Genetic variations of interleukin-1 and -6 genes and risk of cervical intraepithelial neoplasia☆
Research highlights
► IL-1 and -6 seem to play a key role in immune response and carcinogenesis. ► IL1A −889 is independently associated with the risk of high grade CIN. ► Evaluation of IL-1 SNPs could help to identify patients, who are at risk of high grade CIN.
Introduction
High grade cervical intraepithelial neoplasia (CIN 2–3) is the precursor of cervical cancer, which is the second most common gynecological cancer among women worldwide [1]. It is well known that a high-risk human papillomavirus (HPV) infection is the necessary cause for CIN [2]. As the majority of these infections are transient and do not lead to CIN, an effective host immune response and genetic factors seem to have a major influence on the risk of CIN [3], [4]. Therefore interleukins (IL) seem crucial for the susceptibility of CIN 2–3 as they play a key role in cellular immunity and carcinogenesis.
Interleukin-1 and IL-6 are prominent members of the interleukin family. IL-1 comprises the cytokines IL-1alpha (IL-1a), IL-1beta (IL-1b) and a specific receptor antagonist (IL-1RA) [5]. IL-1a and IL-1b are proinflammatory cytokines involved in the modulation of host response to microbial invasion, inflammation, and tissue injury [6]. Secretion of IL-1 initiates a proinflammatory cascade with the subsequent production of tumor necrosis factor-α, interferon-γ, IL-2 and IL-12. IL-1RA neutralizes IL-1 action by binding to the IL-1 receptors (IL-1RI and IL-1RII) without exerting any effector function [7]. Several studies suggest that IL-1 production is related to the immune response against HPV-associated cervical cancer [8], [9], [10]. IL-6, a phosphorylated glycoprotein, is involved in various physiological and patho-physiological processes such as hematopoiesis, C-reactive protein synthesis and bone metabolism [11], [12]. Moreover IL-6 seems to be crucially involved in HPV-clearance [13], [14].
The role of IL-1 and IL-6 in carcinogenesis and tumor progression has been extendedly studied [15], [16], [17]. The production and release of IL-1 and IL-6 by tumor cells results in an autocrine and paracrine induction of prometastatic genes and subsequently leads to proliferation and prolonged survival in human squamous cancer cells [18], [19], [20]. Clinical studies in cervical cancer patients report that elevated IL-1 and IL-6 serum levels are associated with poor prognosis [21], [22].
The IL-1 gene cluster on chromosome 2q14.2 comprises 3 related genes within a 430-kb region, IL-1A, IL-1B, and IL-1RN, which encode the pro-inflammatory cytokines IL-1a, IL-1b, and their endogenous receptor antagonist IL-1RA, respectively [23]. In vitro and in vivo studies demonstrate that IL1-A and IL1-B gene polymorphisms [24], [25] correspond with altered IL-1a and IL-1b protein expression, respectively [24], [26]. Regarding the IL1 receptor antagonist, the IL1RN allele 2 has been repeatedly associated with changes of the IL-1RA protein expression [27], [28]. The human IL-6 gene is located within a 303 bp region on chromosome 7p21–24 [29]. The common IL-6 promoter G174C gene polymorphism has been repeatedly reported to be associated with IL-6 protein expression [30], [31], [32].
The IL1RN VNTR intron 2, IL1B −511, and IL1B exon 5 + 3953 gene polymorphisms have been reported to be associated with cervical cancer risk and progression [33], [34], [35]. The IL6 promoter − 174 gene polymorphism is associated with risk of cervical cancer in a Brazilian and an Indian cohort [36], [37].
While IL-1 and -6 gene polymorphisms have been extensively studied in cervical cancer, no studies have evaluated these genetic variations in cervical cancer precursor lesions. Therefore we evaluate the association between five common IL-1 and -6 gene polymorphisms and risk of high grade CIN. As the susceptibility to a disease is usually determined by multiple genetic variations, rather than single-locus polymorphisms, we also perform haplotype analysis to test for high-risk combinations of these five polymorphisms.
Section snippets
Patients
Women, who were referred to the Department's outpatient clinic between 2004 and 2009 for cervical dysplasia because of a cytological result “atypical cells of undetermined significance (ASC-UCS)” or higher, were asked to participate at the present study. If the women agreed by signing the informed consent, they were asked to fill out a questionnaire regarding socio-economic factors and sexual behavior (total number of pregnancies, lifetime number of sexual partners, smoking status [yes
Results
Patients' characteristics for women with CIN 2–3 and controls are given in Table 1. Women in the control group were older (mean [standard deviation] 34.6 [12.0] years. vs. 31.1 [7.9]; p = 0.01) than women with CIN 2–3. This finding represents the epidemiologic characteristics of the patients visiting our outpatient clinic for general gynecology, as patients in the control group are older than the patients visiting our outpatient clinic for cervical dysplasia. This difference remained significant
Discussion
In the present study, the single nucleotide polymorphisms IL1A −889 was independently associated with risk of high grade CIN. This is the first time that the association between this polymorphisms and risk of CIN was investigated.
The presence of at least one T allele of IL1A − 889 was associated with a reduced susceptibility of CIN (OR 0.3 [0.1–0.7]). Interestingly, this association was only observed in the multivariable regression model. Therefore we further investigated the discrepancy between
Conflict of interest statement
The authors declare that they have no competing interests.
Acknowledgments
The present study was financially supported by the following research grants: “Medical Scientific Fund of the Mayor of the City of Vienna” and “Hans und Blanca Moser Stiftung.” Special thanks goes to Ingrid Schiebel and Eva Schuster for their critical help in technical assistance.
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Role of IL-1 gene polymorphisms in common solid cancers
2023, Multifaceted Role of IL-1 in Cancer and InflammationPrioritization and Meta-analysis of regulatory SNPs identified IL6, TGFB1, TLR9 and MMP7 as significantly associated with cervical cancer
2022, CytokineCitation Excerpt :However, Qian et al., 2010 had shown that the rs1143627 TC/CC genotype is significantly associated with increased cervical cancer risk in Chinese population [OR = 1.60; 95% CI = 1.16–2.21], whereas Wang et al., 2019 showed that the AA genotype was significantly associated [54,55]. Similarly for the rs16944 polymorphism, literature survey revealed that 8 case-control studies were available from Korean, Egyptian, Austrian, Tunisian, Indian, Bangladeshi and Chinese populations, which have shown association with cervical cancer [54–60]. On performing a meta-analysis on these eight studies with 1596 patients and 1960 controls against 5 models (allele, dominant, recessive, heterozygous and homozygous) we observed that no significant association is present between this polymorphism and cervical cancer.
Cervical Cancer in Women Aged 35 Years and Younger
2016, Clinical TherapeuticsCitation Excerpt :If the aggressiveness and presence of cervical cancer in a young woman is due to a genetic alteration, we would expect that would most likely be seen in regional studies such as the Japanese study compared with the genetically diverse population in the United States. There does appear to be an association of cervical cancer with a large variety of polymorphisms in a wide variety of genes, including genes that regulate immunity and susceptibility,29 cytokine production,30,31 angiogenesis, tumor suppressor pathways,32,33 and signal transducer and activator of transcription pathways.34 Investigations are ongoing to identify genetic alterations that may make women less likely to clear persistent HPV infections and more susceptible to the development of cervical cancer.
Lessons and implications from association studies and post-GWAS analyses of cervical cancer
2015, Trends in GeneticsAssociation of an insertion/deletion polymorphism in IL1A 3'-UTR with risk for cervical carcinoma in Chinese Han Women
2014, Human ImmunologyCitation Excerpt :Since the immune response plays an important role in human carcinogenesis, polymorphisms in genes that potentially affect both cytokine production and the immune response are candidates to influence susceptibility to CC [15]. Emerging evidence has demonstrated the association between interleukin-1 gene polymorphisms IL1A-889 and the risk of high grade CIN (cervical intraepithelial neoplasia) which is considered as cervical precancerosis, suggested a crucial role interleukin-1α play in HPV-related immune response and carcinogenesis [36]. Previous studies have identified that the allele I of this insertion/deletion polymorphism disrupted a binding site of microRNA-122 and microRNA-378, thereby increasing transcription of IL-1α.
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Grant support: C. Grimm and S. Leodolter: Work funded by “Medical Scientific Fund of the Mayor of the City of Vienna”. C. Grimm: Work funded by “Hans und Blanca Moser Stiftung”.