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Molecular investigation of association between common IL-6 polymorphism with cytomegalovirus (CMV) infection and recurrent miscarriage in Iranian women

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Abstract

Background

Recurrent pregnancy loss (RPL) is described as two or more spontaneous abortions. To date, scientists in various fields of knowledge, such as genetics, endocrinology, anatomy, immunology, and microbiology, have identified some important factors that affect abortions; nonetheless, the precise basic etiology is not determined in up to 50% of RPL cases. Human cytomegalovirus (CMV) infection and host genetic background, like IL-6 SNP polymorphisms, play important roles in RPL etiology.

Objective

This study aimed to evaluate the relationships among single nucleotide polymorphisms (-634C/G and -174 G/C) in the IL-6 gene with CMV infection and the risk of RPL for early detection and treatment.

Materials and methods

This case–control study was carried on 80 Iranian females with RPL and 80 healthy females as controls. DNA was extracted from samples and CMV and IL6 SNPs were detected using Tetra ARMS-PCR. Statistics were analyzed by Epi Info TM and SPSS software by X2 test for the roles of CMV detection and two polymorphisms in RPL.

Results

The results indicated an increased rate of CMV infection in the RPL group (44%) compared to the control group (25.45%). The prevalence of IL-6-634C/G genotype among RPL patients with CMV infection was 80%, while the frequency of this genotype among RPL patients without CMV infection was 50%. Furthermore, no substantial relation was found between IL-6-174 G/C genotypes and RPL (p = 0.005).

Conclusion

This study not only indicated a significant role for CMV in RPL, but also showed an association between CMV and allele G in IL6-634 among Iranian women. In addition, the findings suggested the use of CMV and IL-6-634 GG genotypes as diagnostic and prognostic biomarkers for RPL in the Iranian population.

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Data availability

Input data for the analyses is available from the corresponding authors upon request.

References

  1. Giakoumelou S et al (2016) The role of infection in miscarriage. Hum Reprod Updat 22(1):116–133

    Article  CAS  Google Scholar 

  2. Cannon MJ, Schmid DS, Hyde TB (2010) Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 20(4):202–213

    Article  PubMed  Google Scholar 

  3. Chakravarti A, Kashyap B, Matlani M (2009) Cytomegalovirus infection: an Indian perspective. Indian J Med Microbiol 27(1):3–11

    Article  CAS  PubMed  Google Scholar 

  4. Adler SP (2011) Screening for cytomegalovirus during pregnancy. Infect Dis Obstet Gynecol. https://doi.org/10.1155/2011/942937

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yinon Y, Farine D, Yudin MH (2010) Screening, diagnosis, and management of cytomegalovirus infection in pregnancy. Obstet Gynecol Surv 65(11):736–743

    Article  PubMed  Google Scholar 

  6. Nigro G et al (2011) Role of the infections in recurrent spontaneous abortion. J Matern Fetal Neonatal Med 24(8):983–989

    Article  PubMed  Google Scholar 

  7. Al-Mousawi HT, AL-Hajjar QN (2020) Immunogenic diagnosis of human cytomegalovirus infection in aborted and pregnant women in Babylon Governorate. J Coll Basic Educ (وقائع المؤتمر العلمي الدولي الثاني/نقابة الاكاديميين العراققيين)

  8. Al Mana H et al (2019) The current status of cytomegalovirus (CMV) prevalence in the mena region: a systematic review. Pathogens 8(4):213

    Article  CAS  PubMed Central  Google Scholar 

  9. Vueba AJAN (2022) Prevalence and serological characterization of toxoplasmosis, rubella and cytomegalovirus infection in pregnant women of Luanda, Angola: geospatial analysis of the infections, its association with socio-demographic and clinical determinants. 00500: Universidade de Coimbra

  10. Navti OB, Al-Belushi M, Konje JC (2021) Cytomegalovirus infection in pregnancy—an update. Eur J Obst Gynecol Reprod Biol 258:216–222

    Article  CAS  Google Scholar 

  11. Ford HB, Schust DJ (2009) Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol 2(2):76

    PubMed  PubMed Central  Google Scholar 

  12. Jauniaux E et al (2006) Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 21(9):2216–2222

    Article  PubMed  Google Scholar 

  13. Baqer NN et al (2022) The association of IL-3, IL-17A, and IL 27 serum levels with susceptibility to toxoplasmosis in recurrent abortion of Iraqi women. Exp Parasitol. https://doi.org/10.1016/j.exppara.2022.108217

    Article  PubMed  Google Scholar 

  14. Madduru D et al (2021) Association of reduced maternal sHLA-G5 isoform levels and elevated TNF-α/IL-4 cytokine ratio with recurrent pregnancy loss: a study on south Indian women. Scand J Immunol 94(4):e13095

    Article  CAS  PubMed  Google Scholar 

  15. Rezaei A, Dabbagh AJMSM (2002) T-helper (1) cytokines increase during early pregnancy in women with a history of recurrent spontaneous abortion. Med Sci Monit 8(8):CR607–CR610

    CAS  PubMed  Google Scholar 

  16. Daher S et al (2003) Associations between cytokine gene polymorphisms and recurrent pregnancy loss. J Reprod Immunol 58(1):69–77

    Article  CAS  PubMed  Google Scholar 

  17. Prigoshin N et al (2004) Cytokine gene polymorphisms in recurrent pregnancy loss of unknown cause. J Reprod Immunol 52(1):36–41

    Article  Google Scholar 

  18. Wang W et al (2020) T helper (Th) cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/tfh cells. Front Immunol 11:2025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Garossi N, Rassi H, Godarzvand MJIJABR (2016) Molecular analysis of G1691A mutation in factor 5 Leiden and its relation with mtDNA common deletion in human recurrent pregnancy loss. Int J Adv Biotechnol Res 8:350–358

    Google Scholar 

  20. Nematollahi Z et al (2015) The association between single nucleotide polymorphism in interleukin-27 gene and recurrent pregnancy loss in Iranian women. Iran J Reprod Med 13(4):209

    PubMed  PubMed Central  Google Scholar 

  21. Jasper MJ, Tremellen KP, S.A.J.J.o.r.i. Robertson, (2007) Reduced expression of IL-6 and IL-1α mRNAs in secretory phase endometrium of women with recurrent miscarriage. J Reprod Immunol 73(1):74–84

    Article  CAS  PubMed  Google Scholar 

  22. Unfried G et al (2003) A polymorphism of the interleukin-6 gene promoter and idiopathic recurrent miscarriage. Hum reprod 18(2):267–270

    Article  CAS  PubMed  Google Scholar 

  23. Abbaspour Rodbaneh E et al (2021) GJB2 mutations in Iranian Azeri population with autosomal recessive nonsyndromic hearing loss (ARNSHL): first report of c.238 C>A mutation in Iran. J Clin Lab Anal 35(11):e240249

    Article  Google Scholar 

  24. Nasirshalal M et al (2021) Identification of a novel heterozygous mutation in the MITF gene in an Iranian family with Waardenburg syndrome type II using next-generation sequencing. J Clin Lab Anal 35(6):e23792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sierra S, Stephenson M (2006) Genetics of recurrent pregnancy loss. Seminars in reproductive medicine. Thieme Medical Publishers Inc, NewYork

    Google Scholar 

  26. Lijnschoten GV, Stals F, Evers JL, Bruggeman CA, Havenith MH (1994) Geraedts JP The presence of cytomegalovirus antigens in karyotyped abortions. Am J Reprod Immunol 32(3):211–220

    Article  PubMed  Google Scholar 

  27. Li RY, Tsutsui YJT (2000) Growth retardation and microcephaly induced in mice by placental infection with murine cytomegalovirus. Teratology 62(2):79–85

    Article  CAS  PubMed  Google Scholar 

  28. Shams S et al (2011) Prevalence and detection of cytomegalovirus by polymerase chain reaction (PCR) and simple ELISA in pregnant women. Afr J Biotechnol 10(34):6616–6619

    Google Scholar 

  29. Makhseed M et al (2001) Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Hum Reprod 16(10):2219–2226

    Article  CAS  PubMed  Google Scholar 

  30. Bahadori M et al (2014) IL-6, IL-10 and IL-17 gene polymorphisms in Iranian women with recurrent miscarriage. Iran J Immunol 11(2):97–104

    PubMed  Google Scholar 

  31. Zammiti W et al (2006) Association of-592C/A,-819C/T and-1082A/G interleukin-10 promoter polymorphisms with idiopathic recurrent spontaneous abortion. MHR: Basic Sci Reprod Med 12(12):771–776

    CAS  Google Scholar 

  32. Li D et al (2021) The role of immune cells in recurrent spontaneous abortion. Reprod Sci 28(12):3303–3315

    Article  PubMed  Google Scholar 

  33. Favaro RR et al (2021) Immunomodulatory properties of extracellular vesicles in the dialogue between placental and immune cells. Am J Reprod Immunol 85(2):e13383

    Article  PubMed  Google Scholar 

  34. Li WX, Xu XH, Jin LP (2021) Regulation of the innate immune cells during pregnancy: an immune checkpoint perspective. J Cell Mol Med 25(22):10362–10375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Babbage SJ et al (2001) Cytokine promoter gene polymorphisms and idiopathic recurrent pregnancy loss. J Reprod Immunol 51(1):21–27

    Article  CAS  PubMed  Google Scholar 

  36. Campanile G et al (2021) Local action of cytokines and immune cells in communication between the conceptus and uterus during the critical period of early embryo development, attachment and implantation—implications for embryo survival in cattle: a review. Theriogenology 167:1–12

    Article  CAS  PubMed  Google Scholar 

  37. Kaminski VDL et al (2018) IL-17 blood levels increase in healthy pregnancy but not in spontaneous abortion. Mol Biol Rep 45(5):1565–1568

    Article  CAS  PubMed  Google Scholar 

  38. Kamali-Sarvestani E et al (2005) Cytokine gene polymorphisms and susceptibility to recurrent pregnancy loss in Iranian women. J Reprod Immunol 65(2):171–178

    Article  CAS  PubMed  Google Scholar 

  39. Rafiee N, Rassi H, Godarzvand MJIJABR (2016) Molecular analysis of G202010A mutation in factor II of blood coagulation and its relationship with polymorphism rs5030737 of MBL gene in recurrent pregnancy loss. Int J Adv Biotechnol Res 8:359–367

    Google Scholar 

  40. Saijo Y et al (2004) Single nucleotide polymorphisms in the promoter region of the interleukin-6 gene and the risk of recurrent pregnancy loss in Japanese women. Fertil Steril 81(2):374–378

    Article  CAS  PubMed  Google Scholar 

  41. Arshad M, Bhatti A, John P (2018) Identification and in silico analysis of functional SNPs of human TAGAP protein: a comprehensive study. PLoS ONE 13(1):e0188143

    Article  PubMed  PubMed Central  Google Scholar 

  42. Falahi S et al (2021) A comprehensive in Silico analysis of the functional and structural impact of single nucleotide polymorphisms (SNPs) in the human IL-33 gene. Comput Biol Chem 94:107560

    Article  CAS  PubMed  Google Scholar 

  43. Torabi R et al (2009) The relationship between polymorphisms of blood coagulation factor V gene and recurrent pregnancy losses. J Reprod Infertil 9(4):305–316

    Google Scholar 

  44. Nasiri M, Rasti ZJHI (2016) CTLA-4 and IL-6 gene polymorphisms: risk factors for recurrent pregnancy loss. Hum Immunol 77(12):1271–1274

    Article  CAS  PubMed  Google Scholar 

  45. Ma J et al (2017) Association between TNF, IL1B, IL6, IL10 and IFNG polymorphisms and recurrent miscarriage: a case control study. Reprod Biol Endocrinol 15(1):1–6

    Article  Google Scholar 

  46. Abo-alella DA et al (2021) Interleukin-6-634 G/C gene polymorphisms in recurrent pregnancy loss among Egyptian women: does it make a difference? Meta Gene 30:100955

    Article  CAS  Google Scholar 

  47. Daher S et al (2012) Genetic polymorphisms and recurrent spontaneous abortions: an overview of current knowledge. Am J Reprod Immunol 67(4):341–347

    Article  CAS  PubMed  Google Scholar 

  48. Velez D et al (2007) Ethnic differences in interleukin 6 (IL-6) and IL6 receptor genes in spontaneous preterm birth and effects on amniotic fluid protein levels. Ann Hum Genet 71(5):586–600

    Article  CAS  PubMed  Google Scholar 

  49. Salimi E et al (2020) Association of promoter region polymorphisms of IL-6 and IL-18 genes with risk of recurrent pregnancy loss: a systematic review and meta-analysis. Fet Pediatr Pathol 39(4):346–359

    Article  Google Scholar 

  50. Prasad P et al (2017) Differential expression of circulating Th1/Th2/Th17 cytokines in serum of Chlamydia trachomatis-infected women undergoing incomplete spontaneous abortion. Microb Pathog 110:152–158

    Article  CAS  PubMed  Google Scholar 

  51. Williams DM et al (1997) Humoral and cellular immunity in secondary infection due to murine Chlamydia trachomatis. Infect Immun 65(7):2876–2882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Edmunds WJ et al (2000) The pre-vaccination epidemiology of measles, mumps and rubella in Europe: implications for modelling studies. Epidemiol Infect 125(3):635–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Janan A et al (2013) Study on seroprevalence of cytomegalovirus in pregnant women and the Association of Cytomegalovirus Seropositivity to spontaneous abortion. J Mazandran Univ Med Sci 23(105):36–42

    Google Scholar 

  54. Ebadi P et al (2011) Seroprevalence of CMV and Rubella in women with recurrent spontaneous abortion in comparison with normal delivery. J Fasa Univ Med Sci 1(3):136–141

    Google Scholar 

  55. Ding J et al (2021) M2 macrophage-derived G-CSF promotes trophoblasts EMT, invasion and migration via activating PI3K/Akt/Erk1/2 pathway to mediate normal pregnancy. J Cell Mol Med 25(4):2136–2147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ma J et al (2017) Association between TNF, IL1B, IL6, IL10 and IFNG polymorphisms and recurrent miscarriage: a case control study. Reprod Biol Endocrinol: RB&E 15(1):83–83

    Article  Google Scholar 

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Acknowledgements

The authors express their gratitude to all patients and their families for their contributions to this study.

Funding

These authors have not disclosed any funding.

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Author notes

  1. Parisa Pourroostaei Ardakani, Bahareh Rahimi and Mohammad Panahi have equally contributed to this article.

Authors and Affiliations

  1. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran

    Parisa Pourroostaei Ardakani & Babak Karimian

  2. Department of Medical Biotechnology, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran

    Bahareh Rahimi

  3. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohammad Panahi

  4. Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Kazhaal sheykhi

  5. Texas Biomedical Research Center, San Antonio, TX, USA

    Hamzeh Rahimi

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  1. Parisa Pourroostaei Ardakani
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Contributions

PPA and BR and MP: methodology, conceptualization, and writing the original manuscript. KS and BK: methodology, editing, and writing sections of the manuscript. HR: supervision, project administration, review and editing of the manuscript. All authors read and approved the final draft.

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Correspondence to Hamzeh Rahimi.

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All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Pourroostaei Ardakani, P., Rahimi, B., Panahi, M. et al. Molecular investigation of association between common IL-6 polymorphism with cytomegalovirus (CMV) infection and recurrent miscarriage in Iranian women. Mol Biol Rep 49, 9499–9507 (2022). https://doi.org/10.1007/s11033-022-07835-x

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