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Polymorphisms in proinflammatory cytokine genes, effect on gene expression and association with preterm delivery in Saudi females
Corresponding Author(s) : Ramesa Shafi Bhat
Cellular and Molecular Biology,
Vol. 64 No. 10: Issue 10
Abstract
Genetic polymorphism in proinflammatory cytokine genes may be associated with the etiology of preterm birth (PTB). The current study was designed with the aim to explore the association of genetic polymorphisms and mRNA expression of IL-1α, IL-1β, and TNF-α gene with preterm birth in the Saudi population. Genotyping of genomic DNA of 50 PTB patients and an equal number of controls were carried out using TaqMan Genotyping assay kits. Gene expression of each gene was carried out using quantitative RT-PCR. The cytokine levels in the serum of PTB patients and controls were measured by ELISA. A statistically significant association was observed between the rs361525 alleles (G and A) of TNF-α and PTB, where the mutant A allele was significantly protective against PTB development (OR= 0.362; χ2=4.31; p=0.038). The gene expression of all studied genes (IL1α, IL-1β, IL-6, and TNF-α) was higher in the PTB patients, but the results reached significance only for IL-1β (p=0.035). Elevated gene expression was also evident from the level of these proteins in plasma, where the level of IL1α, IL-β were significantly higher in the serum of PTB patients compared to the controls, however, IL6 and TNF-α were significantly lower despite higher gene expression. For IL6, the lower level could be due to tocolytic treatment that was given to all women suffering from PTB. Receiver operating curves (ROC) were drawn for the studied cytokines. In conclusion, this study revealed that rs361525 polymorphism plays a role as a protective marker for PTB and the levels of IL-1α, IL-6, TNF- α can be used as predicative biomarkers for PTB I Saudi women.
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- Murphy DJ. Epidemiology and environmental factors in preterm labour. Best Pract Res Clin Obstet Gynaecol. 2007;21:773–789.
- Sheikh IA, Ahmad E, Jamal MS, Rehan M, Assidi M, Tayubi IA, AlBasri SF, Bajouh OS, Turki RF, Abuzenadah AM, Damanhouri GA, Beg MA, Al-Qahtani M (2016) Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update. BMC Genomics 17:759
- Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Preterm Birth: Causes, Consequences, and Prevention. Washington DC: National Academies Pres; 2007.
- Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery, N Engl J Med , 2000,. 342 ,1500-1507
- Hillier SL, Witkin SS, Krohn MA, Watts DH, Kiviat NB, Eschenbach DA. The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection, Obstet Gynecol , 1993, 81 . 941-948)
- Greig PC, Murtha AP, Jimmerson CJ, Herbert WN, Roitman-Johnson B, Allen J. Maternal serum interleukin-6 during pregnancy and during term and preterm labor, Obstet Gynecol , 1997, 90 . 465-469)
- . Sata F, Toya S, Yamada H, Suzuki K, Saijo Y, Yamazaki A, et al. Proinflammatorycytokine polymorphisms and the risk of preterm birth and low birthweight ina Japanese population. Mol Hum Reprod. 2009;15:121–30.
- Jones NM, Holzman C, Friderici KH, Jernigan K, Chung H, Wirth J, et al.Interplay of cytokine polymorphisms and bacterial vaginosis in the etiologyof preterm delivery. J Reprod Immunol. 2010;87:82–9.
- Velez DR, Fortunato SJ, Williams SM, Menon R. Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic fluid protein concentrations in preterm birth. Hum Mol Genet. 2008;17:1619–30.
- Goncalves LF, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 2002;8:3–13.
- Keelan JA, Blumenstein M, Helliwell RJA, Sato TA, Marvin KW, Mitchell MD. Cytokines, prostaglandins and parturition: a review.Placenta 2003;17:S33– S46.
- ShankarR, johnson MP, williamson NA, cullinane F, purcell A W, Moses, E. K. & Brennecke, s. P. 2010. Molecular markers of preterm labor in the choriodecidua. Reprod sci, 17, 297-310.
- Zhu Q, Sun, j. & Chen, y. 2014. Preterm birth and single nucleotide polymorphisms in cytokine genes. Translational pediatrics, 3, 120-134.
- Holst, d. & Garnier, y. 2008. Preterm birth and inflammation”the role of genetic polymorphisms. European journal of obstetrics & gynecology and reproductive biology, 141, 3-9.
- Huizinga T. W, westendorp R G, bollen E L, keijsers V, Brinkman B M, langermans J. A, breedveld F C, verweij C L, Van De Gaer l & Dams l. 1997. Tnf-α promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients. Journal of neuroimmunology, 72, 149-153.
- Behrman R E & butler A S 2007. Biological pathways leading to preterm birth. Washington (dc): national academies press (us); 2007.
- Awasthi S, monikapandey V S & Dixit P. 2015. Association of tnf-α and il-1 β gene polymorphisms with preterm birth-replication study and meta-analysis
References
Murphy DJ. Epidemiology and environmental factors in preterm labour. Best Pract Res Clin Obstet Gynaecol. 2007;21:773–789.
Sheikh IA, Ahmad E, Jamal MS, Rehan M, Assidi M, Tayubi IA, AlBasri SF, Bajouh OS, Turki RF, Abuzenadah AM, Damanhouri GA, Beg MA, Al-Qahtani M (2016) Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update. BMC Genomics 17:759
Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Preterm Birth: Causes, Consequences, and Prevention. Washington DC: National Academies Pres; 2007.
Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery, N Engl J Med , 2000,. 342 ,1500-1507
Hillier SL, Witkin SS, Krohn MA, Watts DH, Kiviat NB, Eschenbach DA. The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection, Obstet Gynecol , 1993, 81 . 941-948)
Greig PC, Murtha AP, Jimmerson CJ, Herbert WN, Roitman-Johnson B, Allen J. Maternal serum interleukin-6 during pregnancy and during term and preterm labor, Obstet Gynecol , 1997, 90 . 465-469)
. Sata F, Toya S, Yamada H, Suzuki K, Saijo Y, Yamazaki A, et al. Proinflammatorycytokine polymorphisms and the risk of preterm birth and low birthweight ina Japanese population. Mol Hum Reprod. 2009;15:121–30.
Jones NM, Holzman C, Friderici KH, Jernigan K, Chung H, Wirth J, et al.Interplay of cytokine polymorphisms and bacterial vaginosis in the etiologyof preterm delivery. J Reprod Immunol. 2010;87:82–9.
Velez DR, Fortunato SJ, Williams SM, Menon R. Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic fluid protein concentrations in preterm birth. Hum Mol Genet. 2008;17:1619–30.
Goncalves LF, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 2002;8:3–13.
Keelan JA, Blumenstein M, Helliwell RJA, Sato TA, Marvin KW, Mitchell MD. Cytokines, prostaglandins and parturition: a review.Placenta 2003;17:S33– S46.
ShankarR, johnson MP, williamson NA, cullinane F, purcell A W, Moses, E. K. & Brennecke, s. P. 2010. Molecular markers of preterm labor in the choriodecidua. Reprod sci, 17, 297-310.
Zhu Q, Sun, j. & Chen, y. 2014. Preterm birth and single nucleotide polymorphisms in cytokine genes. Translational pediatrics, 3, 120-134.
Holst, d. & Garnier, y. 2008. Preterm birth and inflammation”the role of genetic polymorphisms. European journal of obstetrics & gynecology and reproductive biology, 141, 3-9.
Huizinga T. W, westendorp R G, bollen E L, keijsers V, Brinkman B M, langermans J. A, breedveld F C, verweij C L, Van De Gaer l & Dams l. 1997. Tnf-α promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients. Journal of neuroimmunology, 72, 149-153.
Behrman R E & butler A S 2007. Biological pathways leading to preterm birth. Washington (dc): national academies press (us); 2007.
Awasthi S, monikapandey V S & Dixit P. 2015. Association of tnf-α and il-1 β gene polymorphisms with preterm birth-replication study and meta-analysis