Volume 24, Issue 5 (Dec - Jan 2021)                   2021, 24(5): 434-443 | Back to browse issues page


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Sahmani M, Ahmadi N, Asadian S, Dabaghi Ghaleh T, Javadi A. Relationship between rs3918242 Polymorphism of Matrix Methaloproteinase-9 Gene and Preeclampsia in Pregnant Women. Journal of Inflammatory Diseases. 2021; 24 (5) :434-443
URL: http://journal.qums.ac.ir/article-1-3066-en.html
1- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.
2- Department of Obstetrics and Gynecology, Kosar Hospital, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran.
3- Department of Social Science, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran. , javadi_a@yahoo.com
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1. Introduction
Preeclampsia is a complex disorder with a prevalence of 5%-8% in pregnant women [1].The disease is associated with hypertension, proteinuria, edema, clotting disorders in arteries, and dysfunction of endothelial cells [1]. These disorders mostly occur after the first week of pregnancy, although in the second half of pregnancy, during and after delivery it may also be observed. The etiology of this disease is unknown. Some studies have reported the role of genetic factors in the incidence of preeclampsia, especially the genes involved in oxidative stress, angiogenesis, connective tissue disorders and coagulation system [2, 3].
Studies have shown that matrix Metalloproteinases (MMPs) are involved in the development of some chronic connective tissue, cardiovascular, pulmonary, and autoimmune diseases [4, 5, 6]. These enzymes damage endothelial cells by destroying connective tissue components [7, 8]. MMP9 is a member of the MMP family, located on the long arm of chromosome number 20 (20q13.12), and is active in the reconstruction of placenta and uterine arteries. Functional –1562C>T polymorphism in the promoter region of MMP9 gene (rs3918242) is associated with high transcriptional activity and increased enzyme levels in tissue and biological fluid [9, 10]. In some studies, an association between rs3918242 polymorphism and increased incidence of preeclampsia have been reported, while in other studies, no association has been found between them [14, 15, 17]. Considering the contradictory results, this study aims to evaluate the frequency of rs3918242 polymorphism and its relationship with preeclampsia in pregnant women.

2. Materials and Methods
This case-control study was conducted on 100 pregnant women with preeclampsia (case group) and 100 healthy pregnant women (control group). Samples were recruited from the fertility center of Kowsar Hospital in Qazvin, Iran. The criteria for Preeclampsia was a systolic blood pressure >140 mmHg and/or a diastolic blood pressure >90 mmHg on two occasions >6 hours apart after 20 weeks of gestation but before the onset of labour, plus a proteinuria >2+ (on dipstick test) or >0.3 g/24. Exclusion criteria were: Multiple pregnancies, and a history of hypertension, cardiovascular disease, diabetes, kidney, liver and infectious diseases. Blood samples for molecular genetic assessments were collected in tubes containing EDTA as anticoagulant, and their DNAs were extracted from human leukocyte nuclei isolated from whole blood, and the target DNA was then amplified by Polymerase Chain Reaction (PCR) method. Restriction Fragment Length Polymorphism (RFLP) assays were designed for the identified polymorphisms. The PCR was performed by the forward primer (-5´-GCCTGGCACATAGTAGGCCC-3´) and reverse primer (-5´-CTTCCTAGCCAGCCGGCATC-3’). PCR product was digested with SphI restriction enzyme. Restriction fragments were visualized on 2% agarose gel stained with ethidium bromide. Data analysis was performed only on the data with no missing values (90 with preeclampsia and 99 healthy peers).

3. Results
The frequency of CC, CT and TT genotypes were 84.8%, 13.1% and 2% in the control group and 47.8%, 47.8% and 4.2% in the case group, respectively. The risk of developing preeclampsia in women with CT genotype was 6.2 times higher than in women with CC genotype (P<0.001). Although there was no statistically significant relationship between the frequency of TT and CC genotypes and the incidence of preeclampsia, the risk of developing preeclampsia in women with TT genotype was 4.3 times higher than in women with CC genotype.

4. Discussion and Conclusion
In this study, was investigated the association of rs3918242 polymorphism in the MMP9 gene and the risk of preeclampsia. The results showed that CT genotype and T allele of the polymorphism had association with increased risk of preeclampsia in pregnant women. Single nucleotide polymorphism of the MMP-9 gene (rs3918242) regulates the expression of this protein as well as its enzymatic activity by modulating the binding of transcription factors in the promoter region of MMP9 gene [18]. There are conflicting results regarding the association between this polymorphism of the MMP-9 gene and preeclampsia. Some studies have reported the association of CC genotype or C allele of rs3918242 polymorphism with an increased risk of preeclampsia in pregnant women [21, 22], while no such relationship has been found in other studies [17, 21, 23]. Coleman et al. suggested that the frequency of T allele in women with preeclampsia is a factor associated with reduced the risk of preeclampsia [24], which is consistent with our findings. Pali et al. reported a significant relationship between T allele and blood pressure, but its association with preeclampsia in pregnant women was not found [5]. In the study by Leonardo et al., no significant relationship between this polymorphism and preeclampsia was observed. 
The frequency of CC, CT and TT genotypes in patients in our study were 78%, 14% and 1%, respectively. Compared to the study by Leonardo et al. [25], the frequency of CC and CT genotype in our patients was lower while the frequency of TT genotype was higher. Meng et al. showed a significant association of rs3918242 polymorphism with the incidence of preeclampsia [26]. Consistent with our results, Rahimi et al. showed that the presence of TT and CT alleles of rs3918242 polymorphism is a biomarker of susceptibility to preeclampsia in pregnant women [17]. However, the frequency of TT and CT genotypes in patients was significantly different from those in our study. The discrepancy may be because of difference in ethnicity, race, lifestyle, diet and eating habits. Therefore, in order to investigate the effect of different genes on the incidence of preeclampsia, it is recommended that other factors and the severity of preeclampsia be examined in future studies

Ethical Considerations
Compliance with ethical guidelines

The present study obtained its ethical approval from the Research Ethics Committee of Qazvin University of Medical Sciences (Code: QUMS.REC.1396.244).

Funding
This study was extracted from MA. thesis of second author approved by Department of Clinical Biochemistry, School of Medicine, Qazvin University of Medical Sciences.

Authors' contributions
Writing – original draft, and writing – review & editing: Mehdi Sahmani and Amir Javadi; resources and validation: Nilofar Ahmadi, Somayeh Asadian and Amir Javadi; methodology and data analysis: Amir Javadi; editing & review and project administration: Mehdi Sahmani , Talaat Dabaghi Ghaleh

Conflict of interest
The authors declare no conflict of interest.

Acknowledgments
The authors would like to thank the efforts of Ms. Zahra Rashvand, a laboratory expert, during the study.

References
  1. Mayrink J, Costa ML, Cecatti JG. Preeclampsia in 2018: Revisiting concepts, physiopathology, and prediction. Sci World J. 2018; 2018:6268276. [DOI:10.1155/2018/6268276] [PMID] [PMCID]
  2. Ahmed NA, Hamdan HZ, Kamis AH, Adam I. The association of the prothrombin G20210A single-nucleotide polymorphism and the risk of preeclampsia: Systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2020; 253:162-9. [DOI:10.1016/j.ejogrb.2020.08.005] [PMID]
  3. Hill LD, York TP, Kusanovic JP, Gomez R, Eaves LJ, Romero R, et al. Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia. PLoS One. 2011; 6(1):e16681. [DOI:10.1371/journal.pone.0016681] [PMID] [PMCID]
  4. Sakowicz A, Lisowska M, Biesiada L, Rybak-Krzyszkowska M, Gach A, Sakowicz B, et al. Association of maternal and fetal single-nucleotide polymorphisms in metalloproteinase (MMP1, MMP2, MMP3, and MMP9) genes with preeclampsia. Dis Markers. 2018; 2018:1371425. [DOI:10.1155/2018/1371425] [PMID] [PMCID]
  5. Palei ACT, Sandrim VC, Amaral LM, Machado JSR, Cavalli RC, Lacchini R, et al. Matrix metalloproteinase-9 polymorphisms affect plasma MMP-9 levels and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy. Pharmacogenomics J. 2012; 12(6):489-98. [DOI:10.1038/tpj.2011.31] [PMID]
  6. Valenzuela FJ, Pérez-Sepúlveda A, Torres MJ, Correa P, Repetto GM, Illanes SE. Pathogenesis of Preeclampsia: The Genetic component. J Pregnancy. 2012; 2012:632732. [DOI:10.1155/2012/632732] [PMID] [PMCID]
  7. Aas PA, Otterlei M, Falnes PØ, Vågbø CB, Skorpen F, Akbari M, et al. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 2003; 421(6925):859-63. [DOI:10.1038/nature01363] [PMID]
  8. Bartek J, Lukas J. DNA repair: Damage alert. Nature. 2003; 421(6922):486-8. [DOI:10.1038/421486a] [PMID]
  9. Farina AR, Mackay AR. Gelatinase B/MMP-9 in tumour pathogenesis and progression. Cancers. 2014; 6(1):240-96. [DOI:10.3390/cancers6010240] [PMID] [PMCID]
  10. Awakura Y, Ito N, Nakamura E, Takahashi T, Kotani H, Mikami Y, et al. Matrix metalloproteinase-9 polymorphisms and renal cell carcinoma in a Japanese population. Cancer Lett. 2006; 241(1):59-63. [DOI:10.1016/j.canlet.2005.10.005] [PMID]
  11. Gai X, Lan X, Luo Z, Wang F, Liang Y, Zhang H, et al. Association of MMP-9 gene polymorphisms with atrial fibrillation in hypertensive heart disease patients. Clin Chim Acta. 2009; 408(1-2):105-9. [DOI:10.1016/j.cca.2009.07.020] [PMID]
  12. Wang L, Zhang D, Yu Y, Guan H, Qiao C, Shang T. RNA interference-mediated silencing of Laminin Receptor 1 (LR1) suppresses migration and invasion and down-regulates Matrix Metalloproteinase (MMP)-2 and MMP-9 in trophoblast cells: Implication in the pathogenesis of preeclampsia. J Mol Histol. 2013; 44(6):661-8. [DOI:10.1007/s10735-013-9515-6] [PMID]
  13. Rasstrigina IM, Milovanov AP, Fokina TV, Kadyrov M. The intensity of expression of matrix metalloproteinases type 2 and type 9 by invasive trophoblast cells in uncomplicated pregnancy and preeclampsia. Arkh Patol. 2014; 76(3):24-9. [In Russian] [PMID]
  14. Lockwood CJ, Basar M, Kayisli UA, Guzeloglu-Kayisli O, Murk W, Wang J, et al. Interferon-γ protects first-trimester decidual cells against aberrant matrix metalloproteinases 1, 3, and 9 expression in preeclampsia. Am J Pathol. 2014; 184(9):2549-59. [DOI:10.1016/j.ajpath.2014.05.025] [PMID] [PMCID]
  15. Mckirdy A, Marks L. PP060. Matrix metalloproteinases-2 and -9 and their inhibitors: A role in the development of pre-eclampsia? Pregnancy Hypertens Int J Womens Cardiovasc Health. 2012; 2(3):274-5. [DOI:10.1016/j.preghy.2012.04.171] [PMID]
  16. Feng H, Wang L, Zhang M, Zhang Z, Guo W, Wang X. Ratio of matrix metalloproteinase-2 to -9 is a more accurate predictive biomarker in women with suspected pre-eclampsia. Biosci Rep. 2017; 37(2):BSR20160508. [DOI:10.1042/BSR20160508] [PMID] [PMCID]
  17. Rahimi Z, Kazemian L, Malek-Khosravi Sh, Najafi F, Rahimi Z. 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. Arch Gynecol Obstet. 2015; 291(1):45-51. [DOI:10.1007/s00404-014-3376-4] [PMID]
  18. Verma S, Kesh K, Gupta A, Swarnakar S. An overview of matrix metalloproteinase 9 polymorphism and gastric cancer risk. Asian Pac J Cancer Prev. 2015; 16(17):7393-400. [DOI:10.7314/APJCP.2015.16.17.7393] [PMID]
  19. Zhang Z, Wu X, Cai T, Gao W, Zhou X, Zhao J, et al. Matrix metalloproteinase 9 gene promoter (rs 3918242) mutation reduces the risk of diabetic microvascular complications. Int J Environ Res Public Health. 2015; 12(7):8023-33. [DOI:10.3390/ijerph120708023] [PMID] [PMCID]
  20. Cotignola J, Reva B, Mitra N, Ishill N, Chuai Sh, Patel A, et al. Matrix Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma. BMC Med Genet. 2007; 8:10. [DOI:10.1186/1471-2350-8-10] [PMID] [PMCID]
  21. Kang L, Chen CH, Yu CH, Chang CH, Chang FM. An association study of interleukin-4 gene and preeclampsia in Taiwan. Taiwan J Obstet Gynecol. 2014; 53(2):215-9. [DOI:10.1016/j.tjog.2014.04.017] [PMID]
  22. Sun C, Zhang Q, Hu B, Zhang K. Investigation of the association between matrix metalloproteinase-9 genetic polymorphisms and development of pre-eclampsia in Chinese pregnant women. Genet Mol Res. 2016; 15(3):gmr.15038355. [DOI:10.4238/gmr.15038355]
  23. Luizon MR, Palei ACT, Sandrim VC. Polymorphisms and haplotypes in candidate genes related to angiogenesis and endothelial dysfunction in preeclampsia. J Pregnancy. 2012; 2012:914704. [DOI:10.1155/2012/914704] [PMID] [PMCID]
  24. Coolman M, de Maat M, Van Heerde WL, Felida L, Schoormans S, Steegers EAP, et al. Matrix metalloproteinase-9 gene -1562C/T polymorphism mitigates preeclampsia. Placenta. 2007; 28(7):709-13. [DOI:10.1016/j.placenta.2006.06.017] [PMID]
  25. Leonardo DP, Albuquerque DM, Lanaro C, Baptista LC, Cecatti JG, Surita FG, et al. Association of nitric oxide synthase and matrix metalloprotease single nucleotide polymorphisms with preeclampsia and its complications. PLoS One. 2015; 10(8):e0136693. [DOI:10.1371/journal.pone.0136693] [PMID] [PMCID]
  26. Meng H, Qi M, Liu Y, Xu L, Li Q. Research on correlation between MMP-9 and early-onset preeclampsia. Int J Clin Exp Med. 2016; 9(9):17442-8. http://www.ijcem.com/files/ijcem0034617.pdf
  27. Laskowska M. Altered maternal serum Matrix Metalloproteinases MMP-2, MMP-3, MMP-9, and MMP-13 in severe early- and late-onset preeclampsia. Biomed Res Int. 2017; 2017:6432426. [DOI:10.1155/2017/6432426] [PMID] [PMCID]
 
Type of Study: Research | Subject: Biochemistry

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