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. 2025 Sep 26;104(39):e44585. doi: 10.1097/MD.0000000000044585

Use of bidirectional Mendelian randomization to unveil the association of Helicobacter pylori infection and pancreatic cancer

Jingping Hu a,b, Lintao Dong a,b, Fang Wang a,*
PMCID: PMC13593244  PMID: 41029074

Abstract

Helicobacter pylori (H pylori), a common gram-negative bacterium and known carcinogen, causes chronic infection. Recent studies suggest its link to extra-gastric cancers, including pancreatic cancer, but conflicting findings due to confounding factors hinder clear association. Using summary-level data from genome-wide association studies, we analyzed the bidirectional causal relationship between H pylori-related antibody-mediated immune responses and pancreatic cancer. We further validated the results using generalized summary-data-based Mendelian randomization (GSMR). We found that the levels of H pylori outer membrane protein (OMP) antibody can significantly increase the risk of pancreatic cancer (OR: 1.8122, 95% CI: 1.3192–2.4894, P < .001). These results were consistent with the weighted median algorithm (OR: 1.9638, 95% CI: 1.2686–3.0399, P = .002). Furthermore, the results from GSMR were also consistent with the above results (OR: 1.7099, 95% CI: 1.2632–2.3144, P <  .001). Elevated H pylori OMP antibody levels are associated with increased pancreatic cancer risk. OMP may serve as a potential vaccine target for future prevention strategies.

Keywords: antibody-mediated immune response, genetic summary-data-based Mendelian randomization, Helicobacter pylori, Mendelian randomization, pancreatic cancer

1. Introduction

Pancreatic cancer is one of the deadliest cancers, with a median survival period of approximately 4 months and a 5-year survival rate of 13%.[1] Additionally, pancreatic cancer progresses rapidly and usually worsens within just a few months of diagnosis.[2] The treatment of pancreatic cancer mainly includes surgery, chemotherapy, radiotherapy, and targeted therapy. Surgery is the only possible cure, but it is restricted to early-stage patients. Due to late-stage diagnosis, many patients are no longer eligible for surgical resection at the time of presentation.[3] However, the etiological mechanism of pancreatic cancer is still unclear, and environmental, and lifestyle risk factors and genetic predisposition may contribute to the development of pancreatic cancer. At present, scholars believe that it involves a variety of factors, including gene mutations (such as changes in KRAS, p53, and other genes), chronic inflammation (such as chronic pancreatitis), and changes in the pancreatic microenvironment.[4] Chronic inflammation and immune responses can induce the continuous expression of pro-inflammatory cytokines (such as TNF-α and IL-6), thereby activating signaling pathways such as Hh and Wnt-β-catenin, promoting tumor cell proliferation, anti-apoptosis and immune escape.[5] Epithelial-mesenchymal transformation (EMT) may also be one of the pathogeneses because it contributes to the invasion and metastasis of cancer cells.[6] Therefore, it is urgently necessary to deeply clarify the inflammation-related signaling network, the regulatory mechanism of EMT, and the key molecular interactions between the tumor microenvironment and immune response in pancreatic cancer, so as to provide a solid theoretical basis for the development of targeted therapy and immunotherapy strategies.

H pylori is a spiral-shaped gram-negative bacterium that is the most common chronic bacterial infection worldwide. Recently, in 2021, the National Toxicology Program’s 15th report on Carcinogens listed chronic H pylori infection as a “substance known or reasonably expected to be carcinogenic to humans.”[7] If H pylori infection is not eradicated, prolonged infection may lead to disease progression and an increased risk of mucosa-associated lymphoid tissue lymphoma, gastric cancer, and other cancers.[8,9] In recent years, it has been found that chronic infection of H pylori may also be associated with a variety of extra-gastric malignant diseases, such as pancreatic cancer, esophageal cancer, and colorectal cancer.[10–12] Although the exact mechanism by which H pylori infection promotes the occurrence and development of pancreatic cancer is still under exploration, some scholars have proposed that it may involve several biological theories. H pylori infection causes chronic reactions in the gastrointestinal mucosa. The persistent inflammatory state may affect the adjacent pancreatic tissue through paracrine means, leading to persistent oxidative stress and DNA damage.[13,14] Inflammation-related cytokines can further promote the proliferation of abnormal cells and immune escape. H pylori infection may also activate the Wnt/β-catenin signaling pathway, which plays a central role in carcinogenesis by promoting the expansion of cancer stem-like cells.[15,16] In addition, H.pylori weakens the body’s ability to recognize and eliminate abnormal pancreatic cells by affecting the immune microenvironment.[17] Lifestyle factors, genetic susceptibility, and the virulence factors of the bacterial strain can all act in concert with H pylori infection to increase the risk of pancreatic cancer.[18] Interestingly, although new studies have continuously appeared in recent years on whether there is an association between pancreatic cancer and H pylori, their conclusions have been inconsistent. This may be because most studies did not adequately adjust for confounders at the time of data aggregation, making it difficult to draw a definitive conclusion on whether there is an association between H pylori and pancreatic cancer.

In this study, we aimed to analyze the causal relationship between 7 antibody immune responses to H pylori and pancreatic cancer. We chose to use the antibody-mediated immune response data after H pylori infection because antibodies can reflect the host’s long-term immune memory of H pylori infection, which is helpful for a more comprehensive understanding of the long-term association between infection and pancreatic cancer and its underlying mechanism. Mendelian randomization (MR) infers the potential causal relationship between exposure factors and outcomes by using genetic variations as instrumental variables (IVs).[19] In this study, we further employed the generalized summary Mendelian Randomization (GSMR) method. GSMR accounts for the linkage disequilibrium (LD) among genetic variations in its analysis and identifies and eliminates pleiotropic single-nucleotide polymorphisms (SNPs) through the Heterogeneity in Dependent Instruments (HEIDI) outlier test, thereby enhancing the reliability and efficiency of causal estimation.[20] Since previous epidemiological studies have failed to establish a causal relationship between H pylori infection and pancreatic cancer, we used data from the genome-wide association study (GWAS) to apply bidirectional two-sample MR and GSMR to clarify the complex causal relationship between them.

2. Materials and methods

2.1. Research design

The data used in this MR Study were approved by the ethical review committee of the relevant research professional institutions. Therefore, no additional ethical scrutiny was required. All experimental results were described in detail in the text and Supplementary Materials. In this study, we used 7 antibodies against H pylori as the exposure database, and European patients with pancreatic cancer as the outcome (in Fig. 1). Two-sample bidirectional MR method was used to analyze the causal relationship between H pylori and pancreatic cancer. Based on MR, we also employed the GSMR method to verify the results obtained by the above method. In this study, SNPs were defined as IVs.

Figure 1.

Figure 1.

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The schematic flowchart showing the study design of H pylori and pancreatic cancer. H pylori = Helicobacter pylori.

2.2. Data source

The exposure data used in our analysis came from aggregated GWAS results for 7 antibody immune responses associated with H pylori infection as proposed by Butler-Laporte et al. These antibody types were used to evaluate the host immune response to various H pylori components, including overall IgG seropositivity and antibodies targeting specific antigens such as cytotoxin-associated gene A (CagA), catalase, 60-kDa heat shock protein (GroEL), outer membrane protein (OMP), urease subunit (UREA), and vacuolating cytotoxin A (VacA). The summary statistics were obtained respectively from GWAS analyses of 8735, 985, 1558, 2716, 2640, 2251, and 1571 participants, which were available in the MRC-IEU UK Biobank (UKB) OpenGWAS.[21] We extracted IVs for pancreatic cancer from the GWAS conducted by Jiang et al, which included 232 cases and 456,116 controls, covering a total of 1,701,334 SNPs.[22] Detailed information of all data can be found in Table 1.

Table 1.

Details of the genome-wide association studies and datasets used in this study.

Exposure or outcome Links for datadownload PMID
Pancreatic cancer https://www.ebi.ac.uk/gwas/studies/GCST90043861 34737426
Anti-helicobacter pylori IgG seropositivity https://www.ebi.ac.uk/gwas/studies/GCST90006910 33204752
Helicobacter pylori CagA antibody levels https://www.ebi.ac.uk/gwas/studies/GCST90006911 33204752
Helicobacter pylori catalase antibody levels https://www.ebi.ac.uk/gwas/studies/GCST90006912 33204752
Helicobacter pylori GroEL antibody levels https://www.ebi.ac.uk/gwas/studies/GCST90006913 33204752
Helicobacter pylori OMP antibody levels https://www.ebi.ac.uk/gwas/studies/GCST90006914 33204752
Helicobacter pylori UREA antibody levels https://www.ebi.ac.uk/gwas/studies/GCST90006915 33204752
Helicobacter pylori VacA antibody levels https://www.ebi.ac.uk/gwas/studies/GCST90006916 33204752
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CagA = cytotoxin-associated gene A, OMP = outer membrane protein, UREA = urease subunit, VacA = vacuolating cytotoxin A.

2.3. MR analysis

We applied 5 MR analysis methods, including inverse variance weighted (IVW), MR-Egger, Weighted Median, MR-PRESSO, and simple mode and weighted mode to analyze the relationship between all antibody-mediated immune responses and pancreatic cancer.[23–25] SNPs that reached a genome-wide significance level (P < 1 × 10−5) were used as IVs of antibody-mediated immune responses associated with H pylori. To investigate the reverse causal relationship, we used the following selection criteria to select genetic IVs, setting a GWAS significance threshold of P < 5 × 10−5 for SNPs associated with pancreatic cancer. Then, we clumped the GWAS significant SNPs from each split’s GWAS with a clumping window of 10,000 kb and an r² threshold of 0.001. All non-matching alleles were aligned, and the signs of the beta estimates were flipped.[26] We calculated the F statistics of the selected SNPs to detect the strength of the IVs at a threshold of F > 10, which is typically recommended in MR analysis. Then, we excluded SNPs associated with confounders that interfere with the pathway between H pylori infection and pancreatic cancer.[27] We estimated heterogeneity among IVs by using Cochran Q statistic.[28] We used the MR-Egger intercept method and the MR-PRESSO to assess bias that might be caused by horizontal pleiotropy. Finally, we conducted a leave-one-out analysis to evaluate the robustness of MR Results.

2.4. GSMR approach

In our primary analysis, we adopted GSMR, a flexible approach that tested the causal relationship between risk factors (or phenotypes) and disease by using aggregated GWAS data from independent studies for MR analysis and using multiple near-independent IVs. For the genetic IVs in the exposure, we selected genome-wide significance SNPs (r2 threshold of 0.05, P-value threshold of 1 × 10−5) for each feature by using a linkage elimination algorithm and used the “1000 genome (1000G) Phase III European sample as a reference estimates for LD.” In the reverse analysis, for GWAS summary statistics for pancreatic cancer, we selected independent SNPs with an LD threshold of r2 < 0.05 and a P-value threshold of 5 × 10−5. Then, the HEIDI outlier method was applied to remove IVs with strong predictive pleiotropy effects, and the P-value threshold is set to .01 in the HEIDI outlier filtering analysis.[29] All analyses were performed using “TwoSampleMR,” “foreach,” “gsmr2” and “ggplot2” in R version 4.3.1 for data visualization and analysis.

2.5. Ethical statement

Participants consented to the GWAS as per the original protocols, and all ethical approvals were obtained by the original authors.

3. Result

3.1. Association between H pylori and pancreatic cancer by MR

After removing palindromic and ambiguous SNPs, non-proxy SNPs, the number of SNPs used as IVs for each exposure was presented in Tables S1 and S3 (Supplemental Digital Content, https://links.lww.com/MD/Q107). This table also provided the variances interpreted as exposure instruments and F statistics. All F-values were >10, indicating that our study provided strong statistical power to detect potential causal effects between H pylori and pancreatic cancer. We analyzed the levels of several H pylori-related antibodies, including anti-H pylori IgG seropositivity and antibodies against specific antigens such as CagA, catalase, GroEL, OMP, UREA, and VacA. In our research, the IVW algorithm was the main method, and viewed other methods as auxiliary. We observed an increased risk of pancreatic cancer for every one standard deviation increase in H pylori OMP antibody levels (OR: 1.8122, 95% CI: 1.3192–2.4894, P < .001), the results were consistent with the Weighted median algorithm (OR: 1.9638, 95% CI: 1.2686–3.0399, P =  .002), and both were statistically significant (Table S4, Supplemental Digital Content, https://links.lww.com/MD/Q107). However, other antibody-mediated immune responses associated with H pylori infection were not found to have a statistically significant causal effect. In addition, to further explore the causal relationship between pancreatic cancer and H pylori, we also used reverse MR to detect whether there was a reverse causal relationship between them. The results showed that pancreatic cancer did not affect the level of H pylori antibody-mediated immune response (in Fig. 2).

Figure 2.

Figure 2.

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Forest plot illustrating the bidirectional two-sample Mendelian Randomization analysis of H pylori and pancreatic cancer. H pylori = Helicobacter pylori.

3.2. Association between H pylori and pancreatic cancer by GSMR

After the ordinary bidirectional two-sample MR, we further applied GSMR analysis to ensure the robustness of the analysis. The GSMR method can effectively identify and eliminate multiple groups of genetic variants, thus reducing bias and improving the reliability of causal reasoning. In the GSMR results, each standard deviation increase in H pylori OMP antibody levels was associated with an increased risk of pancreatic cancer (OR: 1.7099, 95% CI: 1.2632–2.3144, P <  .001). The OR of other H pylori-related antibody-mediated immune responses was >1, but there was no statistical significance. In addition, pancreatic cancer did not affect the level of antibody-mediated immune response to H pylori in the GSMR (in Fig. 3).

Figure 3.

Figure 3.

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The forest plot depicts the bidirectional GSMR effect of H pylori and pancreatic cancer. GSMR = generalized summary Mendelian randomization, H pylori = Helicobacter pylori.

3.3. Sensitivity analysis

To ensure that the results were accurate and reliable, we assessed the sensitivity of each antibody immune response. Cochran Q test (Table S2, Supplemental Digital Content, https://links.lww.com/MD/Q107) and funnel plot (Figs. S1 and S2, Supplemental Digital Content, https://links.lww.com/MD/Q108) were used to detect heterogeneity. Horizontal pleiotropy was detected by the MR-Egger intercept method and the MRPRESSO method (Table S2, Supplemental Digital Content, https://links.lww.com/MD/Q107). The results showed that when pancreatic cancer was the outcome and H pylori UREA antibody levels were used as the exposure, MR Egger and IVW are found to be heterogeneous (Q = 42.91; Q-P value =  .01). No heterogeneity or pleiotropy was found in other results. Leave-one-out analysis did not identify any single SNP with a significant influence on the overall causal estimate (Figs. S3 and S4, Supplemental Digital Content, https://links.lww.com/MD/Q108).

4. Discussion

H pylori is a spiral-shaped gram-negative bacterium known to be associated with gastric and duodenal ulcers and gastric cancer.[30,31] With further study, researchers have found that H pylori is associated with the occurrence and development of some extra-gastric diseases. The association between H pylori infection and pancreatic cancer has remained inconclusive despite extensive investigation. In bidirectional two-sample MR analysis, our study found that genetically predicted H pylori OMP antibody levels are causally associated with the development of pancreatic cancer. OMP plays a key role in the attachment and colonization of gastric mucosa by H pylori, and the presence of antibodies indicates that an infection has occurred or is currently present. Xu et al evaluated the association between H pylori infection and pancreatic cancer by conducting a meta-analysis of 17 studies. The results showed a significant association between H pylori infection and pancreatic cancer, but no significant association was found in CagA and VacA-positive strains.[32] Xiao et al conducted a meta-analysis of 9 studies from different regions and found a weak association between H pylori infection and pancreatic cancer.[33] Guo et al’s meta-analysis also obtained the same result, but due to statistical heterogeneity and publication bias, the conclusion needs to be further verified by basic experiments.[34] It is noteworthy that Huang et al conducted a case-control study on the pathology of 448 patients with pancreatic cancer and their controls and found that the risk of pancreatic cancer was seropositive with H pylori in the European population (OR = 0.96; 95% CI: 0.70, 1.31) or CagA seropositive (OR = 1.07; 95% CI: 0.77, 1.48) were not relevant.[35] Interestingly, Schulte et al collected blood samples from 580 patients and 626 controls and used an enzyme-linked immunosorbent assay (ELISA) kit to determine the seroprevalence of H pylori and its virulent protein CagA. No association was observed between positive serum antibodies to H pylori and the risk of pancreatic cancer. Notably, the study also found that CagA-negative H pylori was associated with an increased risk of pancreatic cancer (OR 1.23; 95% CI: 0.83–1.82), suggesting that the association between H pylori and pancreatic cancer may depend on different strain types of H pylori.[36] This finding is consistent with our study, which also identified a causal relationship between H pylori OMP antibody levels and adenocarcinoma, while H pylori CagA antibody levels showed no causal relationship with pancreatic cancer. This may be because some meta-analyses did not consider whether the included population is smokers,[37] as smokers have a higher incidence of H pylori and pancreatic cancer than nonsmokers.[38] It may also be due to different detection methods that lead to different results.[39] Most existing studies only detect H pylori IgG or IgM antibodies to determine the infection, once either of the IgG or IgM antibodies is seropositivity, it is identified as H pylori infection. However, this approach does not adequately consider levels of other key antigens of H pylori, such as Catalase, GroEL, OMP, UREA, and VacA antibodies, which may also play an important role in the pathogenic mechanism. H pylori detection methods include invasive and noninvasive methods. Invasive methods are histological examination, rapid urease test, or bacterial culture by gastroscopy sampling, while noninvasive methods include breath tests, serum antibody testing, and fecal antigen testing. Although invasive tests (such as gastroscopy combined with gastric mucosal biopsy for histopathology of H pylori) can provide a definitive diagnosis, they are not beneficial for pregnant women. Therefore, noninvasive diagnostic methods such as serum antibody tests, urea breath tests, and fecal antigen tests are the preferred common detections. The detection of H pylori IgG antibodies in the patient’s serum by ELISA can reflect the current or previous infection status. This is because it takes 6 to 12 months for the antibodies to turn negative after the eradication of H pylori, which leads to different test results.[40] Therefore, our study used serum-based detection of antibody-mediated immune responses to H pylori, offering a noninvasive approach suitable for vulnerable populations such as pregnant women, children, and the elderly. Secondly, the serum levels of H pylori IgG antibodies, CagA, Catalase, GroEL, OMP, UREA, and VacA are detected by ELISA. The advantage of this multi-indicator test is that it provides a more comprehensive assessment of H pylori infection status, especially infection caused by different strains and virulence factors.

Scholars have proposed several possible mechanisms to explain how H pylori increases the risk of pancreatic cancer. After long-term colonization of the gastric mucosa by H pylori, the gastric mucosa usually undergoes a series of pathological changes, such as chronic superficial gastritis, atrophic gastritis, intestinal metaplasia, and dysplasia. The development of multifocal atrophic gastritis can lead to the loss of parietal cells, which in turn can lead to low or no gastric acid, and it is worth noting that about one-third of gastric cancer occurs in patients with acid deficiency. Too low stomach acid can lead to bacterial overgrowth and an increase in N-nitroso compounds. Through blood circulation, N-nitrosamines may be transported to the pancreas, resulting in the activation of oncogenes in the pancreatic duct epithelium.[41–43] Juhua Luo et al concluded through a large number of cohort studies that they were consistent with the previously proposed hypothesis model that “H pylori infection promotes the occurrence of pancreatic cancer through gastric body colonization, low gastric acid state and the formation of nitrosamines in the stomach,” which also provides some support for us.[44] Another possible mechanism involves H pylori colonization in the antrum, which may lead to excess gastric acid, which stimulates the duodenum to release uninhibited secretin and induces the basal bicarbonate secretion of the pancreatic duct, thereby causing the proliferation of the pancreatic ductal epithelial cells (PDECs) through increased DNA synthesis. Excessive proliferation of PDECs, accumulation of genetic mutations, and persistent chronic inflammation, leading to the occurrence and development of pancreatic cancer.[45] Our study found that genetically elevated levels of H pylori OMP antibodies are a risk factor for pancreatic cancer, for which clinical evidence is lacking. H pylori OMPs play a crucial role in the infection process, especially during bacterial attachment, colonization, and persistent infection. These proteins help H pylori attach to gastric epithelial cells early in infection, increasing its virulence.[46] We hypothesize that seropositivity for H pylori OMP antibodies may contribute causally to the development of pancreatic cancer. However, the main function of OMP protein is adhesion, and although it enhances the virulence of H pylori, in the absence of the combined action of key virulence factors such as CagA and VacA, the promotional effect of single OMP antibody-positive strains in the development of pancreatic cancer may be relatively weak. The rise of antibiotic-resistant H pylori strains has made vaccine development an urgent research priority. Because of their ability to adhere to and trigger host cell immune responses, OMPs are considered immune antigens. Researchers are also using proteomic approaches to assess whether OMP could be a candidate for vaccine.[47] As the role of H pylori OMP in adhesion and triggering host immune responses is gradually revealed, OMP shows great prospects as a potential target for vaccine development in the prevention and treatment of pancreatic cancer in the future. Specifically, the OMP vaccine is expected to prevent H pylori from playing a promoting role in the early development of pancreatic cancer by inhibiting the adhesion process of H pylori, thereby reducing the persistent colonization of the bacteria in the stomach and other digestive tract tissues.

Our research has several advantages. First, the combination of MR and GSMR analysis clarifies the causal direction and minimizes confounding bias. Second, all GWAS data come from participants of European descent, suggesting that population stratification has less impact on our results. Most importantly, the exposure data in our study use antibody-mediated immune responses to a variety of H pylori-related proteins or factors, which, compared with other studies that directly evaluate H pylori itself, provide a deeper reflection of the body’s immune system’s long-term response to H pylori infection and its potential impact on cancer risk. For example, different virulence factors of H pylori have different biological functions and may have different effects on cancer risk. By analyzing these specific factors, it is possible to identify specific virulence factors associated with disease risk; different strains of H pylori may carry different virulence factors and have different effects on the disease. However, some limitations to our study should be noted. First, H.pylori is a highly heterogeneous bacterium, and numerous studies have confirmed that its virulence varies across geographic regions.[48,49] For instance, the H pylori seroprevalence in Germany (defined as positivity for at least 3 antigens) is 48%.[50] In the study by Meira Epplein et al, it was found that the seropositive rate of H pylori in African Americans was higher than that in white people.[51] Another study shows that in the Asian region, with the improvement of social and economic levels, the serological positive rate of H pylori has been gradually decreasing, among which the infection rate in developed countries is significantly lower than that in developing and underdeveloped countries.[52] The seropositivity rates vary among different provinces in China. For instance, it is 58.3% in Guangxi, China,[53] while the IgG seropositivity rate in Beijing is 31.7%.[54] The data samples used in this study were all from European populations. Due to the differences in genetic background among these populations, the generalizability of the research results may be somewhat limited. Secondly, in this study, serum antibodies were used as indicators of H pylori infection. However, some studies have pointed out that some antigens of H pylori have molecular mimicry with the host’s own proteins, and these antibodies may cross-react with host proteins such as heat shock protein 60 (HSP60), forming nonspecific immune signals. For example, H pylori GroEL has up to 54% sequence homology and 92% coverage with human HSP60, providing a structural basis for cross-reaction, and anti-H pylori Hsp60 antibodies have been found to cross-bind to human Hsp60. This indicates that the current antibody level may not fully represent the immune response of a specific strain or virulence factor, thereby reducing the specificity of antibody-mediated indicators and the accuracy of infection recognition.[55] Finally, MR is a powerful tool for exploring the potential causal relationship between exposure and disease, but its results cannot replace clinical trials. Meanwhile, we also plan to isolate and purify H pylori OMP-specific antibodies from the patient’s serum for further research on the potential pathogenic mechanism between this strain and pancreatic cancer.

Acknowledgments

We appreciate all the participants and investigators for sharing these data.

Author contributions

Conceptualization: Jingping Hu, Fang Wang.

Data curation: Lintao Dong.

Formal analysis: Jingping Hu, Lintao Dong.

Methodology: Jingping Hu.

Writing – original draft: Jingping Hu, Lintao Dong.

Writing – review & editing: Fang Wang.

Supplementary Material

medi-104-e44585-s001.xlsx (206.3KB, xlsx)
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medi-104-e44585-s002.pdf (658.4KB, pdf)
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Abbreviations:

CagA
cytotoxin-associated gene A
ELISA
enzyme-linked immunosorbent assay
EMT
epithelial-mesenchymal transition
GroEL
60-kDa heat shock protein
GSMR
generalized summary Mendelian randomization
GWAS
genome-wide association study
H pylori
Helicobacter pylori
HEIDI
heterogeneity in dependent instruments
HSP60
heat shock protein 60
IVs
instrumental variables
IVW
inverse variance weighted
LD
linkage disequilibrium
MR
Mendelian randomization
OMP
outer membrane protein
PDECs
pancreatic ductal epithelial cells
SNPs
single-nucleotide polymorphisms
UREA
urease subunit
VacA
vacuolating cytotoxin A

This work was supported by the National Natural Science Foundation of China (Grant No. 82460563, project title: The role and mechanism of PFKFB4 in inhibiting SIRT2 autophagic degradation to regulate RelA acetylation and promote chemoresistance in colorectal cancer).

The authors have no conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Supplemental Digital Content is available for this article.

How to cite this article: Hu J, Dong L, Wang F. Use of bidirectional Mendelian randomization to unveil the association of Helicobacter pylori infection and pancreatic cancer. Medicine 2025;104:39(e44585).

JH and LD contributed to this article equally.

Posted history: This manuscript was previously posted to bioRxiv: doi: https://doi.org/10.21203/rs.3.rs-7168408/v1.

Contributor Information

Jingping Hu, Email: hujingping2024@163.com.

Lintao Dong, Email: 664772318@qq.com.

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