Causal relationship between human papillomavirus and 4 gynecological diseases：two-sample Mendelian randomization study

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Data may be preliminary. 10 February 2025 V1 Latest version Share on Causal relationship between human papillomavirus and 4 gynecological diseases：two-sample Mendelian randomization study Authors : Zixun Zhuang 0000-0001-9708-4439 , Xian Ge , Ye-man Wang , Ting-ting Shang , and Qing-ling Ren [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173917802.23070718/v1 427 views 141 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective: Human papillomavirus (HPV) is a widespread sexually transmitted infection primarily affecting women. While its link to cervical cancer is well-established, its potential role in other gynecological diseases, such as polycystic ovarian syndrome (PCOS), irregular menstruation (IM), endometrial cancer (EC), and endometriosis, remains underexplored. Observational studies may be subject to residual confounding, but Mendelian randomisation (MR) utilises genetic variants as instrumental variables to strengthen causal inference and mitigate confounding bias. Design: A two-sample MR study. Setting: Summary statistics from published genome-wide association studies (GWAS) in European ancestry populations. Population or sample: Genetic instruments for HPV susceptibility were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS database. Methods: Inverse-variance weighted (IVW) MR was used to assess the causal association between HPV and gynecological diseases. Sensitivity analyses, including weighted median and MR-Egger, were performed to assess robustness. Steiger tests were conducted to confirm the direction of causality. Main outcome measures: Female-specific genetic association estimates for gynecological diseases were extracted from large-scale GWAS datasets. Results: Genetically predicted HPV susceptibility was associated with an increased risk of EC (odds ratio [OR] 1.0973, 95% confidence interval [CI] 1.0030–1.2005, P = 0.0429) and endometriosis (OR 1.0610, 95% CI 1.0029–1.1225, P = 0.0392). Scatter plots and forest plots supported HPV as a risk factor for EC and endometriosis. Sensitivity analyses indicated no significant heterogeneity or horizontal pleiotropy. Each single nucleotide polymorphism (SNP) had a minimal influence on the overall results. Steiger tests confirmed the validity of the causal direction. However, no causal relationship was found between HPV and PCOS or IM. Conclusions: This study provides evidence that genetically predicted HPV susceptibility is a risk factor for EC and endometriosis, while no causal relationship was identified for PCOS or IM. These findings offer novel insights into HPV-related gynecological disease prevention and treatment strategies. Causal relationship between human papillomavirus and 4 gynecological diseases：two-sample Mendelian randomization study Zi-xun Zhuang 1,2* , Xian Ge 1,2* , Ye-man Wang 1 , Ting-ting Shang 1,2 , Qing-ling Ren 1,2✉ 1 Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China 2 The Chinese Clinical Medicine Innovation Center of Obstetrics, Gynecology, and Reproduction in Jiangsu Province, Nanjing, Jiangsu, China * Zi-xun Zhuang and Xian Ge contributed equally to this work ✉Correspondence : Qing-ling Ren. Email: [email protected] Funding: National Natural Science Foundation of China (Grant No. 82074478), Key program of Administration of Traditional Chinese Medicine of Jiangsu Province, China (Grant No. ZX202102), Jiangsu Province Leading Talents Cultivation Project for Traditional Chinese Medicine（Grant No. SLJ0307） Keywords: human papillomavirus | endometrial cancer | endometriosis | polycystic ovarian syndrome | irregular menstruation Objective: Human papillomavirus (HPV) is a widespread sexually transmitted infection primarily affecting women. While its link to cervical cancer is well-established, its potential role in other gynecological diseases, such as polycystic ovarian syndrome (PCOS), irregular menstruation (IM), endometrial cancer (EC), and endometriosis, remains underexplored. Observational studies may be subject to residual confounding, but Mendelian randomisation (MR) utilises genetic variants as instrumental variables to strengthen causal inference and mitigate confounding bias. Design: A two-sample MR study. Setting: Summary statistics from published genome-wide association studies (GWAS) in European ancestry populations. Population or sample: Genetic instruments for HPV susceptibility were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS database. Methods: Inverse-variance weighted (IVW) MR was used to assess the causal association between HPV and gynecological diseases. Sensitivity analyses, including weighted median and MR-Egger, were performed to assess robustness. Steiger tests were conducted to confirm the direction of causality. Main outcome measures: Female-specific genetic association estimates for gynecological diseases were extracted from large-scale GWAS datasets. Results: Genetically predicted HPV susceptibility was associated with an increased risk of EC (odds ratio [OR] 1.0973, 95% confidence interval [CI] 1.0030–1.2005, P = 0.0429) and endometriosis (OR 1.0610, 95% CI 1.0029–1.1225, P = 0.0392). Scatter plots and forest plots supported HPV as a risk factor for EC and endometriosis. Sensitivity analyses indicated no significant heterogeneity or horizontal pleiotropy. Each single nucleotide polymorphism (SNP) had a minimal influence on the overall results. Steiger tests confirmed the validity of the causal direction. However, no causal relationship was found between HPV and PCOS or IM. Conclusions: This study provides evidence that genetically predicted HPV susceptibility is a risk factor for EC and endometriosis, while no causal relationship was identified for PCOS or IM. These findings offer novel insights into HPV-related gynecological disease prevention and treatment strategies. 1 | Introduction Human papillomavirus (HPV) is a highly prevalent group of over 200 related viruses that primarily infect epithelial cells of the skin and mucosal membranes [1, 2] . As one of the most common sexually transmitted infections, nearly 80% of sexually active individuals will become infected with HPV at some point in their lives [3] . While most HPV infections resolve spontaneously, persistent infection with high-risk HPV types, such as HPV-16 and HPV-18, is closely associated with various malignancies, most cancer [4, 5] . In addition to its well-established oncogenic role, the potential contribution of HPV to other gynecological diseases, mediated through chronic infection, immune modulation, and its effects on the reproductive system, remains a subject of ongoing investigation [6, 7] . This study examines four major gynecological diseases: polycystic ovarian syndrome (PCOS), irregular menstruation (IM), endometrial cancer (EC), and endometriosis. These conditions not only represent significant health concerns due to their high prevalence but also have substantial implications for women’s reproductive health [8-11] . However, the role of HPV in their pathogenesis remains inadequately explored. PCOS affects approximately 6-12% of women worldwide and is characterized by irregular menstrual cycles, hyperandrogenism, and polycystic ovaries[12]. Some studies have explored the potential role of HPV in modulating inflammatory responses, which are also a hallmark of PCOS[13]. However, direct evidence linking HPV infection to the chronic inflammation observed in PCOS remains limited. Irregular menstruation (IM) refers to menstrual cycles that deviate from the typical 28-day pattern, often due to hormonal disruptions or other gynecological disorders [14] . Although research on the connection between HPV and IM is sparse, HPV’s ability to induce chronic inflammation and alter immune responses could potentially contribute to menstrual irregularities, particularly through its effects on the cervix or endometrial tissue [15] . Endometrial cancer (EC) is a common gynecological malignancy, with its incidence steadily rising [11] . Major risk factors for EC include obesity, prolonged estrogen exposure, and diabetes [16] . While no definitive link has been established between HPV infection and EC, emerging studies suggest that persistent HPV infection might play a role in endometrial carcinogenesis [17] . This may occur through mechanisms similar to those observed in cervical cancer, such as chronic inflammation and immune dysregulation [18] . Endometriosis, affecting around 10% of women globally, is characterized by the growth of endometrial-like tissue outside the uterus, which often leads to pelvic pain and infertility[19]. The pathophysiology of endometriosis is complex, involving genetic, immune, and hormonal factors[20]. While the direct involvement of HPV in the development of endometriosis remains uncertain, the virus’s potential to induce immune responses and inflammation in the pelvic region could influence its progression, warranting further investigation[21]. This study utilizes Mendelian randomization (MR), a robust statistical method that employs genetic variants as instrumental variables to infer causal relationships between exposures and outcomes, thus minimizing confounding and reverse causality[21]. MR has been effectively applied in numerous studies to investigate causal relationships, including the links between genetic variants and diseases such as cardiovascular conditions and cancers[22]. By applying MR, this study aims to explore the causal relationship between HPV infection and the aforementioned gynecological diseases, potentially providing novel insights into their pathophysiology and informing future prevention strategies. 2 | Method 2.1 | Data collection The relevant eQTL data of MR was acquired from IEU open GWAS database (https://gwas.mrcieu.ac.uk/). The prot-c-2623_54_4 was data for HPV with 501,428 single nucleotide polymorphisms (SNPs) derived from 997 European populations. The finn-b-E4_POCS was data for POCS with 16,379,676 SNPs from 118,870 European populations (POCS: control = 642: 118,228). Meanwhile, the ukb-d-N92 was data for IM with 12,983,417 SNPs from 361,194 European populations (IM: control = 8,475: 352,719). The EBI-A-GCST90018838 was data for EC with 24,135,295 SNPs from 240,027 European populations (EC: control = 2,188: 237,839). The finn-b-N14_ENDOMETRIOSIS was data for endometriosis with 16,377,306 SNPs from 77,257 European populations (case: control = 8,288: 68,969). 2.2 | MR analysis HPV was considered as an exposure factor, and 4 kinds of gynecological diseases (PCOS, IM, EC, and endometriosis) were regarded as the outcome, then MR was implemented utilizing “TwoSampleMR” package (v 0.6.6)[23]. The MR consisted of 3 assumptions: (1) instrumental variables (IVs) were linked to HPV; (2) IVs could only influence outcomes by HPV; (3) IVs were not link to potential confounders. Exposure factor (HPV) was read and IVs were identified utilizing “extract_instruments” function. The screening criteria for IVs: (1) IVs with linkage disequilibrium were removed with kb = 10, clump=TRUE, and r 2 = 0.001 ; (2) P 10. Besides, outcome variables ( 4 kinds of gynecological diseases ) were extracted utilizing “extract_outcome_data” function and screened with rsq=0.8 and proxies = TRUE combined with IVs. Moreover, “harmonise_data” function was implemented to unify the effect uniformity and effect dimension. MR analysis was performed combining the 5 algorithms utilizing “mr” function. The 5 algorithms are MR Egger, Weighted Median, Weighted Mode, Simple Mode, and Inverse Variance Weighted (IVW)[23-26]. The main results mentioned by IVW (P 1 indicates the exposure factor presents a risk, nevertheless, the exposure factor is a protective factor. Subsequently, to determine the relationship connecting exposure factors and consequences, “ mr_scatter_plot ” function was implemented to draw correlation scatter plot combining SNP-exposure effect and SNP-outcome effect. Besides, “ mr_forest_plot ” function was employed to obtain forest plot to evaluate the diagnostic performance of SNP sites of the effect of each individual exposure factor on the final outcome. Then, “ mr_funnel_plot ” was performed to draw funnel plot to determine whether MR followed Mendel’s second randomization law by combining β and standard error of IVs. Furthermore, for the purpose of appraising the trustworthiness of MR analysis results, sensitivity analyses were produced, which mainly included horizontal pleiotropy test, leave-one-out (LOO) test, and heterogeneity test. Heterogeneity analysis was performed utilizing “mr_heterogeneity” function. P > 0.05 was used for fixed-effect IVW, and P 0.05). LOO analysis was performed utilizing “mr_leaveoneout” function to observe whether the results changed after removing each SNP. Finally, in order to verify that the results of the forward analysis were not disturbed by the reverse causal effect, Steiger reverse causality test was performed utilizing “steiger_filtering” function. The results showed that Steiger-dir was TRUE and Steiger-pval was significant (P<0.05), indicating that the relationship in which exposure factors caused the outcome was correct. 2.3 | Statistical analysis All bioinformatics analyses were performed utilizing the R software (v 4.2.2). 3 | Results 3.1 | Causal connection between HPV and 4 kinds of gynecological diseases MR was performed with HPV as the exposure factor and gynecological diseases as the outcome, and the following conclusions were obtained. According to the screening criteria of exposure factors, the 7 SNPs corresponding to exposure factors were gained as IVs for subsequent analysis ( Supplementary Table 1 ). The MR results indicated that HPV had a significant causal relationship with EC (OR: 1.0973 [95% CI: 1.0030 - 1.2005], P = 0.0429) ( Table 1 ) and endometriosis (OR: 1.0610 [95% CI: 1.0029 - 1.1225], P = 0.0392) utilizing IVW ( Table 2 ), therefore HPV was a risk factor for EC and endometriosis. Nevertheless, no causal link existed between HPV and PCOS (P = 0.8184) ( Table 3 ). Similarly, HPV and IM were not causally related (P = 0.9120) ( Table 4 ). Therefore, a further exploration of the causal relationship between HPV and EC or endometriosis were carried out. The scatter plot indicated the intercept was close to 0, and the slope was positive, so HPV was a risk factor for EC ( Figure 1A ) and endometriosis ( Figure 1B ) and was not affected by confounding factors. The forest plot indicated that the diagnostic value of IVW for SNPs was greater than 0, again indicating that HPV was a risk factor for EC ( Figure 1C ) and endometriosis ( Figure 1D ). Besides, funnel plot indicated MR analysis of EC ( Figure 1E ) and endometriosis ( Figure 1F ) conformed to Mendel’s second randomization law . To sum up, HPV was a risk factor for EC and endometriosis. 3.2 | Sensitivity analysis The above EC and endometriosis that had a causal relationship with HPV were further analyzed for sensitivity. The heterogeneity test results showed P > 0.05, demonstrating that HPV and EC ( Table 5 ) or endometriosis ( Table 6) presented no heterogeneity. Similarly, horizontal pleiotropy test also showed P > 0.05, which suggested there was no presence of horizontal pleiotropy between HPV and EC ( Table 7 ) and between HPV and endometriosis ( Table 8 ). Subsequently, LOO analysis presented that each SNP had little effect on the EC ( Figure 2A ) and endometriosis ( Figure 2B ). 3.3 | Steiger test After sensitivity analysis, Steiger test indicated that steiger-dir was TRUE and P < 0.05 regardless of whether it was for EC ( Table 9 ) or endometriosis ( Table 10 ), so the MR results between HPV and EC and between HPV and endometriosis were correct. 4 | Discussion 4.1 | Main Findings Our findings provide evidence that genetically predicted HPV infection is causally associated with an increased risk of EC (OR: 1.0973, P = 0.0429) and endometriosis (OR: 1.0610, P = 0.0392), while no significant causal relationship was observed with PCOS or IM. Sensitivity analyses, including MR-Egger and Cochran’s Q test, did not indicate substantial pleiotropy or heterogeneity, reinforcing the robustness of our results. 4.2 | Strengths and Limitations A major strength of this study is the application of two-sample MR, which leverages genetic variants as instrumental variables to infer causal relationships while minimizing confounding and reverse causation. The use of large genome-wide association study (GWAS) datasets enhances statistical power, and the inclusion of multiple sensitivity analyses strengthens the validity of our findings. However, several limitations should be considered. First, MR assumes that instrumental variables are strongly associated with the exposure (HPV infection), are independent of confounders, and influence the outcome solely through the exposure. Although our analyses suggest minimal pleiotropy, unmeasured confounding due to genetic or environmental factors cannot be entirely excluded. Second, our study population consists predominantly of individuals of European ancestry, limiting the generalizability of these findings to other ethnic groups. Finally, while our results indicate a causal link between HPV and EC/endometriosis, the precise molecular mechanisms remain unclear and require further experimental validation. 4.3 | Interpretation In EC, persistent HPV infection may drive malignant transformation through chronic inflammation, immune evasion, and direct oncogenic effects[27]. HPV’s E6 and E7 oncoproteins disrupt key tumor suppressor pathways by degrading p53 and retinoblastoma protein (pRb), leading to uncontrolled cellular proliferation and inhibition of apoptosis[28]. In cervical cancer, these mechanisms are well documented, but accumulating evidence suggests that similar pathways may operate in endometrial carcinogenesis[29]. HPV DNA has been detected in endometrial tissues, and its presence has been correlated with molecular alterations characteristic of malignant transformation, including epigenetic modifications and increased oxidative stress[30, 31]. Furthermore, chronic HPV-induced inflammation promotes a tumor-permissive microenvironment by modulating cytokine networks and disrupting immune surveillance, which could facilitate oncogenic progression in the endometrium[32]. However, inconsistencies in prior observational studies highlight the need for further validation through large-scale, tissue-specific investigations[17, 33]. The observed causal relationship between HPV and endometriosis may be linked to the virus’s ability to induce immune dysregulation and sustain chronic inflammation within the pelvic cavity[34, 35]. HPV infection alters local immune responses by downregulating antigen presentation, suppressing interferon pathways, and upregulating pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), all of which have been implicated in endometriosis pathophysiology[36]. Persistent inflammation can enhance ectopic endometrial cell adhesion, proliferation, and angiogenesis, key processes in endometriosis development[37]. These findings support the hypothesis that microbial infections may act as environmental triggers that exacerbate immune dysfunction in genetically susceptible individuals. Future studies should investigate whether HPV-mediated immune alterations influence the severity and progression of endometriosis. In contrast, our study found no evidence supporting a causal relationship between HPV and PCOS or IM. Given the limited research exploring these associations, previously reported links—if any—may be influenced by shared risk factors such as obesity, metabolic dysfunction, or lifestyle-related variables[38]. While systemic inflammation has been proposed as a contributor to PCOS pathogenesis, our findings indicate that HPV infection is unlikely to play a direct role in its development[39]. Similarly, menstrual irregularities are predominantly driven by hormonal dysregulation rather than viral infection[40]. These findings have significant clinical implications. If HPV infection contributes to EC and endometriosis, expanding HPV vaccination programs beyond cervical cancer prevention may offer broader gynecological health benefits. Further research is needed to delineate the molecular mechanisms underlying these associations and to determine whether HPV-targeted interventions could mitigate the risk of HPV-associated gynecological diseases. 5. Conclusion Using Mendelian randomization, we explored the causal relationship between HPV and four gynecological diseases: PCOS, IM, EC, and endometriosis. Our results show that HPV is a significant risk factor for EC and endometriosis, but not for PCOS or IM. Sensitivity and Steiger tests confirmed the robustness of these findings. These results provide new insights into HPV’s role in gynecological disease pathogenesis and suggest potential benefits of extending HPV vaccination to prevent EC and endometriosis. Author Contributions ZXZ and XG conceived the study idea and drafted the manuscript, with TTS, ZXL, YMW and QLR providing critical revisions and contributing to the interpretation of results. All authors approved the final version of the manuscript. Ethics Statement All data used within this study were at the summary level only. As no individual-level data were accessed, no ethical approval was necessary. Conflicts of Interest All authors declare no conflicts of interest. Data Availability Statement Summary statistics for HPV, EC, endometriosis, PCOS, and IM were obtained from the IEU Open GWAS database (https://gwas.mrcieu.ac.uk/) and can be accessed under the following study IDs: prot-c-2623_54_4 (HPV), EBI-A-GCST90018838 (EC), finn-b-N14_ENDOMETRIOSIS (endometriosis), finn-b-E4_POCS (PCOS), and ukb-d-N92 (IM). References 1. Arroyo Mühr LS, Gini A, Yilmaz E, Hassan SS, Lagheden C, Hultin E, et al. Concomitant human papillomavirus (HPV) vaccination and screening for elimination of HPV and cervical cancer. Nat Commun. 2024;15(1):3679.2. Oyouni AAA. Human papillomavirus in cancer: Infection, disease transmission, and progress in vaccines. J Infect Public Health. 2023;16(4):626-31.3. Chesson HW, Dunne EF, Hariri S, Markowitz LE. The estimated lifetime probability of acquiring human papillomavirus in the United States. Sex Transm Dis. 2014;41(11):660-4.4. Schiffman M, Doorbar J, Wentzensen N, de Sanjosé S, Fakhry C, Monk BJ, et al. 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Keywords adenomyosis: basic science carcinoma of the cervix: basic science carcinoma of the endometrium: basic science epidemiology epidemiology: general gynaecology Authors Affiliations Zixun Zhuang 0000-0001-9708-4439 Jiangsu Province Hospital of Chinese Medicine View all articles by this author Xian Ge Jiangsu Province Hospital of Chinese Medicine View all articles by this author Ye-man Wang Jiangsu Province Hospital of Chinese Medicine View all articles by this author Ting-ting Shang Jiangsu Province Hospital of Chinese Medicine View all articles by this author Qing-ling Ren [email protected] Jiangsu Province Hospital of Chinese Medicine View all articles by this author Metrics & Citations Metrics Article Usage 427 views 141 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Zixun Zhuang, Xian Ge, Ye-man Wang, et al. Causal relationship between human papillomavirus and 4 gynecological diseases：two-sample Mendelian randomization study. 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