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
|
|
DISCUSSION
In the present case-control study, we investigated
the associations among six SNPs in selected candidate
cytokine genes and the risk of ULM in the Slovenian
population. Results of our study suggest that an association
of ULM with rs20541 (IL13) exists, but for the other
analyzed candidate SNPs in selected genes, we could not
confirm association with ULM development in Slovenian
women. Our study showed that SNP rs20541 in the IL13
gene is associated with a significantly decreased risk of
ULM development. The presence of the TT genotype of
IL13 rs20541 SNP may have a protective role against ULM
development in Slovenian women. So far, an association
between rs20541 (IL13) and some tumors such as renal
cell carcinoma [26], bladder cancer [27] and glioblastoma
[23] has been reported, but no study to date reports the
relationship between rs20541 (IL13) and the presence of
ULM. Chu et al. [26] showed the same protective effect of the rs20541 (IL13) TT genotype for renal cell carcinoma
development in a Chinese population. The SNP
rs20541 (IL13) is a functional polymorphism located in
exon 4, conferring a change in the amino acid sequence
from arginine (Arg) to glutamine (Gln) at codon 130 and
it could influence the transcriptional expression of IL-13
[26]. Graves et al. [28] demonstrated that the rs20541
(IL13) A allele (Gln) compromises IgE production and
elevated serum IgE levels in 1399 children from three
different populations. Several epidemiological studies
suggest an inverse association between IgE levels and
the risk of glioma [29,30], non-Hodgkin lymphoma [30]
and pancreatic cancer [31]; however, to date, there are
no epidemiological studies available on the relationship
between IgE levels and ULM. The IL13 gene encodes
IL-13, a pleiotropic Th2 cytokine secreted by many cell
types, but especially activated T-cells. Interleukin-13 plays
a critical role in many aspects of allergic reaction onset
by inducing IgE synthesis [32]. A gene expression study
detected over-expression of IL13 in ULM compared with
myometrial tissue [33], which increased the expression of
tumor necrosis factor-α (TNF-α), one of the leiomyoma
growth factors [34]. The IL13 gene also caused overexpression
and release of matrix metallo-proteinases required
for promoting cell proliferation and invasion of tumors
[35]. In some tumors, IL-13 inhibits tumor immuno-surveillance
by acting as a tumor cell growth factor [36].
Terabe et al. [37] demonstrated that IL-13 is necessary for
down-regulation of tumor immuno-surveillance in a tumor
model through the IL-4R-STAT 6 pathway. Furthermore,
natural killer T (NKT) cells in response to tumor growth,
could produce IL-13 and induce myeloid cells to secrete
transforming growth factor-β (TGF-β) that inhibits tumor
immuno-surveillance in several mouse tumor models [38].
Most published association studies in ULM so far used as
a control group general population. However, as there are
many women in the general population with undetected
ULM, estimated to be around 9.0% [39], it is important to
include as many women as possible with proven absence
of ULM in the control group, as we did in our study. It
should be acknowledged that the limitation of the study
was the relatively low number of participants because high
prevalence of the disease would call for a large sample
size. Nonetheless, the strength of the present study was a
precise selection of participants with regard to the presence
of ULM.
In our study, we also analyzed SNPs in other IL genes,
IL4, IL4R, IL12RB1, IL12B and IL23R. However, no statistically
significant associations has been found between
different genotypes and ULM. The IL-13 and IL-4 have
similar immunoregulatory functions and share a common
IL-4R chain on their receptors [40].They play a critical role in the down-regulation of anti-tumor immunity [40].
Both, or at least one copy of the T allele in the rs2070874
(IL4) polymorphism is associated with higher IL-4 serum
levels [20]. The study by Sosna et al. [14] tested the same
rs2070874 (IL4) polymorphism and they observed an association
with the risk for ULM.
An association between rs1801275 (IL4R) and a
lower age at first sexual intercourse in solitary ULM, and
between rs1801275 (IL4R) and age at diagnosis in the
group of patients with multiple ULM has been found.
Likewise, a recent genome-wide association study of
125,667 UK Biobank participants identified 38 loci associated
with age at first sexual intercourse with several
of these loci having associations with other reproductive
and behavioral traits, such as age at first birth, number of
children, irritable temperament and risk-taking propensity
[41]. Our observations could be explained by the fact that
a lower age at first sexual intercourse presents a higher
risk of contracting sexually transmitted diseases (STD).
Another possibility is that hormonal factors associated
with perimenopause and/or the culmination after 20-30
years of stimulation by sex hormones could predispose
individuals toward ULM occurrence [6].
For the first time, we provide evidence that rs1801275
(IL4R) is a possible contributor to different age at diagnosis
of patients with multiple ULM. Our data suggest that
carriers of the AA or AG genotypes may exhibit both a
later onset of the disease and a higher risk for developing
multiple ULM. Additionally, logistic regression confirmed
a codependent association of rs1801275 in IL4R, adenomyosis,
positive family history and an earlier menarche
in patients with multiple ULM. Some in vitro data suggest
a common pathogenetic mechanisms in adenomyosis and
ULM [42]. Another well-known risk factor associated with
ULM is familial predisposition, which increases the risk
of ULM in female relatives of women with ULM [43].
Early onset of menarche increases the overall number of
myometrium cell divisions resulting in an increased chance
of mutation within some genes expressed in the myometrium
[44]. In our study, we showed that in multiple ULM
patients, CT and TT genotypes of rs20541 (IL13) additionally
predispose patients to lower E2 levels compared to
the CC genotype. The 17β-estradiol (E2) is an established
stimulator of ULM growth through binding to the α and
β estrogen receptors subtypes (ER) and upregulates the
gene expression of multiple growth factors [45]. Shao et
al. [18] demonstrated that 17β-estradiol concentrations
were lower in multiple ULM compared to solitary ULM.
In conclusion, our study suggests that the polymorphism
rs20541 in the IL13 gene may be associated with a
decreased risk for ULM development. Additionally, SNP
rs1801275 in the IL4R gene predisposes the risk for solitary
ULM in patients with a lower age at first sexual intercourse
and a risk for multiple ULM in patients with earlier onset
of disease. Further research on a larger sample size in
ethnically diverse populations, including a subsequent
functional evaluation, is warranted. Currently, there are not
enough data on ULM in association to the selected genes to
perform meta-analysis. However, when more association
studies of these candidate SNPs have been accumulated
in the future, the meta-analysis will be possible and our
study is an important step toward this goal.
|
|
|
|
 |
Number 27
VOL. 27 (2), 2024 |
Number 27
VOL. 27 (1), 2024 |
Number 26
Number 26 VOL. 26(2), 2023 All in one |
Number 26
VOL. 26(2), 2023 |
Number 26
VOL. 26, 2023 Supplement |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
