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
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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 individual’s
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 receptor’s 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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