Abstract
Purpose
Pre-eclampsia is a relatively common pregnancy disorder. Serum concentrations of certain pro-inflammatory molecules and cytokines like interleukin-23 may affect the pathogenesis of pre-eclampsia. The interleukin-23 receptor (IL-23R) gene plays an important role in the progression of inflammatory and autoimmune diseases and IL-23 polymorphisms might influence the susceptibility of pre-eclampsia. The aim of the recent study was to establish the association between IL-23R gene polymorphisms and the susceptibility for developing of pre-eclampsia.
Methods
One hundred and fifty-eight pregnant patients with pre-eclampsia and 153 controls were genotyped using RFLP-PCR and AS-PCR. Also, an in silico analysis was performed to predict possible effects of these variations on IL-23R mRNA and protein structures.
Results
The frequency of the AG genotype of rs11209026 is related to a higher risk of pre-eclampsia. The mutant C and A allele in rs10889677 and rs11209026 SNPs, respectively, are correlated with the risk of pre-eclampsia and they are more frequent in severe late onset PE. We found higher frequency of the haplotype CG in patients with pre-eclampsia in comparison to healthy controls, as well as, the CG haplotype frequency significantly increased the risk of PE in severe, early onset, and late onset sub-groups. The results of computational analysis predicted rs11209026 and rs10889677 SNPs as functional variations, which can influence IL-23R mRNA and protein.
Conclusions
The results of present study show positive association between polymorphisms in the IL-23R gene and pre-eclampsia. Therefore, the presence of IL-23R rs11209026, rs10889677 polymorphism might be markers for the genetic susceptibility to pre-eclampsia.
Similar content being viewed by others
References
Steegers EA, Von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376(9741):631–44.
Redman CW, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic inflammatory response—a review. Placenta. 2003;24:S21–7.
Redman CW, Sargent IL. Placental stress and pre-eclampsia: a revised view. Placenta. 2009;30:38–42.
Myers J, Mires G, Macleod M, Baker P. In preeclampsia, the circulating factors capable of altering in vitro endothelial function precede clinical disease. Hypertension. 2005;45(2):258–63.
Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol. 1999;180(2):499–506.
Jahantigh D, Mousavi M, Forghani F, Javan MR, Movahedinia S, Rezaei M. Association between maternal circulating IL-27 levels and preeclampsia. Cytokine. 2018;102:163–7.
Fu B, Tian Z, Wei H. TH17 cells in human recurrent pregnancy loss and pre-eclampsia. Cell Mol Immunol. 2014;11(6):564–70.
Arngrimsson R, Bjornsson S, Geirsson RT, Bjornsson H, Walker JJ, Snaedal G. Genetic and familial predisposition to eclampsia and preeclampsia in a defined population. Int J Gynecol Obstet. 1991;35(2):191–2.
Chesley LC, Cooper DW. Genetics of hypertension in pregnancy: possible single gene control of pre-eclampsia and eclampsia in the descendants of eclamptic women. BJOG Int J Obstet Gynaecol. 1986;93(9):898–908.
Adams EM, Finlayson A. Familial aspects of pre-eclampsia and hypertension in pregnancy. Obstet Gynecol Surv. 1962;17(3):350–1.
Haram K, Mortensen JH, Nagy B. Genetic aspects of preeclampsia and the HELLP syndrome. J Pregnancy. 2014;2014:1–13.
Schmella MJ, Roberts JM, Conley YP, Ren D, Storvold GL, Ingles SA, et al. Endoglin pathway genetic variation in preeclampsia: a validation study in Norwegian and Latina cohorts. Pregnancy Hypertens. 2018;12:144–9.
Soellner L, Kopp KM, Mütze S, Meyer R, Begemann M, Rudnik S, et al. NLRP genes and their role in preeclampsia and multi-locus imprinting disorders. J Perinat Med. 2018;46(2):169–73.
Gray KJ, Saxena R, Karumanchi SA. Genetic predisposition to preeclampsia is conferred by fetal DNA variants near FLT1, a gene involved in the regulation of angiogenesis. Am J Obstet Gynecol. 2018;218(2):211–8.
Williams RR, Hunt SC, Hopkins PN, Wu LL, Lalouel JM. Evidence for single gene contributions to hypertension and lipid disturbances: definition, genetics, and clinical significance. Clin Genet. 1994;46(1):80–7.
Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, et al. Cytokine gene polymorphism in human disease: on-line databases, supplement 1. Genes Immun. 2001;2(2):61–70.
Vural P, Degirmencioglu S, Saral NY, Demirkan A, Akgul C, Yildirim G, et al. Tumor necrosis factor α, interleukin-6 and interleukin-10 polymorphisms in preeclampsia. J Obstet Gynaecol Res. 2010;36(1):64–71.
Faisel F, Romppanen EL, Hiltunen M, Helisalmi S, Punnonen K, Salonen J, et al. Polymorphism in the interleukin 1 receptor antagonist gene in women with preeclampsia. J Reprod Immunol. 2003;60(1):61–70.
Saarela T, Hiltunen M, Helisalmi S, Heinonen S, Laakso M. Polymorphisms of interleukin-6, hepatic lipase and calpain-10 genes, and preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2006;128(1–2):175–9.
Hollis-Moffatt JE, Merriman ME, Rodger RA, Rowley KA, Chapman PT, Dalbeth N, et al. Evidence for association of an interleukin 23 receptor variant independent of the R381Q variant with rheumatoid arthritis. Ann Rheum Dis. 2009;68(8):1340–4.
Zhang XY, Zhang HJ, Zhang Y, Fu YJ, He J, Zhu LP, et al. Identification and expression analysis of alternatively spliced isoforms of human interleukin-23 receptor gene in normal lymphoid cells and selected tumor cells. Immunogenetics. 2006;57(12):934–43.
Xavier JM, Shahram F, Davatchi F, Rosa A, Crespo J, Abdollahi BS, et al. Association study of IL10 and IL23R–IL12RB2 in Iranian patients with Behcet's disease. Arthritis Rheum. 2012;64(8):2761–72.
Jahantigh D, Colagar AH, Salimi S. Genetic polymorphisms and haplotypes of the DJ-1 gene promoter associated with the susceptibility to male infertility. J Assist Reprod Genet. 2017;34(12):1673–82.
Salimi S, Nakhaee A, Jafari M, Jahantigh D, Sandooghi M, Zakeri Z, et al. Combination effect of GSTM1, GSTT1 and GSTP1 polymorphisms and risk of systemic lupus erythematosus. Iran J Public Health. 2015;44(6):814–21.
Salimi S, Keshavarzi F, Mohammadpour-Gharehbagh A, Moodi M, Mousavi M, Karimian M, et al. Polymorphisms of the folate metabolizing enzymes: association with SLE susceptibility and in silico analysis. Gene. 2017;637:161–72.
Mohammadpour-Gharehbagh A, Salimi S, Keshavarzi F, Saeidian F, Mousavi M, Teimoori B, et al. Genetic variants in 3′-UTRs of MTHFR in the pregnancies complicated with preeclampsia and bioinformatics analysis. J Cell Biochem. 2018;119(1):773–81.
Jahantigh D, Hosseinzadeh Colagar A. XRCC5 VNTR, XRCC6 -61C>G, and XRCC7 6721G>T gene polymorphisms associated with male infertility risk: evidences from case-control and in silico studies. Int J Endocrinol. 2017;2017(4795076):1–16.
Yong YO, Lin HE. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15(2):97–8.
Perez-Sepulveda A, Torres MJ, Khoury M, Illanes SE. Innate immune system and preeclampsia. Front Immunol. 2014;5:244.
de Lima TH, Sass N, Mattar R, Moron AF, Torloni MR, Franchim CS, et al. Cytokine gene polymorphisms in preeclampsia and eclampsia. Hypertens Res. 2009;32(7):565.
Mohajertehran F, Afshari JT, Rezaieyazdi Z, Ghomian N. Association of single nucleotide polymorphisms in the human tumor necrosis factor-α and interleukin 1-β genes in patients with pre-eclampsia. Iran J Allergy Asthma Immunol. 2012;11(3):224–9.
Li J, Liu M, Zong J, Tan P, Wang J, Wang X, et al. Genetic variations in IL1A and IL1RN are associated with the risk of preeclampsia in Chinese Han population. Sci Rep. 2014;4:5250.
Yalcin B, Atakan N, Dogan S. Association of interleukin-23 receptor gene polymorphism with B ehçet disease. Clin Exp Dermatol. 2014;39(8):881–7.
Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–3.
Rueda B, Orozco G, Raya E, Fernandez-Sueiro JL, Mulero J, Blanco FJ, et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann Rheum Dis. 2008;67:1451–4.
Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 2008;4:e1000041.
Jiang Z, Hennein L, Tao Y, Tao L. Interleukin-23 receptor gene polymorphism may enhance expression of the IL-23 receptor, IL-17, TNF-α and IL-6 in Behcet’s disease. PLoS One. 2015;10(7):e0134632.
Pidasheva S, Trifari S, Phillips A, Hackney JA, Ma Y, Smith A, et al. Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS One. 2011;6(10):e25038.
Sarin R, Wu X, Abraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc Natl Acad Sci. 2011;108(23):9560–5.
Hazlett J, Stamp LK, Merriman T, Highton J, Hessian PA. IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis. Genes Immun. 2012;13(3):282–7.
Huber AK, Jacobson EM, Jazdzewski K, Concepcion ES, Tomer Y. Interleukin (IL)-23 receptor is a major susceptibility gene for graves’ ophthalmopathy: the IL-23/T-helper 17 axis extends to thyroid autoimmunity. J Clin Endocrinol Metab. 2008;93(3):1077–81.
Zwiers A, Kraal L, van de Pouw Kraan TC, Wurdinger T, Bouma G, Kraal G. Cutting edge: a variant of the IL-23R gene associated with inflammatory bowel disease induces loss of microRNA regulation and enhanced protein production. J Immunol. 2012 Jan;18:1101494.
Wang H, Guo M, Liu F, Wang J, Zhou Z, Ji J, et al. Role of IL-17 variants in preeclampsia in Chinese Han women. PLoS One. 2015;10(10):e0140118.
Lau SY, Guild SJ, Barrett CJ, Chen Q, McCowan L, Jordan V, et al. Tumor necrosis factor-alpha, interleukin-6, and interleukin-10 levels are altered in preeclampsia: a systematic review and meta-analysis. Am J Reprod Immunol. 2013;70(5):412–27.
Funding
This study supported by grant number 171/94 (Zbmu.1.REC.1396.25) from the Zabol University of Medical Sciences.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Jahantigh, D., Forghani, F. & Zidanloo, S.G. Interleukin-23 receptor (IL-23R) gene polymorphisms and haplotypes associated with the risk of preeclampsia: evidence from cross-sectional and in silico studies. J Assist Reprod Genet 36, 1523–1536 (2019). https://doi.org/10.1007/s10815-019-01479-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-019-01479-w