Condyloma acuminatum (CA) is a common sexually transmitted disease, which is caused by human papillomavirus (HPV) infection. HPV is a highly diverse virus and can be classified into over 160 types. HPV infection is also associated with malignant disorders like cervical cancer, penile cancer and their precursors.1 HPV genotype was reported to be associated with high-risk versus intermediate-risk outcome and survival of invasive cervical cancer.2,3 Previous studies have suggested that other factors including host immunogenetics are important in the pathogenesis of these HPV-related diseases.4,5 Some studies have shown that the polymorphisms of human leukocyte antigen (HLA) genes are related with HPV infection.6,7 HLA-G and HLA-DQB1 polymorphisms may represent risk factors in HPV infected subjects.8,9 However, there have been few researches on genetic factors associated with CA or HPV infection.

The innate and cell-mediated immune responses are both crucial in the immunity against viruses, and inflammatory cytokines play key roles in both immune responses through modulating viral replication.10,11 Interleukin (IL)-18 is a member of the IL-1 inflammatory cytokine super family, which is produced primarily by activated macrophages and monocytes. At first, IL-18 was mistakenly believed to be an interferon (IFN)-γ inducing factor12 possessing other major immunomodulatory functions, including the induction and synthesis of IFN-γ in T cells and natural killer cells, stimulating naïve T cells to differentiate into Th1 cells, as well as enhancing killing competence of T cells and natural killer cells.13 Recently, IL-18 has been implicated in host resistance to viral infection and amplification.14,15

The IL-18 gene is positioned on chromosome 11q22.2-q22.3, and has six exons and five introns.16 Single nucleotide polymorphisms (SNPs) in the promoter region of IL-18 have been reported to play a critical role in controlling the IL-18 gene expression by influencing its transcriptional factor binding ability. Two of the most common SNPs, −607C/A and −137G/C, have been shown to be correlated with IL-18 gene transcription and IL-18 protein production, resulting in higher levels of IL-18 in humans.17 Our previous study showed that the serum level of IL-18 in CA patients was significantly higher than in healthy controls.18 These two functional IL-18 SNPs have been investigated in many diseases, including various cancers such as cervical cancer, bladder cancer, oral cancer, and viral diseases such as hepatitis B virus and HPV infections.19–22 However, no research has been conducted on the involvement of IL-18 SNPs in CA.

In this study, for the first time, we investigated the correlation of −607C/A and −137G/C SNPs in the IL-18 gene promoter region with the susceptibility of CA in a Chinese patient cohort. CA patients were further divided into sexual contact group and non-sexual contact group to explore the potential role of IL-18 gene promoter SNPs in CA.

CA, also known as genital warts, is a contagious disease in the genital and peripheral anus region caused by HPV infection. There are two thought-provoking phenomenons: one is that HPV is so common that most people in their sexually active period will be infected at least once in their lives.23 However, 90% of HPV infections are eliminated by the immune system within two years. Second, HPVs could give rise to a series of diseases, including most cervical cancers, most anal cancers, and almost half of head and neck cancers. They are also involved in the development of troublesome benign epithelial lesions, such as CA, bowenoid papulosis, and laryngeal papillomas. These results suggest that host immunological condition and genetic setting may play important roles in the occurrence and development of HPV-related diseases. One study showed that the invariant natural killer T (iNKT) cells might exhibit a vital effect on restraining immunity. iNKT cells were found accumulated in cervical tissues during the onset and development from HPV infection to cervical intraepithelial neoplasia (CIN), demonstrating that iNKT cells and IFN-γ expression could also be associated with the HPV infection period.24 Another study implied that IL-18 played an important role in the process of IFN-γ induction in an immuno-suppressive cutaneous environment resulted from HPV oncogene-actuated hyperplasia.25 Interestingly, chronic IL-18 activation could inhibit iNKT cells,26 and compromised NKT cell activity was observed in CA patients.27 These two earlier studies together might also hint a negative correlation between IL-18 and severity of CA via iNKT cells.

In the network of inflammatory cytokines, IL-18 is a crucial link between innate and adaptive immunity. On the other hand, HPV can also directly impair immunity by disturbing the IFN signal conduction pathway, regulating antigen presentation and subsequently controlling IL-18 biological activity.28 IL-18 may also participate in protective cell-mediated immune reaction against HPV infections, and thus regulate CA development. In our study, we investigated the correlation between specific SNPs in the IL-18 gene promoter and CA in a Chinese cohort. We found that there were no significant differences in genotypic, allelic frequencies of the IL-18 −607C/A, and −137G/C SNPs between overall CA patients and healthy controls. Although a few studies implicated IL-18 in risk of HPV infection in patients with and without cervical intraepithelial lesion or HPV-related cervical squamous cell carcinoma (CSCC),29,30 no correlation between IL-18 −607C/A, 137G/C SNPs and CA had been previously reported. The reason of no dominant differences may be the underpowered sample size or population heterogeneity. It is also possible that there are other SNPs more important for the regulation of gene expression in IL-18.

HPV is mainly transmitted sexually, but it can also be transmitted via non-sexual contact. For example, the presence of CA on the genitals of young children can occasionally be caused by HPVs originated from elsewhere on the body, such as the hands.24 Sharing of swimsuits, underwear or bath towels, and even the non-sexual touching during routine care such as diapering, have been suggested to cause HPV infection. In our study, we explored the relationship of genotype distributions and allelic frequencies among CA patients with sexual contact, non-sexual contact and control group. We first provided direct evidence that IL-18 promoter −137G/C SNP was correlated with NSC CA in patients. Comparison of the IL-18 −137G/C polymorphism allele and genotype frequencies between non-sexual contact and control groups showed a statistically significant increase in the frequencies of the GC, CC genotypes and C allele in NSC CA group.

IL-18 is an important mediator of innate and cell-mediated immunity. Previous study showed that risk of various cancers was significantly elevated when G was mutated to C allele at IL-18 −137G/C polymorphism.31,32 NSC CA patients may have compromised innate and cell-mediated immunity and are thus more susceptible to HPV infections. The statistically significant increase in the frequencies of the GC, CC genotypes and C allele in our study may indicate the conclusion that, polymorphism −137G/C in IL-18 promoter is significantly correlated with risk of CA in NSC patients. However, due to the smaller sample size in NSC CA patients than SC CA patients and healthy controls, more subjects are need for future studies to further verify this conclusion.

The authors declare that they have no competing interests.

Not applicable.