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.



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