Molecular Biology Reports

, Volume 46, Issue 4, pp 4529–4536 | Cite as

The effect of miR-146a rs2910164 and miR-149 rs2292832 polymorphisms on preeclampsia susceptibility

  • Saeedeh SalimiEmail author
  • Fatemeh Eskandari
  • Mahnaz Rezaei
  • Mehrnaz Narooei-nejad
  • Batool Teimoori
  • Atefeh Yazdi
  • Minoo Yaghmaei
Original Article


Preeclampsia (PE) is a gestational disorder and genetic and epigenetic alterations can affect its pathogenesis. Some evidences showed that the altered expression of miRNAs in the placentas complicated by PE. The blood samples from 219 PE and 242 normotensive pregnant women and placental tissue samples from 111 PE and 119 normotensive women were collected. MiR-146a and miR-149 polymorphisms were genotyped in blood samples and placentas using PCR–RFLP method. The frequencies of maternal miR-146a rs2910164 GC and CC genotypes did not differ between PE and control groups. However, the miR-146a rs2910164 G/C polymorphism was associated with an increased risk of PE in dominant (OR 1.5, 95% CI 1–2.1; P = 0.04) and allelic (OR 1.4, 95% CI 1–1.9; P = 0.04) but not recessive models. Moreover, the maternal GC and CC genotypes were associated with a 1.9- and 3.4-fold increased risk of severe PE (OR 1.9, 95% CI 1.1–3.2; P = 0.02 and OR 3.4, 95% CI 1.3–9; P = 0.01, respectively) and miR-146a rs2910164 polymorphism could increase risk of severe PE in dominant and recessive models (OR 2.1, 95% CI 1.3–3.4; P = 0.004 and OR 2.6, 95% CI 1–6.7; P = 0.04). The placental miR-146a rs2910164 polymorphism was associated with PE susceptibility in dominant (OR 1.8, 95% CI 1.1–3; P = 0.03) and allelic models (OR 1.7, 95% CI 1.1–2.5; P = 0.02). The frequencies of maternal and placental miR-149 rs2292832 genotypes were not different between two groups and these genotypes were not associated with PE or severe PE risk. In conclusion, according to logistic regression analysis the maternal/placental miR-146a rs2910164 G/C polymorphism was associated with PE and/or severe PE risk.


microRNAs Polymorphism Placenta Pre-eclampsia 



The study was funded by Zahedan University of Medical Sciences (No 7871).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

This study was approved by the ethics committee of Zahedan University of Medical Sciences (IR. ZAUMS. REC.1395.76).


  1. 1.
    Jeyabalan A (2013) Epidemiology of preeclampsia: impact of obesity. Nutr Rev 71(Suppl 1):S18–S25. CrossRefPubMedGoogle Scholar
  2. 2.
    Kharaghani R, Cheraghi Z, Okhovat Esfahani B, Mohammadian Z, Nooreldinc RS (2016) Prevalence of preeclampsia and eclampsia in Iran. Arch Iran Med 19(1):64–71PubMedGoogle Scholar
  3. 3.
    Choudhury M, Friedman JE (2012) Epigenetics and microRNAs in preeclampsia. Clin Exp Hypertens 34(5):334–341. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J, Varner MW (2001) Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 344(12):867–872. CrossRefPubMedGoogle Scholar
  5. 5.
    Skjaerven R, Vatten LJ, Wilcox AJ, Ronning T, Irgens LM, Lie RT (2005) Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ 331(7521):877. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Roberts JM, Gammill HS (2005) Preeclampsia: recent insights. Hypertension 46(6):1243–1249. CrossRefPubMedGoogle Scholar
  7. 7.
    Powe CE, Levine RJ, Karumanchi SA (2011) Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation 123(24):2856–2869. CrossRefPubMedGoogle Scholar
  8. 8.
    Roberts JM, Escudero C (2012) The placenta in preeclampsia. Pregnancy Hypertens 2(2):72–83. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Williams PJ, Broughton Pipkin F (2011) The genetics of pre-eclampsia and other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 25(4):405–417. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Peixoto AB, Rolo LC, Nardozza LMM, Araujo Junior E (2018) Epigenetics and preeclampsia: programming of future outcomes. Methods Mol Biol 1710:73–83. CrossRefPubMedGoogle Scholar
  11. 11.
    Mohammadpour-Gharehbagh A, Teimoori B, Narooei-Nejad M, Mehrabani M, Saravani R, Salimi S (2017) The association of the placental MTHFR 3′-UTR polymorphisms, promoter methylation, and MTHFR expression with preeclampsia. J Cell Biochem. CrossRefPubMedGoogle Scholar
  12. 12.
    Keshavarzi F, Mohammadpour-Gharehbagh A, Shahrakipour M, Teimoori B, Yazdi A, Yaghmaei M, Naroeei-Nejad M, Salimi S (2017) The placental vascular endothelial growth factor polymorphisms and preeclampsia/preeclampsia severity. Clin Exp Hypertens 39(7):606–611. CrossRefPubMedGoogle Scholar
  13. 13.
    Bounds KR, Chiasson VL, Pan LJ, Gupta S, Chatterjee P (2017) MicroRNAs: new players in the pathobiology of preeclampsia. Front Cardiovasc Med 4:60. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lv Y, Lu C, Ji X, Miao Z, Long W, Ding H, Lv M (2019) Roles of microRNAs in Preeclampsia. J Cell Physiol 234(2):1052–1061. CrossRefPubMedGoogle Scholar
  16. 16.
    Li CX, Weng H, Zheng J, Feng ZH, Ou JL, Liao WJ (2018) Association between MicroRNAs polymorphisms and risk of ischemic stroke: a meta-analysis in Chinese individuals. Front Aging Neurosci 10:82. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Eskandari F, Rezaei M, Mohammadpour-Gharehbagh A, Teimoori B, Yaghmaei M, Narooei-Nejad M, Salimi S (2018) The association of pri-miRNA-26a1 rs7372209 polymorphism and preeclampsia susceptibility. Clin Exp Hypertens. CrossRefPubMedGoogle Scholar
  18. 18.
    Ryan BM, Robles AI, Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer 10(6):389–402. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zeng J, Yi X, Liu H, Yang Y, Duan Y, Chen H (2018) Polymorphisms in four microRNAs and risk of oral squamous cell cancer: a meta-analysis. Oncotarget 9(9):8695–8705. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sung JH, Kim SH, Yang WI, Kim WJ, Moon JY, Kim IJ, Cha DH, Cho SY, Kim JO, Kim KA, Kim OJ, Lim SW, Kim NK (2016) miRNA polymorphisms (miR146a, miR149, miR196a2 and miR499) are associated with the risk of coronary artery disease. Mol Med Rep 14(3):2328–2342. CrossRefPubMedGoogle Scholar
  21. 21.
    Xiong XD, Cho M, Cai XP, Cheng J, Jing X, Cen JM, Liu X, Yang XL, Suh Y (2014) A common variant in pre-miR-146 is associated with coronary artery disease risk and its mature miRNA expression. Mutat Res 761:15–20. CrossRefPubMedGoogle Scholar
  22. 22.
    Xie YF, Shu R, Jiang SY, Liu DL, Ni J, Zhang XL (2013) MicroRNA-146 inhibits pro-inflammatory cytokine secretion through IL-1 receptor-associated kinase 1 in human gingival fibroblasts. J Inflamm 10(1):20. CrossRefGoogle Scholar
  23. 23.
    Zhang X, Gu Y, Liu X, Yu Y, Shi J, Yu Q, Sun H, Kanu JS, Zhan S, Liu Y (2015) Association of pre-miR-146a rs2910164 polymorphism with papillary thyroid cancer. Int J Endocrinol 2015:802562. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Alipoor B, Meshkani R, Ghaedi H, Sharifi Z, Panahi G, Golmohammadi T (2016) Association of miR-146a rs2910164 and miR-149 rs2292832 variants with susceptibility to type 2 diabetes. Clin Lab 62(8):1553–1561. CrossRefPubMedGoogle Scholar
  25. 25.
    Zou D, Liu C, Zhang Q, Li X, Qin G, Huang Q, Meng Y, Chen L, Wei J (2018) Association between polymorphisms in microRNAs and ischemic stroke in an Asian population: evidence based on 6,083 cases and 7,248 controls. Clin Interv Aging 13:1709–1726. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Maharaj NR, Ramkaran P, Pillay S, Chuturgoon AA (2017) MicroRNA-146a rs2910164 is associated with severe preeclampsia in Black South African women on HAART. BMC Genet 18(1):5. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Abo-Elmatty DM, Mehanna ET (2018) MIR146A rs2910164 (G/C) polymorphism is associated with incidence of preeclampsia in gestational diabetes patients. Biochem Genet. CrossRefPubMedGoogle Scholar
  28. 28.
    American College of O, Gynecologists, Task Force on Hypertension in P (2013) Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 122(5):1122–1131. CrossRefGoogle Scholar
  29. 29.
    Mohammadpour-Gharehbagh A, Teimoori B, Narooei-Nejad M, Mehrabani M, Saravani R, Salimi S (2018) The association of the placental MTHFR 3’-UTR polymorphisms, promoter methylation, and MTHFR expression with preeclampsia. J Cell Biochem 119(2):1346–1354. CrossRefPubMedGoogle Scholar
  30. 30.
    Yan P, Xia M, Gao F, Tang G, Zeng H, Yang S, Zhou H, Ding D, Gong L (2015) Predictive role of miR-146a rs2910164 (C > G), miR-149 rs2292832 (T > C), miR-196a2 rs11614913 (T > C) and miR-499 rs3746444 (T > C) in the development of hepatocellular carcinoma. Int J Clin Exp Pathol 8(11):15177–15183PubMedPubMedCentralGoogle Scholar
  31. 31.
    Tannetta D, Sargent I (2013) Placental disease and the maternal syndrome of preeclampsia: missing links? Curr Hypertens Rep 15(6):590–599. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Mayor-Lynn K, Toloubeydokhti T, Cruz AC, Chegini N (2011) Expression profile of microRNAs and mRNAs in human placentas from pregnancies complicated by preeclampsia and preterm labor. Reprod Sci 18(1):46–56. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Fu G, Brkic J, Hayder H, Peng C (2013) MicroRNAs in human placental development and pregnancy complications. Int J Mol Sci 14(3):5519–5544. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Hayder H, O’Brien J, Nadeem U, Peng C (2018) MicroRNAs: crucial regulators of placental development. Reproduction 155(6):R259–R271. CrossRefPubMedGoogle Scholar
  35. 35.
    Tahamtan A, Teymoori-Rad M, Nakstad B, Salimi V (2018) Anti-inflammatory MicroRNAs and their potential for inflammatory diseases treatment. Front Immunol 9:1377. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhong X, Jiang YZ, Liu P, He W, Xiong Z, Chang W, Zhu J, Cui Q (2016) Toll-like 4 receptor/NFkappaB inflammatory/miR-146a pathway contributes to the ART-correlated preterm birth outcome. Oncotarget 7(45):72475–72485. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Dai Y, Jia P, Fang Y, Liu H, Jiao X, He JC, Ding X (2016) miR-146a is essential for lipopolysaccharide (LPS)-induced cross-tolerance against kidney ischemia/reperfusion injury in mice. Sci Rep 6:27091. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Halkein J, Tabruyn SP, Ricke-Hoch M, Haghikia A, Nguyen NQ, Scherr M, Castermans K, Malvaux L, Lambert V, Thiry M, Sliwa K, Noel A, Martial JA, Hilfiker-Kleiner D, Struman I (2013) MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J Clin Investig 123(5):2143–2154. CrossRefPubMedGoogle Scholar
  39. 39.
    Testa U, Pelosi E, Castelli G, Labbaye C (2017) miR-146 and miR-155: two key modulators of immune response and tumor development. Non-coding RNA 3(3):1. CrossRefGoogle Scholar
  40. 40.
    Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, Garcia-Flores Y, Luong M, Devrekanli A, Xu J, Sun G, Tay J, Linsley PS, Baltimore D (2011) miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 208(6):1189–1201. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Campos CB, Marques TM, Pereira RW, Sandrim VC (2014) Reduced circulating miR-196b levels is associated with preeclampsia. Pregnancy Hypertens 4(1):11–13. CrossRefPubMedGoogle Scholar
  42. 42.
    Hromadnikova I, Kotlabova K, Hympanova L, Krofta L (2016) Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood. Thromb Res 137:126–140. CrossRefPubMedGoogle Scholar
  43. 43.
    Dayan N, Schlosser K, Stewart DJ, Delles C, Kaur A, Pilote L (2018) Circulating MicroRNAs implicate multiple atherogenic abnormalities in the long-term cardiovascular sequelae of Preeclampsia. Am J Hypertens 31(10):1093–1097. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Jeon YJ, Kim SY, Rah H, Choi DH, Cha SH, Yoon TK, Lee WS, Shim SH, Kim NK (2012) Association of the miR-146aC > G, miR-149T > C, miR-196a2T > C, and miR-499A > G polymorphisms with risk of spontaneously aborted fetuses. Am J Reprod Immunol 68(5):408–417. CrossRefPubMedGoogle Scholar
  45. 45.
    He Y, Yu D, Zhu L, Zhong S, Zhao J, Tang J (2018) miR-149 in human cancer: a systemic review. J Cancer 9(2):375–388. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Holtan SG, Creedon DJ, Haluska P, Markovic SN (2009) Cancer and pregnancy: parallels in growth, invasion, and immune modulation and implications for cancer therapeutic agents. Mayo Clin Proc 84(11):985–1000. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Guo L, Tsai SQ, Hardison NE, James AH, Motsinger-Reif AA, Thames B, Stone EA, Deng C, Piedrahita JA (2013) Differentially expressed microRNAs and affected biological pathways revealed by modulated modularity clustering (MMC) analysis of human preeclamptic and IUGR placentas. Placenta 34(7):599–605. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Yang S, Li H, Ge Q, Guo L, Chen F (2015) Deregulated microRNA species in the plasma and placenta of patients with preeclampsia. Mol Med Rep 12(1):527–534. CrossRefPubMedGoogle Scholar
  49. 49.
    Xiaobo Z, Qizhi H, Zhiping W, Tao D (2019) Down-regulated miR-149-5p contributes to preeclampsia via modulating endoglin expression. Pregnancy Hypertens 15:201–208. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Clinical Biochemistry, School of MedicineZahedan University of Medical SciencesZahedanIran
  2. 2.Cellular and Molecular Research CenterZahedan University of Medical SciencesZahedanIran
  3. 3.Department of Medical Genetics, School of MedicineZahedan University of Medical SciencesZahedanIran
  4. 4.Department of Obstetrics and Gynecology, School of MedicineZahedan University of Medical SciencesZahedanIran
  5. 5.Department of Obstetrics and Gynecology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran

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