Elsevier

Gene

Volume 538, Issue 1, 15 March 2014, Pages 176-181
Gene

AT2R − 1332 G:A polymorphism and its interaction with AT1R 1166 A:C, ACE I/D and MMP-9 − 1562 C:T polymorphisms: Risk factors for susceptibility to preeclampsia

https://doi.org/10.1016/j.gene.2013.12.013Get rights and content

Highlights

  • The AT2R − 1332 G allele increased the risk of both mild- and severe-preeclampsia.

  • AT2R GG+GA genotype increased the blood pressure in severe preeclamptic women.

  • Interaction of AT2R G allele with AT1R C allele increased the risk of mild preeclampsia.

  • Combined presence of AT2R G and ACE D alleles increased the risk of preeclampsia.

  • Interaction of AT2R G allele with MMP-9T allele increased the risk of severe preeclampsia.

Abstract

The possible association of angiotensin type 2 receptor (AT2R) − 1332 G:A polymorphism with susceptibility to preeclampsia was studied in 252 women consisted of 155 women with preeclampsia and 97 healthy pregnant women. Also, the interaction of this polymorphism with angiotensin type 1 receptor (AT1R) 1166 A:C, angiotensin converting enzyme insertion/deletion (ACE I/D) and also with matrix metalloproteinase-9 (MMP-9) − 1562 C:T polymorphism was investigated. The AT2R − 1332 G:A polymorphism was detected using PCR–RFLP method. Significantly higher frequencies of GG+GA genotype and G allele of AT2R were observed in mild (80.2%, p = 0.003 and 47.5%, p = 0.012, respectively) and severe (77.8%, p = 0.034 and 48.1%, p = 0.026, respectively) preeclampsia compared to controls (60.8% and 35.1%, respectively). The presence of G allele was associated with 1.69-fold increased risk of preeclampsia (p = 0.005). In severe preeclamptic women, systolic and diastolic blood pressures in the presence of GG+GA genotype were significantly higher compared to those in the presence of AA genotype. The concomitant presence of both alleles of AT2R G and AT1R C was associated with 1.3 times increased risk of mild preeclampsia (p = 0.03). There was an interaction between AT2R G and ACE D alleles that significantly increased the risk of mild and severe preeclampsia by 1.38- and 1.3-fold, respectively. Also, interaction between MMP-9 T and AT2R G alleles increased the risk of severe preeclampsia 1.39-fold (p = 0.028). Our study demonstrated that the G allele of AT2R − 1332 G:A polymorphism is associated with an increased risk of preeclampsia. Also, epistatic interaction of G allele and each allele of the AT1R C, ACE D and MMP-9 T was associated with the risk of preeclampsia. Our findings suggest that the renin–angiotensin system (RAS) variants and gene–gene interactions affect the risk of preeclampsia.

Introduction

Preeclampsia, a complication of pregnancy, is influenced by various factors of ethnicity, parity, health status of placenta, diet and body size. The role of single or multiple genes in the pathogenesis of preeclampsia has been suggested. Renin–angiotensin system (RAS) is stimulated during pregnancy and plays a central role in the regulation of blood pressure during this period. In preeclampsia the stimulation of this system is failed and all components of the system, especially plasma renin activity are reduced (Bouba et al., 2003).

Angiotensin II is a vasoconstrictor octapeptide of RAS that is produced from decapeptide of angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE). Angiotensin II binds to several types of receptors. The angiotensin type 1 receptor (AT1R) mediates vasoconstriction and the proliferative action of angiotensin II, while the type 2 receptor (AT2R) inhibits cell proliferation and mediates apoptosis and works cardio protectively against AT1R (Abd El-Aziz et al., 2012, Alfakih et al., 2005). The cellular effects of angiotensin II in adult humans are mainly mediated by the AT1R (Abd El-Aziz et al., 2012). The RAS activity is modified by variants of the genes coding functional proteins of this pathway (Alfakih et al., 2005).

The AT2R gene is located on the chromosome X at the locus Xq23–26. The AT2R gene consists of three exons and two introns. A common AT2R − 1332 G:A polymorphism (rs14035430) is located within intron 1, 29 bp before the start of exon 2, close to a region that is important for transcriptional activity. This polymorphism is designated as − 1332 G:A according to the translation initiation site of the gene, although it has also been described as + 1675G:A. The AT1R gene locates on chromosome 3q21–q25. The AT1R 1166 A:C polymorphism (rs5186) locates in the 3′-untranslated region of AT1R gene and may be involved in posttranscriptional modification of AT1R mRNA (Alfakih et al., 2005).

An insertion/deletion (I/D) polymorphism of ACE (rs1799752) has been reported. The presence of D allele of ACE I/D polymorphism has been associated with preeclampsia in some populations (Agarwal et al., 2011, Gurdol et al., 2004, Rahimi et al., 2013a, Salimi et al., 2013).

Matrix metalloproteinases (MMPs) are zinc-dependent enzymes which play a crucial role in restructuring the extracellular matrix by activating the secretion of gelatinases, collagenases and proteolytic enzymes. Functional polymorphism of − 1562 C:T (rs3918242) in the promoter of MMP-9 is associated with increased MMP-9 levels (Coolman et al., 2007, Palei et al., 2008).

In one available study the association of AT2R − 1332 G:A polymorphism with the risk of preeclampsia has been examined (Akbar et al., 2009). Variants of RAS genes including ACE I/D, AT1R 1166 A:C and AT2R − 1332 G:A have been associated with hypertension (Akbar et al., 2009). Also, it has been reported that AT2R agonist activates MMP-1 and MMP-9 (Alfakih et al., 2005, Gard, 2010). The aim of the present study was to investigate the possible role of AT2R − 1332 G:A polymorphism in the risk of preeclampsia and also, to examine its possible interaction with AT1R 1166 A:C, ACE I/D, and MMP-9 − 1562 C:T polymorphisms and influence on the risk of preeclampsia in a population from Western Iran.

Section snippets

Materials and methods

One-hundred and fifty two preeclamptic patients including 101 women with mild and 54 women with severe preeclampsia and 97 women with normal pregnancy were enrolled in a case–control study. The preeclamptic women were age matched with controls. Also, mild preeclamptic women were parity matched with both severe preeclamptic patients and controls. The subjects had been admitted to the obstetric clinic of the Imam Reza Hospital of Kermanshah University of Medical Sciences. Patients were all

Results

The characteristics of patients and controls are demonstrated in Table 1. Body mass index and blood pressure (both systolic and diastolic) were significantly higher in both groups of patients than controls. Also, the blood pressure was significantly higher in severe preeclampsia compared to mild preeclampsia. However, the mean gestational age was significantly lower in both groups of patients than in controls and also was significantly lower comparing severe to mild preeclampsia. Comparing the

Discussion

Abnormal uteroplacental circulation and endothelial cell dysfunction are involved in the pathogenesis of preeclampsia (Rahimi et al., 2013c). In preeclampsia maternal blood flow is decreased that might be related to downstream signaling events of angiotensin II peptide of RAS. Two main receptors of AT1R and AT2R mediated the actions of angiotensin II. A balance between AT1R and AT2R might be important in the process of placentation that needs to both cell proliferation and apoptosis. The AT1R

Conclusions

Our study demonstrated that the G allele of AT2R − 1332 G:A polymorphism is associated with an increased risk of preeclampsia. Also, we observed an epistatic interaction between this allele and the C allele of AT1R 1166 A:C, the D allele of ACE I/D and the T allele of MMP-9 − 1562 C:T polymorphisms which results in susceptibility to preeclampsia. Our findings suggest the role of RAS variants and gene–gene interaction in the pathogenesis of preeclampsia.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgments

This work was performed in partial fulfillment of the requirements for the MSc. degree of Mr. Amir Aghaei, Kermanshah University of Medical Sciences, Kermanshah, Iran and was financially supported by a grant from Vice Chancellor for Research of Kermanshah University of Medical Sciences, Kermanshah, Iran.

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