Association among ACE, ESR1 polymorphisms and preeclampsia in Brazilian pregnant women
Introduction
Preeclampsia (PE) is characterized by the onset of hypertension (>140 mmHg systolic or >90 mmHg diastolic) on or after 20 weeks gestation in association or not with proteinuria. Evidences of multisystem impairment, such as renal, liver and neurological dysfunctions can also be present [1]. This disease affects 2–8% of pregnancies worldwide and it is responsible for high maternal and perinatal morbidity and mortality rates [2,3]. PE is traditionally classified according to the blood pressure levels in mild or severe and, more recently, by the onset-time of clinical symptoms, such as early (<34 weeks) or late PE (≥34 weeks) [[4], [5], [6]]. It has been admitted that early and late PE have different etiopathogenesis. Indeed, abnormal placentation and maternal complications are more common in early PE, while late PE is usually less severe and associated with pre-existing maternal conditions, as diabetes mellitus [5,6]. Although PE etiopathogenesis is still unclear, it is a consensus that the placenta plays a key role and that the disease is multifactorial, i.e. caused by a combination of genetic, immunological and environmental factors [7]. Since different genes are associated with the onset and progression of PE, several studies have evaluated the relationship among different polymorphisms and pathogenic mechanisms of the disease. However, the genetic predisposition to PE and its complications remain inconclusive [8].
The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in blood pressure regulation through a series of enzymatic reactions. Angiotensinogen (Agt) is converted to angiotensin (Ang) 1 by renin catalysis, and angiotensin-converting enzyme (ACE) mediates the conversion of Ang 1 to Ang 2 [9]. Circulating and intrarenal RAAS are activated during normal pregnancy to control the salt-water balance and, hence, maternal blood pressure in order to maintain an adequate placental perfusion for the well-being of the mother and fetus [10]. Evidences suggest that the insertion (I) or deletion (D) of a 287-bp fragment in intron 16 of the ACE gene influence the expression and activity of the coded enzyme [11,12].
Estrogens exert their role through binding to a membrane-associated G-protein (GPR30 or GPER) or to nuclear receptors (ESRα or ESR1, and ESRβ or ESR2). When estrogens activate GPR30, rapid non-genomic effects are triggered, but once they bind to nuclear receptors, they exert long-term effects by regulating the transcription of different genes. Evidences suggest that abnormal signaling of estrogen receptors play a role not only in reproductive disorders, but also in cardiovascular and a number of other diseases [13,14]. Indeed, polymorphisms in the estrogen receptor (ESR1) gene have been associated with blood pressure variations [15]. The most frequently studied polymorphisms of the ESR1 gene are located in the first intron (c.454 −397T > C: PvuII restriction site [rs2234693] and c.454 −351A > G: XbaI restriction site [rs9340799]) [16,17], which may affect the expression and function of this nuclear receptor [18].
Considering that hypertension and poor placental perfusion are important features in PE, polymorphisms in the ACE and ESR1 genes could be involved in the predisposition and/or development of the disease. Previous studies have investigated these polymorphisms in PE women, but their results are conflicting [[17], [18], [19], [20], [21]]. Therefore, the goal of this study was to evaluate the frequency of polymorphisms in the ACE (ins/del in intron 16) and ESR1 (rs2234693 and rs9340799) genes in preeclamptic women and normotensive pregnant from the Southeastern State (Minas Gerais) of Brazil.
Section snippets
Study population
This case-control study included 209 Brazilian pregnant women (107 with severe PE and 102 normotensive controls) who were selected at Maternidade Odete Valadares-Belo Horizonte and Hospital Público Regional de Betim (Betim/Brazil), between 2008 and 2011. All women provided an informed written consent and ethics approvals were obtained from the Federal University of Minas Gerais (0530.0.203.000–09) and the public health institutions involved. The clinical data were obtained from medical records
Clinical characteristics
The clinical characteristics of the two groups of pregnant women are shown in Table 1. Proteinuria was only determined in the preeclamptic group, and the median value for this parameter was 2.88g/24h (Interquartile range - IQ = 3.94).
Polymorphisms
The distribution of alleles in the PE group showed no deviation from Hardy–Weinberg equilibrium for the ESR1/rs2234693/rs9340799 polymorphisms, but the ins/del ACE polymorphism deviated from Hardy-Weinberg equilibrium in this group (P = 0.078; P = 0.0.846 and
Discussion
Our findings showed no association among polymorphisms in ACE and ESR1 genes and PE in Brazilian pregnant women. To the best of our knowledge, this is the first study that investigated the polymorphisms rs2234693 and rs9340799 in ESR1 gene in this group from Brazil.
The three polymorphisms were under Hardy–Weinberg equilibrium in PE and normotensive pregnant groups, except the PE group for ACE polymorphism and the normotensive group for ESR1/rs2234693 polymorphism. It suggests that there is not
Conclusion
In conclusion, despite the presumed significance of the ins/del ACE and rs2234693 and rs9340799 ESR1 polymorphisms on mechanisms inherent to hypertension and vascular diseases and their previously reported association with PE in studies conducted on different ethnic groups, our pioneer study did not show an association between these polymorphisms and PE occurrence. Our finding shows that these polymorphisms do not contribute significantly to the development of PE in Brazilian women.
Acknowledgments
The authors thank the staff of the hospitals and the women who participated in this study. KBG, AT and LMSD are grateful for CNPq fellowship.
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