Renin-angiotensin system gene variants and risk of early- and late-onset preeclampsia: A single center case-control study
2019, Pregnancy HypertensionCitation Excerpt :However, the study conducted by Eman et al showed a weak association of the AGTR1-A1166C variant and late onset preeclampsia [33]. AGTR2-C3123A was associated with the risk of preeclampsia according to the study carried out by Zhou et al [19]. Conflicting results were obtained regarding the association of the C344T polymorphism and the risk of preeclampsia.
Association of gene polymorphisms of four components of renin-angiotensin-aldosterone system and preeclampsia in South African black women
2017, European Journal of Obstetrics and Gynecology and Reproductive BiologyCitation Excerpt :The study done by Akbar et al. [4] used AT2R (A1675G) which was different from ours (A1166C). The study done in Australia and New Zealand by Zhou et al. [28] reported that AT1R (A1166C), AT2R (C4599A, A1675G and T1334C) were not associated with PE at 20 weeks pregnancies. However, the A allele and AA genotype of AT2R (C4599A) were associated with PE among Caucasian women with body mass index ≥25 kg/m2 (OR 2.1, 95%CI 1.0–4.2) and (OR 1.9, 95% CI 1.1–3.2).
The paternal polymorphism rs5370 in the EDN1 gene decreases the risk of preeclampsia
2016, Pregnancy HypertensionCitation Excerpt :The -604T/C mutation in the KDR gene in the father and foetus, was associated with preeclampsia [36]. Preeclampsia was also associated with the paternal, maternal and foetal C4599A polymorphism on the AGTR2 gene but only in overweight and obese women [37]. In our study, no differences were found for body mass index (BMI) between the cases and controls, so environmental factors other than BMI may be associated with the disease in the general population of Mexico, which has a 74.6% of incidence of overweight and obesity [38].
Genetic Contributions to Risk of Adverse Pregnancy Outcomes
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