Skip to main content

Advertisement

SpringerLink
Log in

Role of IL-6 −174(G/C) promoter polymorphism in the etiology of early-onset preeclampsia

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

To investigate the relationship between IL-6 −174G/C promoter polymorphism and preeclampsia.

Methods

A total of 140 preeclamptic women and 135 women with normal pregnancy were considered for the present study. A standard amplification refractory mutation system PCR was carried out for genotyping of IL-6 G−174C promoter polymorphism. Genotypic distribution was compared with values predicted by Hardy–Weinberg equilibrium using χ 2 test. Odds ratios and their respective 95 % confidence intervals were used to measure the strength of association.

Results

The frequencies observed, CC, GC and GG, were 53.5, 26.6 and 20 % in patients and 26.6, 23.7 and 49.6 % in the controls. There is a significant difference in the distribution of genotypes and alleles of IL-6 G−174 C between the two groups.

Conclusion

The present study suggests that the IL-6 −174 promoter polymorphism is a major genetic regulator in the etiology of early-onset preeclampsia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Redman CW, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic inflammatory response—a review. Placenta. 2003;24:21–7.

    Article  Google Scholar 

  2. Carty DM, Delles C, Dominiczak AF. Novel biomarkers for predicting preeclampsia. Trends Cardiovasc Med. 2008;18:186–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Pijnenborg R, Robertson WB, Brosens I, Dixon G. Trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta. 1981;2:71–91.

    Article  CAS  PubMed  Google Scholar 

  4. Gerretsen G, Huisjes HJ, Hardonk MJ, Elema JD. Trophoblast alterations in the placental bed in relation to physiological changes in spiral arteries. Br J Obstet Gynaecol. 1983;90:34–9.

    Article  CAS  PubMed  Google Scholar 

  5. Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest. 1997;99:2152–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Lunell NO, Lewander R, Mamoun I, Nylund L, Sarby S, Thornstrom S. Uteroplacental blood flow in pregnancy induced hypertension. Scand J Clin Lab Invest Suppl. 1984;169:28–35.

    Article  CAS  PubMed  Google Scholar 

  7. Zhou Y, Genbacev O, Damsky CH, Fisher SJ. Oxygen regulates human cytotrophoblast differentiation and invasion: implications for endovascular invasion in normal pregnancy and in pre-eclampsia. J Reprod Immunol. 1988;39(1):197–213.

    Google Scholar 

  8. Roberts JM, Gamill HS. Preeclampsia: recent insights. Hypertension. 2005;46:1243–9.

    Article  CAS  PubMed  Google Scholar 

  9. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592–4.

    Article  CAS  PubMed  Google Scholar 

  10. Sargent IL, Germain SJ, Sacks GP, Kumar S, Redman CWG. Trophoblast deportation and the maternal inflammatory response in pre-eclampsia. J Reprod Immunol. 2003;59(2):153–60.

    Article  CAS  PubMed  Google Scholar 

  11. Taylor RN, Grimwood J, Taylor RS, McMaster MT, Fisher SJ, North RA. Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol. 2003;188:177–82.

    Article  CAS  PubMed  Google Scholar 

  12. Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP, Ecker J, Karumanchi SA. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab. 2004;89:770–5.

    Article  CAS  PubMed  Google Scholar 

  13. Levine RJ, Qian C, Leshane ES, Yu KF, England LJ, Schisterman EF, Wataganara T, Romero R, Bianchi DW. Two-stage elevation of cellfree fetal DNA in maternal sera before onset of preeclampsia. Am J Obstet Gynecol. 2004;190:707–13.

    Article  CAS  PubMed  Google Scholar 

  14. Barden A, Ritchie J, Walters B, Michael C, Rivera J, Mori T, Croft K, Beilin L. Study of plasma factors associated with neutrophil activation and lipid peroxidation in preeclampsia. Hypertension. 2001;38:803–8.

    Article  CAS  PubMed  Google Scholar 

  15. Walker JJ. Antioxidants and inflammatory cell response in preeclampsia. Semin Reprod Endocrinol. 1998;16:47–55.

    Article  CAS  PubMed  Google Scholar 

  16. Benyo DF, Smarason A, Redman CW, Sims C, Conrad KP. Expression of inflammatory cytokines in placentas from women with preeclampsia. J Clin Endocrinol Metab. 2001;86:2505–12.

    CAS  PubMed  Google Scholar 

  17. Vince GS, Starkey PM, Austgulen R, Kwiatkowski D, Redman CW. Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor receptors in women with pre-eclampsia. Br J Obstet Gynaecol. 1995;102:20–5.

    Article  CAS  PubMed  Google Scholar 

  18. Sibai BM, Dekker G, Kupferminic M. Pre-eclampsia. Lancet. 2005;365:785–99.

    Article  Google Scholar 

  19. Gammill HS, Roberts JM. Emerging concepts in preeclampsia investigation. Front Biosci. 2007;12:2403–11.

    Article  CAS  PubMed  Google Scholar 

  20. Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol. 2013;209(6):544.

    Article  PubMed  Google Scholar 

  21. Von Dadelszen P, Magee LA, Roberts JM. Sub classification of preeclampsia. Hypertens Pregnancy. 2003;22:143–8.

    Article  Google Scholar 

  22. Huppertz B. Placental origins of preeclampsia: challenging the current hypothesis. Hypertension. 2008;51(4):970–5.

    Article  CAS  PubMed  Google Scholar 

  23. Murphy DJ, Striate GM. Mortality and morbidity associated with early-onset preeclampsia. Hypertens Pregnancy. 2000;19:221–31.

    Article  CAS  PubMed  Google Scholar 

  24. Raghupathy R, Makhseed M, Azizieh F, Hassan N, Al-Azemi M, Al-Shamali E. Maternal Th1- and Th2-type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions. Cell Immunol. 1999;196:122–30.

    Article  CAS  PubMed  Google Scholar 

  25. Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1.

    Article  CAS  PubMed  Google Scholar 

  26. Arntzen KJ, Lien E, Austgulen R. Maternal serum levels of interleukin-6 and clinical characteristics of normal delivery at term. Acta Obstet Gynecol Scand. 1997;76:55–60.

    Article  CAS  PubMed  Google Scholar 

  27. Olah KS, Vince GS, Neilson JP, Deniz G, Johnson PM. Interleukin-6, interferon-gamma, interleukin-8, and granulocyte-macrophage colony stimulating factor levels in human amniotic fluid at term. J Reprod Immunol. 1996;32:89–98.

    Article  CAS  PubMed  Google Scholar 

  28. Imseis HM, Greig PC, Livengood CH 3rd, Shunior E, Durda P, Erikson M. Characterization of the inflammatory cytokines in the vagina during pregnancy and labor and with bacterial vaginosis. J Soc Gynecol Investig. 1997;4:90–4.

    Article  CAS  PubMed  Google Scholar 

  29. Steinborn A, Gunes H, Roddiger S, Halberstadt E. Elevated placental cytokine release, a process associated with preterm labor in the absence of intrauterine infection. Obstet Gynecol. 1996;88:534–9.

    Article  CAS  PubMed  Google Scholar 

  30. Lahiri DK, Nurnberger JI Jr. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991;19(19):5444.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Perrey C, Turner SJ, Pravica V, Howell WM, Hutchinson IV. ARMS-PCR methodologies to determine IL-10, TNF-alpha, TNF-beta and TGF-beta 1 gene polymorphisms. Transpl Immunol. 1999;7(2):127–8.

    Article  CAS  PubMed  Google Scholar 

  32. Daneshmandi S, Ghasemi A, Pourfathollah AA. IL-6-174G/C promoter polymorphism in acute appendicitis. Lab Medicine. 2009;40(10):600–3.

    Article  Google Scholar 

  33. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200–4.

    Article  CAS  PubMed  Google Scholar 

  34. Khong TY, Robertson WB. Spiral artery disease. In: Coulam CB, Faulk WP, McIntyre JA, editors. Immunological obstetrics. New York: Norton; 1980. p. 492–501.

    Google Scholar 

  35. Celik H, Avi B, Alper T. Comparison of maternal serum levels of interleukin-10, interleukin-12, and interleukin-2 in normal and preeclamptic pregnancies. Pregnancy Hypertens Int J Women Cardiovasc Health. 2012;2:39–42.

    Article  Google Scholar 

  36. Terranova PF, Hunter VJ, Roby KF, Hunt J. Tumor necrosis factor-alpha in female reproductive tract. Proc Soc Exp Biol Med. 1995;209:325–42.

    Article  CAS  PubMed  Google Scholar 

  37. Scheller J, Ohnesorge N, Rose-John S. Interleukin-6 trans-signaling in chronic inflammation and cancer. Scand J Immunol. 2006;63:321–9.

    Article  CAS  PubMed  Google Scholar 

  38. Jones SA. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol. 2005;175:3463–8.

    Article  CAS  PubMed  Google Scholar 

  39. Dimitriadis E, White CA, Jones RL, Salamonsen LA. Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update. 2005;11:613–30.

    Article  CAS  PubMed  Google Scholar 

  40. Kupferminc MJ, Peaceman AM, Aderka D, Wallach D, Socol ML. Soluble tumor necrosis factor receptors and interleukin-6 levels in patients with severe preeclampsia. Obstet Gynecol. 1996;88:420–7.

    Article  CAS  PubMed  Google Scholar 

  41. Conrad KP, Miles TM, Benyo DF. Circulating levels of immunoreactive cytokines in women with preeclampsia. Am J Reprod Immunol. 1998;40:102–11.

    Article  CAS  PubMed  Google Scholar 

  42. Desai TR, Leeper NJ, Hynes KL, Gewertz BL. Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathway. J Surg Res. 2002;104:118–23.

    Article  CAS  PubMed  Google Scholar 

  43. Maruo N, Morita I, Ishizaki Y, Murota S. Inhibitory effects of interleukin 6 on prostaglandin I2 production in cultured bovine vascular endothelial cells. Arch Biochem Biophys. 1992;292:600–4.

    Article  CAS  PubMed  Google Scholar 

  44. Hayashi M, Ueda Y, Ohkura T, Inaba N. Interleukin-6 concentrations in the placenta and blood in normal pregnancies and preeclampsia. Horm Metab Res. 2005;37:419–24.

    Article  CAS  PubMed  Google Scholar 

  45. Al-Othman S, Omu AE, Diejomaoh FM, Al-Yatama M, Al-Qattan F. Differential levels of interleukin 6 in maternal and cord sera and placenta in women with pre-eclampsia. Gynecol Obstet Invest. 2001;52:60–5.

    Article  CAS  PubMed  Google Scholar 

  46. Silver RM, Schwinzer B, McGregor JA. Interleukin-6 levels in amniotic fluid in normal and abnormal pregnancies: preeclampsia, small-for-gestational-age fetus, and premature labor. Am J Obstet Gynecol. 1993;169:1101–5.

    Article  CAS  PubMed  Google Scholar 

  47. Olusi SO, Diejomaoh M, Omu A, Abdulaziz A, Prabha K, George S. Interleukins in preeclampsia. Ann Saudi Med. 2000;20(1):4–7.

    CAS  PubMed  Google Scholar 

  48. Kauma SW, Wang Y, Walsh SW. Preeclampsia is associated with decreased placental interleukin-6 production. J Soc Gynecol Investig. 1995;2:614–7.

    Article  CAS  PubMed  Google Scholar 

  49. Greer IA, Lyall F, Perera T, Boswell F, Macara LM. Increased concentrations of cytokines interleukin-6 and interleukin-1 receptor antagonist in plasma of women with preeclampsia: a mechanism for endothelial dysfunction? Obstet Gynecol. 1994;84:937–40.

    CAS  PubMed  Google Scholar 

  50. Valencia Villalvazo EY, Canto-Cetina T, Romero Arauz JF, Coral-Vázquez RM, Canizales-Quinteros S, Coronel A, Carlos Falcón J, Hernández Rivera J, Ibarra R, Polanco Reyes L, Canto P. Analysis of polymorphisms in interleukin-10, interleukin-6, and interleukin-1 receptor antagonist in Mexican-Mestizo women with pre-eclampsia. Genetic testing and molecular biomarkers. 2012;16:1263–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Freeman DJ, McManus F, Brown EA, Cherry L, Norrie J, Ramsay JE, Clark P, Walker ID, Sattar N, Greer IA. Short- and long-term changes in plasma inflammatory markers associated with preeclampsia. Hypertension. 2004;44:708–14.

    Article  CAS  PubMed  Google Scholar 

  52. Stonek F, Hafner E, Metzenbauer M, Katharina S, Stumpflen I, Schneeberger C, Zeisler H, Husslein P, Philipp K. Absence of an association of tumor necrosis factor (TNF)-alpha G308A, interleukin-6 (IL-6) G174C and interleukin-10 (IL-10) G1082A polymorphism in women with preeclampsia. J Reprod Immunol. 2008;77:85–90.

    Article  CAS  PubMed  Google Scholar 

  53. Daher S, Sass N, Oliveira LG, Mattar R. Cytokine genotyping in preeclampsia. Am J Reprod Immunol. 2006;55(2):130–5.

    Article  CAS  PubMed  Google Scholar 

  54. Vural P, Degirmencioglu S, Saral NY, Demirkan A, Akgul C, Yildirim G, Issever H, Eroglu H. Tumor necrosis factor alpha, interleukin-6 and interleukin-10 polymorphisms in preeclampsia. J Obstet Gynaecol Res. 2010;36:64–71.

    Article  CAS  PubMed  Google Scholar 

  55. Drozdzik A, Szlarb N, Kurzawski M. Interleukin‐6 level and gene polymorphism in spontaneous miscarriage. Tissue Antigens. 2013;82(3):171–6.

    Article  CAS  PubMed  Google Scholar 

  56. Weger M, Steinbrugger I, Haas A, März W, El-Shabrawi Y, Weger W, Schmut O, Renner W. Role of the interleukin-6 −174 G>C gene polymorphism in retinal artery occlusion. Stroke. 2005;36(2):249–52.

    Article  CAS  PubMed  Google Scholar 

  57. Losito A, Kalidas K, Santoni S, Jeffery S. Association of interleukin-6 −174G/C promoter polymorphism with hypertension and left ventricular hypertrophy in dialysis patients. Kidney Int. 2003;64(2):616–22.

    Article  CAS  PubMed  Google Scholar 

  58. Galimudi RK, Spurthi MK, Padala C, Kumar KG, Mudigonda S, Reddy SG, Aiyengar TM, Sahu SK, Rani SH. Interleukin 6 (−174G/C) variant and its circulating levels in coronary artery disease patients and their first degree relatives. Inflammation. 2014;37(2):314–21.

    Article  CAS  PubMed  Google Scholar 

  59. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1988;102:1369–76.

    Article  Google Scholar 

  60. Cozen W, Gill PS, Ingles SA, Masood R, Martinez-Maza O, Cockburn MG, Gauderman WJ, Pike MC, Bernstein L, Nathwani BN, Salam MT, Danley KL, Wang W, Gage J, Gundell-Miller S, Mack TM. IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. Blood. 2004;103:3216–21.

    Article  CAS  PubMed  Google Scholar 

  61. Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275:18138–44.

    Article  CAS  PubMed  Google Scholar 

  62. Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of peeclampsia. Am J Reprod Immunol. 1997;37:240–9.

    Article  CAS  PubMed  Google Scholar 

  63. Lockwood CJ, Yen CF, Basar M, Kayisli UA, Martel M, Buhimschi I, Buhimschi C, Joseph Huang S, Krikun G, Schatz F. Preeclampsia-related inflammatory cytokines regulate interleukin-6 expression in human decidual cells. Am J Pathol. 2008;172(6):1571–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Nilsson MB, Langley RR, Fidler IJ. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 2005;65:10794–800.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Ellis J, Wennerholm UB, Bengtsson A, Lilja H, Pettersson A, Sultan B, Wennergren M, Hagberg H. Levels of dimethylarginines and cytokines in mild and severe preeclampsia. Acta Obstet Gynecol Scand. 2001;80:602–8.

    Article  CAS  PubMed  Google Scholar 

  66. Ernerudh J, Ekerfelt C. Cytokine mapping of sera from women with preeclampsia and normal pregnancies. J Reprod Immunol. 2006;70:83–91.

    Article  PubMed  Google Scholar 

  67. Gadonski G, LaMarca BB, Sullivan E, Bennett W, Chandler D, Granger JP. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of interleukin 6. Hypertension. 2006;48:711–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are thankful to all the subjects under the study and also to Basic Scientific Research, Research Fellowship for Meritorious Students from University Grants Commission for providing Junior Research fellowship to Ms. Sowmya Sabnavis.

Author information

Authors and Affiliations

  1. Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, 500 016, India

    Sabnavis Sowmya, Akka Jyothy & Ananthapur Venkateshwari

  2. Government Maternity Hospital, Petlaburz, Hyderabad, India

    Aruna Ramaiah

  3. Department of Genetics, Osmania University, Hyderabad, India

    Pratibha Nallari

Authors
  1. Sabnavis Sowmya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aruna Ramaiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pratibha Nallari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akka Jyothy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ananthapur Venkateshwari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ananthapur Venkateshwari.

Additional information

Responsible Editor: John Di Battista.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sowmya, S., Ramaiah, A., Nallari, P. et al. Role of IL-6 −174(G/C) promoter polymorphism in the etiology of early-onset preeclampsia. Inflamm. Res. 64, 433–439 (2015). https://doi.org/10.1007/s00011-015-0823-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-015-0823-z

Keywords

Search

Navigation