European Journal of Obstetrics & Gynecology and Reproductive Biology
Interleukin-18 gene promoter polymorphisms and recurrent spontaneous abortion
Introduction
Recurrent spontaneous abortion (RSA), the occurrence of three or more consecutive pregnancy losses in the first trimester, occurs in approximately 1% of pregnant women worldwide. A series of etiological factors responsible for RSA are divided into the embryologically driven causes (abnormal embryonic karyotypes) and maternally driven ones affecting the endometrium and/or placenta (luteal phase defect, hyperprolactinemia, hyperhomocysteinemia, uterine anomalies, coagulation disorders, autoimmune diseases, endocrine disorders, and endometrial defects) [1]. Despite these well-established pathophysiological mechanisms, the exact underlying etiology is still poorly understood in up to 50% of RSA cases. Recent studies shed light on the immune mechanism as a cause of a proportion of these idiopathic pregnancy losses [1], [2], [3], [4].
Production of cytokines and the distribution of the immune cells during pregnancy appeared to be critical in pregnancy outcome [1], [2], [3], [4]. Interleukin (IL)-18, initially known as an interferon (IFN)-γ inducing factor, is a member of the IL-1 cytokine family, which is produced by a variety of immune and non-immune cells. It is a unique cytokine capable of enhancing either Th1 or Th2 differentiation depending on the immunologic milieu. It also augments the cytotoxic actions of natural killer and CD8+ T cells [5], [6].
The IL-18 gene is expressed by human chorion and deciduas and is thereby present at the materno-fetal interface [7], [8]. It is also detectable in amniotic fluid and maternal and umbilical cord blood samples [9]. The IL-18 level increases from the first trimester until the onset of labor. It further rises at labor onset and remains constant until the third day of puerperium [10].
The role of IL-18 in pregnancy, labor onset, and pregnancy complications has recently been proposed [10], [11]. Pre-pregnancy levels of IL-18 appear to affect the outcome of the next pregnancy [3], [4] and locally secreted IL-18 is shown to be able to control the implantation process and to cause implantation failure in cases of absence or over-activation [12]. Correspondingly, increased serum and placental levels of IL-18 in complicated pregnancies including preeclampsia, premature rupture of membranes (PROM), acute fatty liver of pregnancy, and fetal growth restriction are observed [7], [9], [10], [11]. Moreover, the levels of IL-18 in cervical mucus and amniotic fluid are higher in women with preterm labor [13].
IL-18 gene expression seems to be regulated by two single nucleotide polymorphisms (SNPs) at positions −607 and −137 in the promoter region of the gene [14]. Furthermore, an individual's IL-18 genotype has been shown to be relevant to several autoimmune disorders such as type 1 diabetes (T1D), juvenile idiopathic arthritis (JIA), and rheumatoid arthritis (RA) [15], [16], [17].
The present study attempts to address the question of whether the polymorphisms of the IL-18 gene promoter at positions −607 (C/A) and −137 (G/C) are associated with the susceptibility of southern Iranian women to RSA.
Section snippets
Subjects
A total of 102 unrelated women (mean age 26.85 ± 12.8 years) with at least three sequential abortions (mean 3.5) and 103 unrelated healthy pregnant female regional volunteers (mean age 25.8 ± 14.8) with at least two successful pregnancies were enrolled in this case-control study. Patients with anatomical, hormonal, chromosomal, infectious, and autoimmune causes of RSA were excluded. The anatomical abnormalities were detected by hysterosalpingography and ultrasound; karyotypes of patients were
Results
Neither patients nor control genotype frequencies significantly differed from those expected according to the Hardy–Weinberg equilibrium (data not shown).
As shown in Table 1, the frequency of the IL-18 gene polymorphism at position −607 showed that the genotype and allele frequencies did not significantly differ between the patient group and the healthy controls (p = 0.25 and p = 0.98, respectively,). The frequencies of CC, CA, and AA genotypes were, in turn, 36.3%, 22.5%, and 41.2% in patients
Discussion
In normal pregnancy a transient depression of maternal cell-mediated immunity is required to prevent the immunological rejection of the semi-allogenic fetus. The hallmark of this immune tolerance is an alteration in T cell responses through a shift from Th1- to Th2-type cytokines. Thus, a down-regulation of Th1 type activity and an enhancement of Th2 reactivity ensure a successful pregnancy, an opposite circumstance to that reported to be the case for RSA patients [1], [2], [3], [4], [19], [20]
Acknowledgments
The authors thank Shirin Farjadian (Department of Immunology, School of Medicine, Shiraz, Iran) for her assistance with the statistical analyses. This work was financially supported by a grant from Shiraz University of Medical Sciences (Grant No. 82-1751) and by Shiraz Institute for Cancer Research.
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