Background
Cervical cancer (CC) is a prevalent malignancy globally, ranking third in terms of occurrence and fourth in terms of mortality among women [
1]. According to global cancer data published by the International Agency for Research on Cancer (IARC) in 2020, there were 604,127 new cases of CC and 341,831 new deaths worldwide [
1]. The primary etiology of CC is attributed to persistent human papilloma virus (HPV) infection, which is detected in nearly 99% of CC cases, with the high-risk subtypes HPV16 and 18 being the most prevalent [
2].
In recent years, there has been a decrease in the global prevalence of CC due to the implementation of CC screening and vaccination programs. However, it is important to note that the incidence of CC still surpasses 85% [
3] and accounts for nearly 90% of deaths in developing nations [
3]. A recent report indicates that China recorded 119,000 newly diagnosed cases of CC in 2020, and the incidence rate continues to rise [
4]. Consequently, CC remains a significant health concern that poses a threat to women’s well-being in China.
A population of patients with rheumatoid arthritis (RA) has been found to have a notable susceptibility to HPV infection and cervical dysplasia, as reported in previous studies [
5]. Extensive cohort studies conducted in Western Europe and North America have demonstrated that female RA patients face a 1.3–1.5 times higher risk of developing significant cervical ectasia compared to women without RA [
6]. Nevertheless, the findings of a meta-analysis yielded contrasting results, indicating that RA patients did not exhibit an elevated risk of developing CC [
5]. Therefore, whether RA patients have an increased risk of CC remains controversial, and further research is needed on this clinical question.
The presence of reverse causality and measurement error in previous observational studies investigating the relationship between RA and CC has hindered the establishment of consistent conclusions. While well-designed randomized controlled trials (RCTs) are regarded as the optimal approach in clinical research to mitigate the limitations of observational studies, they too possess certain constraints. Therefore, in order to enhance the level of evidence-based medicine and ascertain the precise role of RA in CC pathogenesis, further investigation is warranted. A more precise methodology is required for the execution of scientific studies. Mendelian randomization (MR) analysis [
7] is an analytical approach that examines causal connections between genotypes at the genetic level. MR analysis employs genetic variation as an instrumental variable (IV) for the exposure factor in order to evaluate whether alterations in the exposure variable have a direct impact on the outcome, thereby investigating the causal association between the exposure factor and the outcome. Moreover, as a result of the Mendelian random assignment that takes place during the allocation of single-nucleotide polymorphisms (SNPs) to offspring at conception, which consistently happens prior to the development of disease, the susceptibility of analysis using MR to be influenced by exposure is diminished. Consequently, MR analysis is less prone to the constraints encountered in prior observational studies. In this particular investigation, we employed MR analysis to examine the genetic causality between RA and CC, ascertain the risk factors associated with CC development, and furnish fresh evidence regarding the involvement of RA in the progression of CC. We hope to provide clinical evidence for the elucidation of the mechanism of CC development and the prevention and treatment of CC.
Discussion
This study aimed to investigate the causal relationship between RA and the susceptibility to CC using a two-sample MR approach. The findings of this study revealed that RA was significantly associated with an increased risk of CC [OR = 1.096, 95% CI: 1.018–1.180, P = 0.015). These MR results underscore the significance of improving screening and preventive measures for CC in individuals diagnosed with RA, in order to promptly identify both CC and precancerous lesions.
This study is similar to many previous studies showing a 1.5 times higher risk of high-grade cervical atypia and CC in women with RA [
6]. A study by Rojo et al. concluded that autoimmune diseases, such as RA, are a risk factor for CC [
17]. According to Wadstrom et al., CC incidence is higher in women with RA than in the general population over a 12-year follow-up period [
18]. Several studies have indicated a notable increase in antibodies against citrullinated HPV among patients with RA, implying a potential association between HPV and the onset of RA [
19]. Additionally, it has been established that HPV plays a definitive role in the development of CC [
20]. Nevertheless, it is important to note that the majority of existing clinical studies were retrospective in design, rendering them vulnerable to reverse causality and the influence of confounding variables. In this study, MR was used to explore the study of RA and the risk of CC. The findings suggest that patients with RA have a higher risk of developing CC.
According to the findings of the present study, it was observed that a majority of patients diagnosed with RA utilize systemic immunosuppressive or steroid medications [
21]. Furthermore, research has indicated a potential correlation between the utilization of systemic immunosuppressants or steroids and the heightened risk of developing CC. Specifically, the study demonstrates that women with RA who are prescribed immunosuppressants exhibit an increased susceptibility to CC when compared to the general population [
18].
The study identified four SNPs through MR analysis, which corresponded to three genes: HLA-DRB1, HLA-DQB1, and PHTF1. Notably, two of these genes are located in the HLA II region. HLA class II molecules, characterized by CD4 + , play a significant role in both innate and adaptive immune responses and exhibit a complex relationship with cancer risk [
22]. Therefore, it can be inferred that RA-induced CC is likely to be associated with HLA class II molecules. Interleukin-18 (IL-18), produced by various immune and non-immune cells, is known to be involved in the abnormal activation of CD4 + T cells [
23], which is associated with the increased expression of IL-18 in the body. More specifically, IL-18 serves as an IFN-γ inducing factor, directly causing CD4 + T cells and CD8 + T cells to highly express IFN-γ [
24]. The pathogenesis of RA has been linked to the overexpression of IL-18 and the relative deficiency of IL-18-binding protein levels in RA patients [
25]. Since its initial identification, IL-18 has been consistently linked to human HPV infection and CC [
26]. Extensive research has demonstrated that variations in the IL-18 gene can significantly impact its expression and functionality, consequently influencing the susceptibility to CC [
27]. Specifically, specific genetic variants have been found to result in diminished IL-18 expression [
28], thereby elevating the likelihood of developing CC. Conversely, elevated levels of IL-18 have been linked to the eradication of HPV infection and bolstered immune response, consequently diminishing the susceptibility to CC [
26]. Furthermore, IL-18 has been observed to exhibit significant expression in CC cells, with its level of expression being positively correlated with the malignancy extent of CC [
29]. Several investigations have additionally demonstrated that the modulation of IL-18 expression can exert an influence on the proliferation and apoptosis of CC cells [
29]. Furthermore, research has demonstrated that the inhibition of IL-18 binding to its receptor a-chain effectively hinders IL-18-induced interferon-gamma (IFN-γ) production by monocytes and natural killer (NK) cells [
30]. IFN-γ, a key component in the immune response against intracellular infections [
31], is thus implicated in the heightened susceptibility to CC in patients with rheumatoid arthritis, which can be attributed to prolonged usage of immunosuppressive medications and dysregulation of cytokines and chemokines.
This study aimed to investigate the causal relationship between RA and the risk of CC through the application of two-sample MR analysis, which offers several advantages. Firstly, the inclusion of a larger sample size in this study enhances the credibility of the obtained results. Secondly, the utilization of multiple statistical methods, which yield consistent outcomes, ensures the robustness of this study and strengthens the level of certainty in establishing a causal inference. Lastly, in comparison to conventional retrospective studies, this research effectively mitigates the influence of reverse causality and confounding factors. However, there are still some limitations in this study; the databases used in this study were all from the European region, and their global applicability has yet to be demonstrated. Therefore, there is a need to further investigate the relationship between RA and cervical carcinogenesis in other ethnic populations.
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