Abstract
An appropriate ratio of interleukin 1 beta to interleukin 1 receptor antagonist (IL1Ra) is required for successful pregnancy. Our objective was to study the genetic association between IL1RN variable numbers of tandem repeat (VNTR) polymorphism and recurrent pregnancy loss (RPL). To analyze the association between IL1RN VNTR allele and RPL, we investigated the IL1RN VNTR polymorphism in 136 RPL patients and in 200 healthy control women. Meta-analysis on this polymorphism was conducted to support our findings. PCR based approach was used to analyze IL1RN VNTR polymorphism and it was further confirmed by sequencing. Systematic review and meta-analysis was done using electronic database (Pub-Med, Google Scholar and Ovid) up to February 27, 2013. This meta-analysis was assessed by comprehensive meta-analysis software version 2. For meta-analysis 549 cases and 1,450 controls were included. The frequency of IL1RN genotype 2/2 was significantly higher in RPL compared to control group (AORs 3.10, 95 % CI 1.58–6.11, p = 0.001). The presence of rare allele also increased the risk of RPL significantly (ORs 1.63, 95 % CI 1.16–2.29, p = 0.004). The meta-analysis stratified by ethnicity showed that individuals with allele 2 had increased risk of RPL (OR 1.29, 95 % CI 1.04–1.61, p = 0.01), in Asians population by using fixed model. However the data of the present study clearly suggests that IL1RN VNTR polymorphism is a genetic risk factor for pregnancy loss in the study population.
Similar content being viewed by others
References
Wegmann TG, Lin H, Guilbert L, Mosmann TR (1993) Bidirectional cytokine interactions in the maternalfetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14:353–356
Bazer FW, First NL (1983) First pregnancy and parturition. J Anim Sci 57:425–460
Szekeres-Bartho J, Wegmann TG (1996) A progesteronedependent immunomodulatory protein alters the Th1/Th2 balance. J Reprod Immunol 31:81–95
Awata T, Matsumoto C, Urakami T, Hagura R, Amemiya S, Kanazawa Y (1994) Association of polymorphism in the interferon gamma gene with IDDM. Diabetologia 37:1159–1162
He B, Xu C, Yang B, Landtblom AM, Fredrikson S, Hillert J (1998) Linkage and association analysis of genes encoding cytokines and myelin proteins in multiple sclerosis. J Neuroimmunol 86:13–19
Choi YK, Kwak-Kim J (2008) Cytokine gene polymorphisms in recurrent spontaneous abortions: a comprehensive review. Am J Reprod Immunol 60(2):91–110
Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, D’Alfonso S (2001) Cytokine gene polymorphism in human disease: on-line databases. Genes Immun 2:61–70
Dinarello C (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095
van Mourik MS, Macklon NS, Heijnen CJ (2009) Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment. J Leukoc Biol 85(1):4–19
Robertson SA, Seamark RF, Guilbert LJ, Wegmann TG (1994) The role of cytokines in gestation. Crit Rev Immunol 14:239–292
Librach CL, Feigenbaum SL, Bass KE, Cui TY, Verastas N, Sadovsky Y, Quigley JP, French DL, Fisher SJ (1994) Interleukin-1 beta regulates human cytotrophoblast metalloproteinase activity and invasion in vitro. J Biol Chem 269:493–500
Granowitz EV, Clark BD, Vannier E, Callahan MV, Dinarello CA (1992) Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood 79:2356–2363
Granowitz EV, Vannier E, Poutsiaka DD, Dinarello CA (1992) Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: II. IL-1 receptor antagonist inhibits lipopolysaccharide-induced cytokine synthesis by human monocytes. Blood 79:2364–2369
Raghupathy R (1997) Th1-type immunity is incompatible with successful pregnancy. Immunol Today 18(10):478–482
Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Steinkasserer A, Duff GW (1993) Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 91:403–404
Nair RR, Khanna A, Singh K (2012) MTHFR C677T polymorphism and recurrent early pregnancy loss risk in north Indian population. Reprod Sci 19(2):210–215
Genç MR, Gerber S, Nesin M, Witkin SS (2002) Polymorphism in the interleukin-1 gene complex and spontaneous preterm delivery. Am J Obstet Gynecol 187:157–163
Wang ZC, Yunis EJ, De los Santos MJ, Xiao L, Anderson DJ, Hill JA (2002) T helper 1-type immunity to trophoblast antigens in women with a history of recurrent pregnancy loss is associated with polymorphism of the IL1B promoter region. Genes Immun 3:38–42
Levrant S, Coulam CB, Jeyendran RS (2008) Interleukin 1 receptor antagonist gene polymorphisms are not risk factors for recurrent pregnancy loss: evaluation of couples. Am J Reprod Immunol 60:224–228
Dai MZ, Pan YQ, Xu DP, Chen XJ, Qian RJ, Chen DH, Cui TW, Lin A, Yan WH (2010) IL-1 receptor antagonist gene polymorphism in idiopathic recurrent spontaneous abortion in a Chinese Han population. Int J Immunogenet 37:393–396
Karhukorpi J, Laitinen T, Kivelä H, Tiilikainen A, Hurme M (2003) IL-1 receptor antagonist gene polymorphism in recurrent spontaneous abortion. J Reprod Immunol 58:61–67
Agrawal S, Parveen F, Faridi RM, Prakash S (2012) Interleukin-1 gene cluster variants and recurrent pregnancy loss among North Indian women: retrospective study and meta-analysis. Reprod Biomed Online 24(3):342–351
Clark DA, Arck PC, Chaouat G (1999) Why did your mother reject you? Immunogenetic determinants of the response to environmental selective pressure expressed at the uterine level. Am J Reprod Immunol 41:5–22
Calleja-Agius J, Jauniaux E, Pizzey AR, Muttukrishna S (2012) Investigation of systemic inflammatory response in first trimester pregnancy failure. Hum Reprod 27(2):349–357
Witkin SS, Gerber S, Ledger WJ (2002) Influence of interleukin-1 receptor antagonist gene polymorphism on disease. Clin Infect Dis 34(2):204–209
Barlo NP, van Moorsel CH, Korthagen NM, Heron M, Rijkers GT, Ruven HJ, van den Bosch JM, Grutters JC (2011) Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1β in idiopathic pulmonary fibrosis. Clin Exp Immunol 166(3):346–351
Carter MJ, Jones S, Camp NJ, Cox A, Mee J, Warren B, Duff GW, Lobo AJ, di Giovine FS (2004) Functional correlates of the interleukin-1 receptor antagonist gene polymorphism in the co- lonic mucosa in ulcerative colitis. Genes Immun 5:8–15
Korthagen NM, van Moorsel CH, Kazemier KM, Ruven HJ, Grutters JC (2012) IL1RN genetic variations and risk of IPF: a meta-analysis and mRNA expression study. Immunogenetics 64(5):371–377
Shaarawy M, Nagui AR (1997) Enhanced expression of cytokines may play a fundamental role in the mechanisms of immunologically mediated recurrent spontaneous abortion. Acta Obstet Gynecol Scand 76:205–211
Unfried G, Tempfer C, Schneeberger C, Widmar B, Nagele F, Huber JC (2001) Interleukin 1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage. Fertil Steril 75:683
Linjawi S, Li TC, Laird S, Blakemore A (2005) Interleukin-1 receptor antagonist and interleukin-1 beta polymorphisms in women with recurrent miscarriage. Fertil Steril 83:1549–1552
Gremlich S, Fratta S, Rebellato E, Uras R, Reymondin D, Damnon F, Germond M, Gerber S (2008) Interleukin-1 receptor antagonist gene (IL-1RN) polymorphism is a predictive factor of clinical pregnancy after IVF. Hum Reprod 23:1200
Bid HK, Kumar A, Mishra PK, Mittal RD (2004) Study of interleukin-1 receptor antagonist (IL-1Ra) gene polymorphism in healthy individuals from Northern India. Indian J Clin Biochem 19(2):119–123
Acknowledgments
We are thankful to all the patients and volunteers for providing blood samples. This work was financially supported by the Banaras Hindu University, Varanasi, India and Department of Biotechnology, New Delhi, India.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Nair, R.R., Khanna, A. & Singh, K. Association of interleukin 1 receptor antagonist (IL1RN) gene polymorphism with recurrent pregnancy loss risk in the North Indian Population and a meta-analysis. Mol Biol Rep 41, 5719–5727 (2014). https://doi.org/10.1007/s11033-014-3443-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-014-3443-8