POLYMORPHISM OF THE IL13 GENE MAY BE ASSOCIATED WITH UTERINE LEIOMYOMAS IN SLOVENIAN WOMEN
Krsteski J, Jurgec S, Pakiž M, But I, Potočnik U,
*Corresponding Author: Professor Uroš Potočnik, Ph.D., Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia. Tel: +386-2-2345-854, Fax: +386-2- 2345-820, E-mail: uros.potocnik@um.si
page: 51

INTRODUCTION

The most common cause of solid pelvic tumors and an indication for gynecological surgery in women are uterine leiomyomas (ULM), also known as uterine fibroids. Approximately 20.0-40.0% of women during their reproductive period have ULM [1]. These are benign fibrous tumors descendent from a single uterine smooth muscle cell [2]. Clinical problems associated with ULM are excessive bleeding and secondary anemia, increased urinary frequency, pelvic discomfort, bladder and bowel dysfunction, a sensation of pressure in the lower abdomen and pain during intercourse [3]. During the reproductive period of women, infertility and recurrent spontaneous abortions, fetal anomalies and fetal malpresentation have also been associated with leiomyomas [4]. Despite their high prevalence, the etiopathogenesis of the ULM remains unclear. Several predisposing factors, including race, heredity, reproductive factors and lifestyle have been linked to ULM [5]. Furthermore, ULM is a complex disease, which means that interactions between multiple genes, hormones, growth factors, interleukins (ILs), and environment are involved in the tumorigenesis of ULM [6]. Some molecules, including ILs and their receptors, may influence tumor biology, tumor immunology and immuno-surveillance by mediating abnormal cell-cell signaling in the tumor micro-environment [7]. Several studies suggest that ILs and other cytokines are involved in the development of a variety of neoplasms such as glioma [8], gastric cancer [9] and gynecological neoplasms [10]. Moreover, elevated levels of ILs have been found in the uterine cavity of patients with ULM [11]. Interleukin-related single nucleotide polymorphisms (SNPs) might affect IL production and influence the course of the illness, as well as both disease resistance and susceptibility [12]. Thus, certain risk alleles may indicate an individualís degree of genetic predisposition to disease risk. Previous studies have investigated the association between IL1B, IL1Ra, IL2, IL4, IL8, IL12, IL18 and IL12RB1 gene polymorphisms and the occurrence of ULM [13-16]. Some of these studies reported a significant association between IL4, IL1B and IL12RB1 and ULM development [13-15]. In addition, clinical and genetic differences have been noted between subtypes of solitary and multiple ULM [17,18]. In this study, however, we focused on cytokines derived from T helper type 2 (Th2) cells (IL-4, IL-12 and IL-13), hypothesizing that they might be good candidates as they are involved in the avoidance of tumor immuno-surveillance at the molecular level. The IL-23 and IL-12 are closely associated with Th17-helper phenotype and play a role in suppressing tumor immune response [19]. Furthermore, some functional studies showed effect of SNPs in IL4 and IL4R genes on their expression, particularly SNP in the IL4 gene correlates with enhanced IL-4 activity [20] and SNP in the IL4R gene functionally impacts the signaling and upregulating of the receptorís response to IL-4, which in turn results in activation of the STAT6 pathway [21]. Recently, clinical and genetic differences were noted between subtypes of solitary and multiple ULM [17,18]. The aim of our study was to further evaluate polymorphisms in genes coding for ILs, specifically SNPs with a known functional role in IL expression, including IL4 and IL4R, SNPs with previously contradictory results in different populations, including IL12RB1, as well as SNPs previously not yet analyzed for ULM, including IL12B, IL23R and IL13. In addition, we also investigated possible genetic differences between solitary and multiple subtypes of ULM.



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