Association of IL-10 Gene Polymorphism (−819C > T, −592C > A and −1082G > A) with Preterm Birth

  • Monika Pandey
  • Shally Awasthi
  • Urmila Singh
  • Abbas Ali Mahdi
Original Article

Abstract

Objective

To analyze the association of IL-10 gene and its polymorphisms with preterm birth (PTB).

Methods

Five hundred and fifty nine women with term birth and 559 with preterm birth were recruited from Lucknow, India. Genetic association analysis was conducted between cases and controls. Subjects recruited as cases were women (aged between 18–40 y) with singleton delivery before 37 wk of gestation and controls were with delivery after or on 37 wk. The genotyping was performed for rs1800871, rs1800872 and rs1800896 for assessing the allelic distribution, haplotypic association and linkage disequilibrium analysis. IL-10mRNA levels were evaluated by real time quantitative polymerase chain reaction (PCR) method.

Results

The risk of PTB was found significant in women carrying IL-10 (−1082) GA genotype [OR=1.72(1.7–2.5), p=0.006]. The haplotypic analysis of studied polymorphisms for rs1800871, rs1800872 and rs1800896 depicted the association of ATA (p=0.02) and ATC (p=0.01) haplotypes with PTB. The IL-10 mRNA levels were significantly lower in cases (p=0.05).

Conclusions

IL-10 marks a protective impact in the inflammatory pathway of PTB.

Keywords

Cytokines Inflammation Interleukin Gene expression Haplotype Polymorphisms Preterm birth 

Notes

Contributions

MP, SA: Conception or design of the experimental work and data collection; MP, SA, US, AAM: Acquisition, analysis, and interpretation of data. SA will act as guarantor for the paper.

Compliance with Ethical Standards

Conflict of Interest

None.

Source of Funding

The study was financially supported by Indian Council of Medical Research (ICMR) 5/7/513/11-RHN.

References

  1. 1.
    Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011;1221:80–7.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Awasthi S, Pandey M, Sundaram V, Dixit P. Association of TNF- α and IL-1 β gene polymorphisms with preterm birth- replication study and meta analysis. Int J Sci Res (IJSR). 2015;4:1679–85.Google Scholar
  3. 3.
    Behram RE, Butler AS. Preterm birth: causes, consequences and prevention. Washington DC: National Academics Press; 2007.Google Scholar
  4. 4.
    Pandey M, Awasthi S. Prognostic role of interluekin-1 α and β gene polymorphisms in preterm birth. Gene Rep. 2016;4:112–7.CrossRefGoogle Scholar
  5. 5.
    Zhang JM, An J. Cytokines, inflammation and pain. Int Anesthesiol Clin. 2007;45:27–37.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhu Q, Sun J, Chen Y. Preterm birth and single nucleotide polymorphisms in cytokine genes. Transl Pediatr. 2014;3:120–34.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy— review of a new approach. Pharmacol Rev. 2003;55:241–69.CrossRefPubMedGoogle Scholar
  8. 8.
    Robertson SA, Skinner RJ, Care AS. Essential role for IL-10 in resistance to lipopolysaccharide-induced preterm labor in mice. J Immunol. 2006;177:4888–96.CrossRefPubMedGoogle Scholar
  9. 9.
    Mohan AR, Loudon JA, Bennett PR. Molecular and biochemical mechanisms of preterm labour. Semin Fetal Neonatal Med. 2004;9:437–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Challis JR, Sloboda DM, Alfaidy N, et al. Prostaglandins and mechanisms of preterm birth. Reproduction. 2002;124:1–17.CrossRefPubMedGoogle Scholar
  11. 11.
    De Waal MR, Abrams J, Bennett B, Figdor CG, De Vries JE. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991;174:1209–20.CrossRefGoogle Scholar
  12. 12.
    Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991;147:3815–22.PubMedGoogle Scholar
  13. 13.
    Hart PH, Hunt EK, Bonder CS, Watson CJ, Finlay-Jones JJ. Regulation of surface and soluble TNF receptor expression on human monocytes and synovial fluid macrophages by IL-4 and IL-10. J Immunol. 1996;157:3672–80.PubMedGoogle Scholar
  14. 14.
    Fortunato SJ, Menon R, Swan KF, Lombardi SJ. Interleukin-10 inhibition of interleukin-6 in human amniochorionic membrane: transcriptional regulation. Am J Obstet Gynecol. 1996;175:1057–65.CrossRefPubMedGoogle Scholar
  15. 15.
    Fortunato SJ, Menon R, Lombardi SJ. Interleukin-10 and transforming growth factor-β inhibit amniochorion tumor necrosis factor-α production by contrasting mechanisms of action: therapeutic implications in prematurity. Am J Obstet Gynecol. 1997;177:803–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Pomini F, Caruso A, Challis JR. Interleukin-10 modifies the effects of interleukin-1β and tumor necrosis factor-α on the activity and expression of prostaglandin H synthase-2 and the NAD+−dependent 15-hydroxyprostaglandin dehydrogenase in cultured term human villous trophoblast and chorion trophoblast cells 1. J Clin Endocrinol Metab. 1999;84:4645–51.PubMedGoogle Scholar
  17. 17.
    Greig PC, Herbert WN, Robinette BL, Teot LA. Amniotic fluid interleukin-10 concentrations increase through pregnancy and are elevated in patients with preterm labor associated with intrauterine infection. Am J Obstet Gynecol. 1995;173:1223–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Terrone DA, Rinehart BK, Granger JP, Barrilleaux PS, Martin JN, Bennett WA. Interleukin-10 administration and bacterial endotoxin-induced preterm birth in a rat model. Obstet Gynecol. 2001;98:476–80.PubMedGoogle Scholar
  19. 19.
    Rivera DL, Olister SM, Liu X, et al. Interleukin-10 attenuates experimental fetal growth restriction and demise. FASEB J. 1998;12:189–97.PubMedGoogle Scholar
  20. 20.
    Moura E, Mattar R, de Souza E, Torloni MR, Gonçalves-Primo A, Daher S. Inflammatory cytokine gene polymorphisms and spontaneous preterm birth. J Reprod Immunol. 2009;80:115–21.CrossRefPubMedGoogle Scholar
  21. 21.
    Menon R, Fortunato SJ, Velez Edwards DR, Williams SM. Association of genetic variants, ethnicity and preterm birth with amniotic fluid cytokine concentrations. Ann Hum Genet. 2010;74:165–83.CrossRefPubMedGoogle Scholar
  22. 22.
    Sugita N, Kobayashi T, Kikuchi A, et al. Immunoregulatory gene polymorphisms in Japanese women with preterm births and periodontitis. J Reproduct Immunol. 2012;93:94–101.CrossRefGoogle Scholar
  23. 23.
    Nuk M, Orendi K, Rosenberger S, et al. Genetic variations in fetal and maternal tumor necrosis factor-α and interleukin 10: is there an association with preterm birth or periventricular leucomalacia? J Perinatol. 2012;32:27–32.CrossRefPubMedGoogle Scholar
  24. 24.
    Cordeiro CA, Moreira PR, Andrade MS, et al. Interleukin-10 gene polymorphism (− 1082G/a) is associated with toxoplasmic retinochoroiditis. Invest Ophthalmol Vis Sci. 2008;49:1979–82.CrossRefPubMedGoogle Scholar
  25. 25.
    Achyut BR, Tripathi P, Ghoshal UC, Moorchung N, Mittal B. Interleukin-10 (− 819 C/T) and tumor necrosis factor-α (− 308 G/A) gene variants influence gastritis and lymphoid follicle development. Dig Dis Sci. 2008;53:622–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Zammiti W, Mtiraoui N, Cochery-Nouvellon E, Mahjoub T, Almawi WY, Gris JC. Association of-592C/A,-819C/T and-1082A/G interleukin-10 promoter polymorphisms with idiopathic recurrent spontaneous abortion. Mol Hum Rreprod. 2006;12:771–6.CrossRefGoogle Scholar
  27. 27.
    Capasso M, Avvisati RA, Piscopo C, et al. Cytokine gene polymorphisms in Italian preterm infants: association between interleukin-10 –1082 G/A polymorphism and respiratory distress syndrome. Pediatr Res. 2007;61:313–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Pawelczyk E, Nowicki BJ, Izban MG, et al. Spontaneous preterm labor is associated with an increase in the proinflammatory signal transducer TLR4 receptor on maternal blood monocytes. BMC Pregnancy Childbirth. 2010;10:66.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wommack JC, Ruiz RJ, Marti CN, Stowe RP, Brown CE, Murphey C. Interleukin-10 predicts preterm birth in acculturated hispanics. Biol Res Nurs. 2013;15:78–85.CrossRefPubMedGoogle Scholar
  30. 30.
    Makhseed M, Raghupathy R, El-Shazly S, Azizieh F, Al-Harmi JA, Al-Azemi MM. Pro-inflammatory maternal cytokine profile in preterm delivery. Am J Reprod Immunol. 2003;49:308–18.CrossRefPubMedGoogle Scholar
  31. 31.
    Ruiz RJ, Jallo N, Murphey C, Marti CN, Godbold E, Pickler RH. Second trimester maternal plasma levels of cytokines IL-1Ra, Il-6 and IL-10 and preterm birth. J Perinatol. 2012;32:483–90.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Stonek F, Metzenbauer M, Hafner E, Philipp K, Tempfer C. Interleukin-10− 1082 G/A promoter polymorphism and pregnancy complications: results of a prospective cohort study in 1,616 pregnant women. Acta Obstet Gynecol Scand. 2008;87:430–3.CrossRefPubMedGoogle Scholar
  33. 33.
    Mattar R, de Souza E, Daher S. Preterm delivery and cytokine gene polymorphisms. J Reprod Med. 2006;51:317–20.PubMedGoogle Scholar
  34. 34.
    Suárez A, Castro P, Alonso R, Mozo L, Gutiérrez C. Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms. Transplantation. 2003;75:711–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Sata F, Toya S, Yamada H, et al. Proinflammatory cytokine polymorphisms and the risk of preterm birth and low birthweight in a Japanese population. Mol Hum Reprod. 2009;15:121–30.CrossRefPubMedGoogle Scholar
  36. 36.
    Hollegaard MV, Grove J, Thorsen P, et al. Polymorphisms in the tumor necrosis factor alpha and interleukin 1-beta promoters with possible gene regulatory functions increase the risk of preterm birth. Acta Obstet Gynecol Scand. 2008;87:1285–90.CrossRefPubMedGoogle Scholar
  37. 37.
    Schmid M, Haslinger P, Stary S, Leipold H, Egarter C, Grimm C. Interleukin-1 beta gene polymorphisms and preterm birth. Eur J Obstet Gynecol Reprod Biol. 2012;165:33–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Yilmaz Y, Verdi H, Taneri A, et al. Maternal fetal proinflammatory cytokine gene polymorphism & preterm birth. DNA Cell Biol. 2012;31:92–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Bitner A, Kalinka J. IL-1β, IL-6 promoter, TNF-α promoter and IL-1RA gene polymorphisms and the risk of preterm delivery due to preterm premature rupture of membranes in a population of polish women. Arch Med Sci. 2010;6:552–7.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Harper M, Zheng SL, Thom E, et al. Cytokine gene polymorphisms and length of gestation. Obstet Gynaecol. 2011;117:125–30.CrossRefGoogle Scholar
  41. 41.
    Jones NM, Holzman C, Friderici KH, et al. Interplay of cytokine polymorphisms and bacterial vaginosis in etiology of preterm delivery. J Repro Immunol. 2010;87:82–9.CrossRefGoogle Scholar
  42. 42.
    Pu J, Zeng WY. Relationship among TNF-alpha gene promoter −308 site polymorphism, the levels of maternal serum TNF-alpha, and the mRNA expression placental TNF-alpha in preterm labor. Sichuan Da Xue Xue Bao Yi Xue Ban. 2009;40:77–80.PubMedGoogle Scholar
  43. 43.
    Jafarzadeh L, Danesh A, Sadeghi M, Heybati F, Hashemzadeh M. Analysis of relationship between tumor necrosis factor alpha gene (G308A polymorphism) with preterm labor. Int J Prev Med. 2013;4:896–901.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Drews-Piasecka E, Seremak-Mrozikiewicz A, Barlik M, et al. The significance of TNF-alpha gene polymorphisms in preterm delivery. Ginekol Pol. 2014;85:428–34.CrossRefPubMedGoogle Scholar
  45. 45.
    Velez DR, Fortunato SJ, Thorsen S, Lombardi SJ, Williams SM, Menon R. Preterm birth in caucasians is associated with coagulation and inflammation pathway gene variants. PLoS One. 2008;3:e3283.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Heinzmann A, Mailaparambil B, Mingirulli N, Kreuger M. Association of interleukin-13/−4 and toll-like receptor 10 with preterm births. Neonatology. 2009;96:175–81.CrossRefPubMedGoogle Scholar
  47. 47.
    Lorenz E, Hallman M, Marttilla R, Haataja R, Schwartz DA. Association between the Asp299Gly polymorphisms in the toll-like receptor 4 and premature births in the Finnish population. Pediatr Res. 2002;52:373–6.CrossRefPubMedGoogle Scholar
  48. 48.
    Sziksze E, Pap D, Lippai R, et al. Fibrosis related inflammatory mediators: role of the IL-10 cytokine family. Mediat Inflamm. 2015;2015:764641.Google Scholar
  49. 49.
    Iyer SS, Cheng G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol. 2012;32:23–63.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci. 1998;95:9465–70.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Reuss E, Fimmers R, Kruger A, Becker C, Rittner C, Höhler T. Differential regulation of interleukin-10 production by genetic and environmental factors–a twin study. Genes Immun. 2002;3:407–13.CrossRefPubMedGoogle Scholar
  52. 52.
    Turner D, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet. 1997;24:1–8.CrossRefPubMedGoogle Scholar

Copyright information

© Dr. K C Chaudhuri Foundation 2017

Authors and Affiliations

  • Monika Pandey
    • 1
  • Shally Awasthi
    • 1
  • Urmila Singh
    • 2
  • Abbas Ali Mahdi
    • 3
  1. 1.Department of PediatricsKing George’s Medical UniversityLucknowIndia
  2. 2.Department of Obstetrics and GynecologyKing George’s Medical UniversityLucknowIndia
  3. 3.Department of BiochemistryKing George’s Medical UniversityLucknowIndia

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