Arch Gynecol Obstet DOI 10.1007/s00404-014-3376-4

MATERNAL-FETAL MEDICINE

Matrix metalloproteinase-7 A-181G and its interaction with matrix metalloproteinase-9 C-1562T polymorphism in preeclamptic patients: association with malondialdehyde level and severe preeclampsia Ziba Rahimi • Leila Kazemian • Shohreh Malek-Khosravi • Farid Najafi • Zohreh Rahimi

Received: 6 January 2014 / Accepted: 9 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose The abnormal activation of matrix metalloproteinases (MMPs) during pregnancy might be involved in the pathogenesis of preeclampsia. The aim of present study was to investigate the possible influence of MMP-7 A-181G and its interaction with MMP-9 C- 1562T polymorphism on the risk of preeclampsia and lipid peroxidation level. Methods In a case–control study the MMP-7 A-181G and MMP-9 C-1562T polymorphisms were studied in 168 preeclamptic and 154 healthy pregnant women from Western Iran. The MMP-7 and-9 genotypes were detected using polymerase chain reaction–restriction fragment length polymorphism method. Results The frequency of MMP-7 G allele in mild(37.4 %) and severe-preeclampsia (45.6 %) and controls (40.3 %) were not significantly different. In preeclamptic patients in the presence of MMP-7 AG ? GG genotype Z. Rahimi  Z. Rahimi Medical Biology Research Center, Kermanshah University of Medical Sciences, Daneshgah Avenue, P.O. Box: 67148-69914, Kermanshah, Iran e-mail: [email protected] L. Kazemian  S. Malek-Khosravi Department of Obstetrics and Gynecology, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran F. Najafi Research Center for Environmental Determinants of Health, School of Public Health, Kermanshah University of Medical Sciences, Kermanshah, Iran Z. Rahimi (&) Department of Biochemistry, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran e-mail: [email protected]; [email protected]

there was a significantly higher concentration of malondialdehyde (MDA) (10.52 ± 4.18 lM, p = 0.017) compared to that in AA genotype carriers (9 ± 2.89 lM). Also, in the presence of both MMP-7 G and MMP-9 T alleles the MDA concentration (11.6 ± 4.9 lM) was significantly higher compared to the concomitant presence of MMP-7 A and MMP-9 C wild alleles (9.2 ± 3.1 lM, p = 0.02). There was an interaction between two alleles of MMP-7 G and MMP-9 T that significantly increased the risk of severe preeclampsia by 1.4-fold (OR = 1.4, 95 % CI = 1.06– 1.85, p = 0.016). Conclusions The present study indicates lack of a direct influence of MMP-7 A-181G polymorphism on the risk of preeclampsia. However, this polymorphism through elevation of MDA level as a marker of lipid peroxidation and interaction with MMP-9 C-1562T polymorphism might be associated with the risk of severe preeclampsia. Keywords MMP-7 A-181G  MMP-9 C-1562T  Polymorphism  Lipid peroxidation  Preeclampsia

Introduction Preeclampsia is characterized by abnormal placentation and reduced placental perfusion, vasoconstriction, dysfunction of the vascular endothelium and hypertension [1, 2]. Higher incidence of preeclampsia within families with a history of disease suggests some genes may be involved in the etiology of preeclampsia [3]. Matrix metalloproteinases (MMPs) are a family of structurally related, zinc-dependent enzymes that play a crucial role in restructuring the extracellular matrix (ECM) by activating the secretion of gelatinases, collagenases and proteolytic enzymes. Also, tissue inhibitors of matrix

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metalloproteinase (TIMPs) play an essential role in metabolism of ECM through controlling the MMPs activity [4]. During pregnancy, extensive growth and remodeling occurs in the uterus and placenta with activation of various MMPs. The imbalance in the ratio of MMPs to their TIMPs might be involved in the pathogenesis of preeclampsia [5]. The higher MMP-2/TIMP-2 ratio in gestational hypertension has been reported. It has been suggested that remodeling of spiral arteries and regulation of cytotrophoblast invasion might be under control of some MMPs (MMP-2) and their inhibitors (TIMP-2) [4]. Matrix metalloproteinase-7 (MMP-7) or uterine metalloproteinase is a small matrix metalloproteinase belongs to matrilysins group of MMPs [6, 7]. The expression of MMP-7 is mainly regulated at transcriptional level [8] with down-regulation in human endometrium by progesterone and up-regulation during menses [7]. This metalloproteinase degrades casein, fibronectin and gelatin types I, III, IV and V and is involved in the breakdown of collagen during the puerperium [7, 9]. In humans the presence of MMP-7 and its mRNA has been detected in syncytiotrophoblasts during early gestation and in cytotrophoblasts by the third trimester and is a physiologic component of amniotic fluid [9]. The MMP-7 gene locates on chromosome 11q21–q22. The MMP-7 A-181G polymorphism (rs11568818) in the promoter region of MMP-7 gene through affecting the binding of nuclear protein (s) modulates the transcription of the gene [8, 10]. The functional polymorphism of MMP-9 C-1562T (rs3918242) in the promoter region of MMP-9 gene is associated with higher transcriptional activity of the gene and higher MMP-9 level in biological fluids and tissues [4]. It has been reported that the MMP-9 level and activity have been significantly increased in the plasma and umbilical cord arterial wall of preeclamptic newborns [11]. In preeclampsia there is an increased lipid peroxidation as an index of oxidative stress and decreased antioxidant capacity compared to normal pregnancy. Placenta is the major source of oxidative stress during pregnancy. The free radicals are increased in the fetoplacental unit with poor perfusion in preeclamptic women [2, 12]. Increased oxidative stress through endothelial dysfunction resulted in hypertension, proteinuria, edema and platelet activation that manifests as preeclampsia [2]. There is no available report to examine the influence of MMP-7 A-181G polymorphism on the risk of preeclampsia. The aims of present study were to investigate the role of MMP-7 A-181G polymorphism in susceptibility to preeclampsia and its interaction with MMP-9 C-1562T polymorphism on the risk of preeclampsia and lipid peroxidation level in a population from Western Iran.

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Patients and methods In a case–control study 168 preeclamptic patients including 111 women with mild and 57 women with severe preeclampsia and also 154 women with normal pregnancy were investigated. The preeclamptic women were age- and parity-matched with controls. The subjects had been admitted to the obstetric clinic of the Imam Reza Hospital of Kermanshah University of Medical Sciences (Kermanshah, Iran) between May 2010 and April 2011. Patients were all preeclamptic women who consecutively referred to the hospital except those with multiple-birth pregnancy, known hypertension, diabetes, cardiac and renal diseases. There were 20 patients (2 mild- and 18 severe-preeclamptic patients) with earlyonset preeclampsia (before 34 weeks gestation) and 148 patients (109 mild- and 39 severe- preeclamptic patients) with late onset-preeclampsia (after 34 weeks gestation). The samples were collected from controls at gestational age of 36–39 weeks. The gestational age at diagnosis of preeclampsia was between 30 and 39 weeks. All of the patients and controls were from Kermanshah with Kurdish ethnic background. The criteria for diagnosis of preeclampsia were systolic blood pressure equal or higher than 140 mmHg, diastolic blood pressure equal or higher than 90 mmHg, presence of proteinuria by 24-h urinary excretion exceeding 300 mg, a urine protein: creatinine ratio of [0.3, equal or higher than 30 mg/dl protein in random urine sample (1? reaction on a standard urine dipstick). Severe preeclampsia was defined as having C1 of following criteria: blood pressure equal or more than 160/110 mmHg on 2 occasions at least 6 h apart while patient is on bed rest, proteinuria [3? on 2 random urine samples collected at least 4 h apart, headache, visual disturbances, upper abdominal pain, serum creatinine and transaminase elevation, thrombocytopenia, fetal-growth restriction [13]. Informed written consent was obtained from each individual before participation. The study was approved by the Ethics Committee of Kermanshah University of Medical Sciences and was in accordance with the principles of the Declaration of Helsinki II. Biochemical analysis Total serum cholesterol (TC) and triglycerides (TG) were measured by the standard enzymatic method (Pars Azmoon kit, Tehran, Iran) using an automated Technicon RA-1000 system (Technicon Instruments Corporation, NY, USA). The serum low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) levels were measured using commercially available enzyme assay kits (Pars Azmoon kit, Tehran, Iran).

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The serum levels of total antioxidant capacity (TAC) were measured using commercially available kits (Randox Laboratories Ltd., Crumlin, Antrim, N. Ireland, Cat. no. NX2332). Serum level of malondialdehyde (MDA) was measured as MDA–thiobarbituric acid (TBA) adduct using fluorescence detector by highly specific, sensitive, and reproducible method of high performance liquid chromatography as previously described by Agarwal [14]. Genotype analysis DNA was extracted from the leukocyte fraction of the EDTA-treated whole blood using the phenol–chloroform method [15]. The MMP-7 A-181G polymorphism was detected using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). The PCR was conducted using the forward primer of 50 -TGGTACCATAATGTCCT GAATG-30 , and the reverse primer of 50 - TCGTTATTGG CAGGAAGCACACAATGAATT-30 . The obtained PCR product with 150 bp was digested with EcoRI restriction enzyme that in the presence of G allele produced two fragments of 120 and 30 bp. While in the presence of A allele the 150 bp fragment remained intact [16]. The genotypes of MMP-9 C-1562T polymorphism were detected by PCR followed by digestion with Sph I restriction enzyme as previously described [17]. Statistical analysis The allelic frequencies were calculated by the chromosome counting method. The degrees of significance of differences in genotype and allele frequencies of MMP-7 Table 1 Characteristics of preeclamptic and control women

Comparison has been made with healthy pregnant women

Variables

A-181G between patients and controls were calculated using v2 test. Odds ratios (OR) were calculated as estimates of relative risk for the disease and 95 % confidence intervals (CI) were obtained by SPSS logistic regression. The interaction between MMP-7 A-181G with MMP-9 C-1562T was determined using the logistic regression model. The correlation values of clinical data with the MMP-7 polymorphism between studied groups were calculated using linear regression and an unpaired t test. Two-tailed Student’s t test and ANOVA analysis were also used to compare quantitative data. The categorical variables among groups were compared using v2 test. Statistical significance was assumed at the p \ 0.05 level. The SPSS (SPSS Inc., Chicago, IL, USA) statistical software package version 16.0 was used for the statistical analysis.

Results Demographic and biochemical characteristics of preeclamptic patients and healthy pregnant women are demonstrated in Table 1. The body mass index (BMI) in both mild and severe preeclamptic women was significantly higher (32.1 ± 4.2, p \ 0.001 and 31.1 ± 4.3 kg/m2, p \ 0.001, respectively) than that in controls (26.3 ± 4.6 kg/m2). The mean gestational age in mild (36.7 ± 1.8 weeks) and severe (34.9 ± 2.5 weeks) preeclamptic women was significantly lower than that in healthy pregnant women (38 ± 0.9 weeks). No significant difference was detected in lipid profile between patients and controls except for the presence of significantly higher TG concentrations in both mild (177 ± 28.6 mg/dl, p \ 0.001) and

Mild preeclampsia

Severe preeclampsia

Healthy pregnant women (n = 154)

(n = 111)

(n = 57)

Age (years)

29.1 ± 6, p = p = 0.08

29.2 ± 6.4, p = 0.14

27.6 ± 6.5

Body mass index (kg/m2)

32.1 ± 4.2, p \ 0.001

31.1 ± 4.3, p \ 0.001

26.3 ± 4.6

Gestational gage (weeks)

36.7 ± 1.8, p \ 0.001

34.9 ± 2.5, p \ 0.001

Systolic blood pressure (mmHg)

140 ± 11.5, p \ 0.001

161.5 ± 28.2, p \ 0.001

110 ± 9.5

Diastolic blood pressure (mmHg)

88 ± 13.8, p \ 0.001

102.2 ± 16.5, p \ 0.001

72 ± 7.5

38 ± 0.9

Total cholesterol (mg/dl)

233.5 ± 53, p = 0.14

251.8 ± 71.5, p = 0.32

243.1 ± 44.3

TG (mg/dl)

177 ± 28.6, p \ 0.001

181.6 ± 36.9, p \ 0.001

163.5 ± 28.7

HDL-C (mg/dl)

55.2 ± 11.6, p = 0.22

55.1 ± 12.5, p = 0.27

56.9 ± 8.9

LDL-C (mg/dl)

133.3 ± 34.5, p = 0.25

140.2 ± 36.9, p = 0.63

137.9 ± 24.5 6.26 ± 2.7

Malondialdehyde (lM)

9.62 ± 4.1, p \ 0.001

10.34 ± 4.4, p \ 0.001

Total antioxidant capacity (mM)

1.34 ± 0.25, p = 0.057

1.41 ± 0.18, p = 0.53

1.4 ± 0.18

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Arch Gynecol Obstet Table 2 Distribution of MMP7 A-181G genotypes in preeclamptic patients and controls

Mild preeclampsia (n = 111)

Severe preeclampsia (n = 57)

All preeclamptic patients (n = 168)

Controls (n = 154)

AA (%)

41 (36.9)

14 (24.6)

55 (32.7)

53 (34.4)

AG (%)

57 (51.4)

34 (59.6)

91 (54.2)

78 (50.6)

GG (%)

13 (11.7)

9 (15.8)

22 (13.1)

23 (14.9)

v2 = 0.61, p = 0.73

v2 = 1.93, p = 0.38

v2 = 0.45, p = 0.79

70 (63.1)

43 (75.4)

113 (67.3)

v2 = 0.18, p = 0.67

v2 = 1.86, p = 0.17

v2 = 0.1, p = 0.75

MMP-7 genotypes

AG ? GG (%)

101 (65.6)

MMP-7 alleles A (%)

139 (62.6)

62 (54.4)

201 (59.8)

184 (59.7)

G (%)

83 (37.4)

52 (45.6)

135 (40.2)

124 (40.3)

v2 = 0.44, p = 0.5

v2 = 0.98, p = 0.32

v2 = 0.0, p = 0.98

severe (181.6 ± 36.9 mg/dl, p \ 0.001) preeclamptic patients than that in controls (163.5 ± 28.7 mg/dl). Also, a significantly higher level of MDA was detected in mild (9.62 ± 4.1 lM, p \ 0.001) and severe (10.34 ± 4.4 lM, p \ 0.001) preeclamptic patients compared to that in healthy pregnant women (6.26 ± 2.7 lM). There were 20 patients with early-onset and 148 with late-onset preeclampsia. Comparing MMP-7 genotypes between early- and late-onset preeclampsia indicated a trend toward higher frequency of AG ? GG genotype (75 %) among patients with early-onset preeclampsia compared to that in late-onset preeclampsia (66.2 %, p = 0.43). Distribution of MMP-7 A-181G genotypes and alleles are depicted in Table 2. The frequency of AG ? GG genotype in mild- (63.1 %), severe- (75.4 %) and all-preeclamptic patients (67.3 %) was not significantly different compared to that in controls (65.6 %). The frequency of MMP-7 G allele in severe preeclamptic women was tended to be higher (45.6 %) than that in healthy pregnant women (40.3 %, p = 0.32). In preeclamptic patients in the presence of MMP-7 AG ? GG genotype there was a significantly higher TAC level (1.39 ± 0.22 mM, n = 113) compared to that in AA genotype (1.31 ± 0.25 mM, n = 55, p = 0.042). Also, significantly higher concentration of MDA was obtained in the presence of AG ? GG genotype (10.52 ± 4.18 lM, p = 0.017) compared to that in patients with AA genotype (9 ± 2.89 lM). There was an interaction between two mutant alleles of MMP-7 G and MMP-9 T compared to both wild alleles of MMP-7 A and MMP-9 C that significantly increased the risk of severe preeclampsia by 1.4-fold (OR = 1.4, 95 % CI = 1.06–1.85, p = 0.016) which is demonstrated in Table 3. Also, the combined presence of both mutant alleles of MMP-7 and MMP-9 compared to the presence of other combinations of alleles (wild alleles of both genes,

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wild allele of MMP-7 A and mutant allele of MMP-9 T or mutant allele of MMP-7 G and wild allele of MMP-9 C) could increase the risk of severe preeclampsia up to 3.84 [OR = 1.91 (95 % CI 0.94–3.84), p = 0.071]. In patients with early-onset preeclampsia both MMP-9 T and MMP-7 G alleles were concomitantly present in 62.5 % of women compared to the combined presence of both alleles in 36.2 % of women with late-onset preeclampsia but the difference did not reach to a statistical significance (p = 0.14). In preeclamptic patients in the presence of both MMP-7 G and MMP-9 T alleles, the diastolic blood pressure (96.3 ± 9.8 mmHg), HDL-C level (60.6 ± 13.8 mg/dl) and MDA concentration (11.6 ± 4.9 lM) were significantly higher compared to the concomitant presence of wild alleles of MMP-7 A and MMP-9 C [88.7 ± 17.6 mmHg (p = 0.044), 53 ± 8 mg/dl (p = 0.006) and 9.2 ± 3.1 lM (p = 0.02)]. Although systolic blood pressure was tended to be higher (153.4 ± 13.7 mmHg) in the presence of both mutant alleles of MMP-7 and MMP-9 compared to the presence of wild alleles of both genes (144.1 ± 29.1 mmHg) it did not reach to a statistical significance (p = 0.12).

Discussion The present study did not detect an association between the MMP-7 A-181G and the risk of preeclampsia among pregnant women from Western Iran. However, an interaction between both polymorphisms of MMP-7 A-181G and MMP-9 C-1562T was detected with significantly increased risk of severe preeclampsia by 1.4-fold. Also, we found that the combined presence of both mutant alleles compared to the presence of other allele combinations of both genes could increase the risk of severe preeclampsia up to 3.84. Recently, we suggested that the MMP-9

Arch Gynecol Obstet Table 3 Carrier odds ratios interaction between MMP-7 G with MMP-9 T allele in severe preeclamptic patients MMP-7 G

MMP-9 T

Severe preeclampsia n (%) [OR (95 % CI, p)]

Control group n (%)

–

–

54 (50.9 %)

119 (54.6 %)

Reference group

Reference group

?

–

35 (33 %)

78 (35.8 %)

–

?

2 (1.9 %)

9 (4.1 %)

?

?

15 (14.2 %) [1.4 (1.06–1.85, p = 0.016)]

12 (5.5 %)

C-1562T polymorphism might be a susceptibility biomarker for severe and early-onset severe preeclampsia [17]. Also, we detected a synergism between MMP-9 and some of components of renin-angiotensin system (RAS) including ACE I/D and AT2R G-1332A polymorphisms to increase the risk of preeclampsia [17, 18]. The level of extracellular matrix metalloproteinase inducer (EMMPRIN) that by inducing the release of matrix metalloproteinases regulates the initiation and extent of tissue breakdown and remodeling has been increased in preeclamptic patients compared to normotensive and gestational hypertension women [19]. MMP-7 has an important role in the process of implantation and is expressed during the receptive phase localized to endometrial glandular and luminal epithelium [20]. However, in umbilical cord blood no significant difference was detected in MMP7 activity and level between preeclamptic and control samples [5]. We detected a significantly higher serum level of MDA in preeclamptic patients than controls. Previously, we indicated that butyrylcholinesterase activity (BChE) was lower in preeclamptic women compared to healthy pregnant women that might result to a lesser ability to remove pregnancy threatens toxins compared to normal pregnancy [21]. The imbalance between prooxidant production and antioxidant defenses has been implicated in the pathogenesis of preeclampsia [22]. Oxidative stress through lipid peroxidation is involved in the development of preeclampsia [23, 24]. Further, the present study demonstrates that in preeclamptic patients the MMP-7 AG ? GG genotype significantly increased the MDA level compared to MMP-7 AA genotype. Also, there was a synergism between MMP-7 G and MMP-9 T alleles with increased MDA concentration compared to that in the presence of wild alleles of MMP-7 and MMP-9. The presence of MMP-7-181G allele is associated with two- to three-fold higher gene expression and promoter activity of the MMP7-181G allele compared to the -181A allele [16]. MMP-7 activates pro MMP-1, -2, and -9 [5]. It seems increased

MMP-9 activity by MMP-9 T and MMP-7 G alleles and also by MDA level that its concentration is more enhanced in the presence of MMP-7 A-181G polymorphism might be a mechanism responsible for the synergism between MMP7 G and MMP-9 T alleles to increase the risk of preeclampsia. However, this hypothesis remains to be proved. MMP-9 and -2 are involved in oxidative stress by their presence in different tissues. It has been demonstrated that oxidative stress upregulates the expression of MMP-9 and its activity in endothelial cells during hyperglycemia [25]. Also, the higher activity of MMP-9 and increased oxidative stress and inflammatory mediators might be involved in endothelial dysfunction presented in preeclampsia [26]. A significant correlation between plasma pro MMP-9 and lipid peroxidation and protein oxidation has been demonstrated in ethanol induced oxidative stress and vitamin E supplementation has decreased the pro MMP-9 levels in these alcohol treated rats [25]. Abnormal lipid metabolism associated with oxidative stress might be one of the mechanisms by which preeclampsia is developed [23]. In preeclampsia a biochemical imbalance occurs with an increase in oxidative stress and lipid peroxidation and, at the same time, a deficient antioxidant protection [27]. The increased level of malondialdehyde (MDA) as a marker of lipid peroxidation and oxidative stress in preeclamptic women compared to women with normal pregnancy has been reported in some [27–30] but not all studies [31]. Uncontrolled lipid peroxidation through vascular endothelial cell dysfunction may play an important role in the pathophysiology of preeclampsia and eclampsia [32]. Previously, we reported a significantly positive correlation between the serum level of MDA and diastolic blood pressure in preeclamptic women [33]. In the present study significantly higher diastolic blood pressure was obtained in the concomitant presence of MMP-7 G and MMP-9 T alleles compared to that in the presence of wild alleles. We conclude the absence of a direct influence of MMP7 A-181G polymorphism on the risk of preeclampsia. However, this polymorphism through elevation of MDA level as a marker of lipid peroxidation and synergism with MMP-9 C-1562T polymorphism might be associated with the risk of severe preeclampsia.

Limitations of the study One of the limitations of the present study is the small sample sizes of the study groups, mainly the severe preeclamptic group. The lower number of patients available for the analysis of the interactions of both polymorphisms

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of MMP-7 and MMP-9 may also be considered as another limitation. So, the association findings and interactions need to be replicated with larger samples in other populations. Acknowledgments This work was performed in partial fulfillment of the requirements for MD degree of Dr. Leila Kazemian and was financially supported by a grant from Vice Chancellor for Research of Kermanshah University of Medical Sciences, Kermanshah, Iran. Conflict of interest

The authors report no conflicts of interest.

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