Causal association between helicobacter Pylori infection and Sjogren’s syndrome: a bi-directional Mendelian randomization analysis

doi:10.21203/rs.3.rs-4332983/v1

Background: Based on the results of existing observational studies, it can be found that there is a potential link between Helicobacter pylori(H.pylori) infection and Sjogren’s syndrome(SS), but the causal relationshipbetween them remains unknown. This study applied Mendelian randomization (MR) to evaluate the causal relationship between H.pylori infection and SS.

Method: In this study, genome-wide association studies (GWAS) summary statistics on H.pylori infection [sample size=8735 (EBI)] and SS [sample size=368,028 (cases=2495, controls=365533) (FinnGen)] were used. we used bi-directional MR to evaluate the association between H.pylori infection and SS for identifying causation. The major analysis method of MR was performed using inverse-variance weighted(IVW), supplemented by MR-Egger and the weighted median approaches. In addition, the stability and reliability of the results were tested using the retention method, heterogeneity test, and horizontal gene pleiotropy test.

Results: The evidence of the impact of H.pylori infection on SS risk was found in IVW results[odds ratio (OR)=1.6705; 95% confdence interval (CI)=1.0966 to 2.5446; P=0.0168]. Similarly, the evidence of the impact of SS on H.pylori infection risk has also been found(OR=1.0158; 95%CI=1.0033 to 1.0285; P=0.0128).

Conclusion: The results of MR analysis support that H.pylori infection was causally associated with SS, and SS can lead to a higher risk of H.pylori infection.We want to provide novel approaches for continued H.pylori and SS-related research and therapy by evaluating the genetic relationship between H.pylori infection and SS.

mendelian randomization

Helicobacter pylori infection

Sjogren’s syndrome

causal inference

Helicobacter pylori (H.pylori) is a spiral-shaped gram-negative bacteria that easily colonizes in multiple areas such as the stomach and duodenum. According to literature[1], the global infection rate of H.pylori ranges from 18.9–88.7%, with over 4.4 billion people infected, mainly distributed in underdeveloped countries. H.pylori is clinically associated with various gastrointestinal diseases such as gastric tumors, autoimmune gastritis, gastric mucosa associated lymphoid tissue (MALT) lymphoma, and gastrointestinal ulcers. In addition, there is a correlation between H. pylori infection and the occurrence of such extragastrointestinal immune diseases as rheumatic immune disease and autoimmune thyroid disease[2].

Sjogren's syndrome (SS) is a chronic inflammatory autoimmune disease characterized by lymphocyte proliferation and progressive damage to exocrine glands. In addition to impaired function of salivary and lacrimal glands, multiple systems and organs involvement, autoantibodies in serum and hyperimmunoglobulinemia may be present clinically [3].The combined prevalence of SS in the global population is 60.82/100000, with a male to female ratio of 1:10, and females are more commonly affected than males[4].The prevalence of SS in Europe is about 0.23%[5]. At present, the exact etiology and pathogenesis of SS are not clear, and it is generally believed that immune dysfunction is caused by various factors such as genetics, viral infection, and abnormal sex hormones.

In order to explore the possible correlation between H.pylori infection and SS, many scholars have investigated the relationship between H.pylori and its related antibodies in these patients. Studies have found that the average titer of anti-H.pylori serum antibodies in SS patients is significantly higher than that in SLE and RA patients[6]. Another study analyzed the levels of anti HP antibodies in 43 patients with SS and 95 patients in the control group, and found that the levels of these antibodies were significantly increased in SS patients (34% vs 10.5%, P = 0.0001)[7]. The results of this study showed that the infection rate of H. pylori in SS group was significantly higher than that in the healthy population. Although many studies have shown that H.pylori infection promotes SS, there are still other studies on the relationship between the two that have come to the opposite conclusion. Theander et al.[8] found that H.pylori seropositivity is not associated with the presence of immunological markers for SS, such as circulating autoantibodies or lip biopsies with abnormal focal scores. Interestingly, Ram et al.[9] found that H.pylori has a lower infection rate in patients with SS which may play a protective role. H.pylori infection is negatively correlated with the occurrence and development of SS.

It can be seen that the relationship between H.pylori infection and SS has been controversial. Furthermore, the conclusion about causality cannot be solely drawn from the results of observational design, as cohort and cross-sectional studies may have limitations (such as limited sample size, racial differences, and other existing confounding factors).

Mendelian randomization (MR) is a technique that uses genetic variation as an instrumental variable (IV) to assess whether observed associations between exposure factors and outcomes are consistent with causal effects[10]. MR is based on three assumptions: 1) genetic variation is associated with risk factors; 2) genetic variation is not associated with confounders; 3) genetic variation affects outcomes only through risk factors[11]. Since genetic variation is not influenced by other factors such as external environment and social behavior, it is a stable exposure factor over time. Therefore, in observational studies, analytical bias can be minimized by avoiding the influence of confounders and reverse causality on correlation effects through MR methods. In recent years, MR methods have been widely used in studies assessing the causal relationship between exposure and outcome[12].

On this basis, the study aimed to investigate the causal relationship between H.pylori infection and SS, using the data from large-scale GWAS with a bi-directional MR design.

1.1 Ethics

This study was reported according to the STROBE-MR guidelines[13], with data collected from public databases. No ethical approval is required for this study.

1.2 Study design

In this study, a bi-directional MR design was used to investigate the causal association between H.pylori infection and SS[12]. SNPs are used as IVs for MR study to evaluate the causal effect of exposure variables[14]. The overall setup for the current MR study is shown in Figure 1. The validity of MR analysis is subject to three core assumptions: ①the relevance assumption; ②the independence assumption; and ③the exclusion-restriction assumption[11].

1.3 Data sources for anti-helicobacter pylori IgG seropositivity and SS

The summary data of H.pylori infection in GWAS were obtained from the publicly available data compiled by the European Bioinformatics Institute (EBI) database. Meanwhile, the genetic association of SS was available from FinnGen, comprising 2495 European cases and 365533 European controls. The detailed information of GWAS data contained in this study is provided in Table 1.

Table 1: Description of GWAS used for each phenotype.

Phenotype

Data sources

Sample size

SNPs (n)

Ancestry

H.pylori infection

EBI

8735

9,170,312

European

SS

FinnGen

368,028 (2495cases;

365533controls)

20,170,011

European

GWAS: Genome-wide association studies, H.pylori:Helicobacter pylori, SS:Sjogren’s syndrome,

SNPs:Single nucleotide polymorphisms.

1.4 Selection of genetic variants as instrumental variables(IVs)

In this study, MR analysis was performed on the principle that SNP must be significantly correlated with exposure, and the loci of SNP that was significantly associated with H.pylori infection or SS was selected based on a genome-wide threshold of P<5×10^-8. However, for the IVs of H.pylori infection, it turned out that no significant loci or less than three SNPs were obtained. So, a more relaxed threshold (P<5x10^-6) was used in order to include more SNPs that contributed to H.pylori infection.

Meanwhile, linkage disequilibrium (LD) analysis was performed to ensure independence between SNPs (LD, r2<0.001, clumping distance>10,000 kb)[11]. Finally, to ensure that IVs could only affect the outcome through exposure, SNPs associated with confounders were manually eliminated using PhenoScanner[15].

1.5 Statistical analysis

A two-sample MR method was used to evaluate the potential causal relationship between H.pylori infection and SS. Before the MR analysis, a pleiotropy residual sum and outlier (PRESSO) method was adopted to test the horizontal polytropy of the data and the horizontal polytropy was corrected before effect assessment, to ensure the reliability of the MR analysis.

The inverse-variance weighted (IVW) method was primarily used in MR analysis, as it provides consistent estimates of exposure-outcome associations when the IVs are not pleiotropic[16].

Cochran’s Q statistics was applied to assess the heterogeneity across individual SNPs[17].When the P-value of Cochran's Q-test was greater than 0.05, there was no heterogeneity among SNPs. MR-Egger and weighted median were used in complementary analyses[18,19]. Furthermore, the leave-one-out method was used for sensitivity analysis, and the degree of influence of each SNP on causality was carefully observed after removing the final included SNPs one by one.

All data analysis and statistical plots were drawn throughout this study using the TSMR tool (0.5.7), version R 4.3.1. Statistical results were expressed as odds ratio (OR) and 95% confidence interval (95% CI), and P<0.05 was considered statistically significant.

2.1 Genetic instrumental variable selection

Based on a genome-wide threshold of P<5x10^-6, rigorous screening was performed as previously described, resulting in the identification of 17 SNPs with causal associations between H.pylori infection and SS. Meanwhile, 10 SNPs were finally obtained (P<5×10^-8) for MR analysis of the causal association between SS and H.pylori infection. The F-statistics of IVs were all greater than 10, suggesting IVs were generally considered to provide sufficient information for MR studies (Supplementary Tables 1-3).

2.2 Causal effects of H. pylori infection on SS risks

The causal estimates of this MR analysis are shown in Table 2 and Figure 2. The OR of H.pylori infection associated with SS for the three methods (IVW, weighted median, and MR-Egger) was 1.6705 (95% CI: 1.0966-2.5446, P=0.0168), 1.9298 (95% CI: 1.0331-3.6047; P=0.0391), and 1.1493 (95% CI: 0.3035-4.3513; P=0.8403), respectively. The results of our study showed that genetically predicted H.pylori infection was significantly associated with the risk of SS (IVW P<0.05).

Table 2: Causal effects of H.pylori infection on SS risks in MR analysis

Exposure	Outcome	SNPs (n)	MR method	OR	95% CI	P-value	Cochran Q Statistic	Heterogeneity P-value
H.pylori infection	SS	17	IVW	1.6705	(1.0966, 2.5446)	0.0168	19.209	0.2579
			Weighted median	1.9298	(1.0331, 3.6047)	0.0391
			MR-Egger (P for pleiotropy=0.5648)	1.1493	(0.3035, 4.3513)	0.8403	18.775	0.2240
			Weighted mode	2.6847	(0.8791, 8.1986)	0.1021

H.pylori:Helicobacter pylori, SS:Sjogren’s syndrome, SNPs:Single nucleotide polymorphisms.

2.3 Causal effects of SS on H.pylori infection risks

The reverse MR results were presented in Table 3 and Figure 3. The OR of SS associated with H.pylori infection for the three methods (IVW, weighted median, and MR-Egger) was 1.0158 (95% CI: 1.0033-1.0285, P=0.0128), 1.0182 (95% CI: 1.0013-1.0353; P=0.0341), and 1.0256 (95% CI: 0.9924-1.0600; P=0.1697), respectively. The results demonstrated that genetically predicted SS led to a higher risk of H.pylori infection (IVW P<0.05).

Table 3: Causal effects of SS on H.pylori infection risks in MR analysis

Exposure	Outcome	SNPs (n)	MR method	OR	95% CI	P-value	Cochran Q Statistic	Heterogeneity P-value
SS	H.pylori infection	10	IVW	1.0158	(1.0033, 1.0285)	0.0128	12.698	0.1767
			Weighted median	1.0182	(1.0013, 1.0353)	0.0341
			MR-Egger (P for pleiotropy=0.5370)	1.0256	(0.9924, 1.0600)	0.1697	12.071	0.1480
			Weighted mode	1.0179	(1.0011, 1.0349)	0.0650

H.pylori:Helicobacter pylori, SS:Sjogren’s syndrome, SNPs:Single nucleotide polymorphisms.

2.4 Heterogeneity and sensitivity test

Heterogeneity refers to the variability observed in the causal estimates obtained for each SNP. Low heterogeneity suggests increased reliability of MR estimates. In our study, the Cochran’s Q-test demonstrated no evidence of heterogeneity among the IV estimates based on the individual variants (Tables 2, 3). Moreover, the leave-one-out analysis did not detect any SNP outliers, suggesting that our results were stable (Figures 2C, 3C). In addition, the funnel plot displayed no evidence of asymmetry, indicating the absence of directional horizontal pleiotropy (Figures 2D, 3D).

In this study, a bi-directional MR design was utilized to investigate the causal association between H. pylori infection and SS. To the best of our knowledge, this study is the first to use MR methods to assess the causal effects between H.pylori infection and SS. The data of this study revealed that there was a significant causal association between H. pylori infection and SS. H.pylori infection was a strong risk factor for SS (OR=1.6705, 95% CI: 1.0966-2.5446, P<0.05), and SS could lead to a higher risk of H.pylori infection (OR=1.0158, 95% CI: 1.0033-1.0285, P<0.05).

In recent years, studies have shown a correlation between H. pylori infection and SS. Studies also found that SS patients had higher levels of anti-H.pylori serum antibodies than age-matched controls and those with other connective tissue diseases[6,7]. Similar results have been obtained in studies on anti-H.pylori antibodies of Italian SS patients(OR=15.67, 95% CI: 4.5-54.8, P < 0.001)[20].

Due to the high sequence homology between H.pylori and human heat shock protein (HSP), Aragona et al. hypothesized that H.pylori infection may trigger an autoimmune response to its HSP and proposed that HSP60 produced by H.pylori may play a role in the pathogenesis of SS[21]. Thus, the results indicate that the hypothetical role of HSP60 in the development of the immune response both in pSS and secondary SS seems strictly linked to the prevalence of H.pylori infection. Kurata et al. suggested that there may be a cross reactivity between H.pylori and a certain antigen component of platelets[22]. After H.pylori infection, certain components of the body are induced to transform into cross antigens of platelets which are recognized by the body's immune system, suggesting that H.pylori infection may be associated with the occurrence of thrombocytopenia in SS patients.

SS patients are more likely to be infected with H.pylori compared to the normal population[23]. A meta-analysis showed that, 1958 participants (including 619 patients with SS) from nine studies met the inclusion criteria. The total infection rate of H.pylori was 53.83% (1054/1958). The study found that the patients with SS had a significantly higher H. pylori infection rate than those in the control groups (OR=1.19, 95% CI: 1.01-1.41, P=0.033)[24].

El Miedany et al. conducted relevant studies to determine the presence of clinical markers related to H.pylori infection in SS patients and their significance for the treatment of such patients[25].The results revealed that certain risk factors, including age, disease duration, overall disease severity and C-reactive protein (CRP) levels, may be significantly associated with H.pylori infection in SS patients.

The role of H.pylori infection in the pathogenesis of immune diseases is not yet clear. Possible mechanisms include activation of superantigens, activation of polyclonal lymphocytes, molecular antigen imitation, epitope transmission, and bystander activation, all of which are believed to be related to immune dysregulation during infection[26]. So, it can be seen that H.pylori infection may be one of the triggering factors for rheumatic immune disease.

Infection is considered a risk factor for SS, such as viral and bacterial infections. Currently, some studies suggest that dysbiosis of the oral microbiota may induce the occurrence and development of SS by promoting abnormal activation and differentiation of B lymphocytes, leading to a large number of lymphocytes infiltrating the salivary glands[27]. Given the presence of H.pylori in the host's oral cavity, it is also believed that SS may be associated with H.pylori infection.

The persistent presence of H.pylori in the gastric mucosa leads to chronic immune system activation, resulting in sustained cytokine signaling, infiltration of neutrophils, macrophages and lymphocytes into the gastric mucosa, as well as the production of antibodies and effector T cells[28]. Studies have shown that H.pylori infection induces a helper T cell 1 (Th1) response, leading to the production of interleukin-2 (IL-2) and interferon-γ (IFN-γ)[29]. The IL-2 content in the lacrimal gland of SS patients is significantly higher than that in normal individuals, indicating that IL-2 plays a major role in the pathological changes of lacrimal gland tissue and may be one of the main factors causing degeneration of lacrimal gland cells[30]. Other studies have shown that the salivary glands of SS patients are infiltrated with a large number of plasmacytoid dendritic cells (pDCs) which mainly secrete IFN-γ, and IFN-γ in the salivary glands of SS patients can induce dysfunction of salivary gland secretion[31].

Irani et al. confirmed through immunohistochemistry that the level of H.pylori in patients with inflammatory lesions of oral mucosa is higher than that in healthy individuals[32]. Meanwhile, H.pylori may interact with the surface of epithelial cells, directly causing cell damage or producing pro-inflammatory mediators[33]. It can be seen that SS patients with long-term oral lesions are more likely to be infected with H.pylori. Furthermore, in a latest meta-analysis，a total of 224 patients were diagnosed with SS, of which 94 patients (41.96%) with SS were infected with H.pylori. The multivariable analysis demonstrated that hypergammaglobulinemia could be the independent risk factor of H. pylori infection in patients with SS[34].

The relationship between H.pylori infection and SS was explore in this study from a genetic perspective, and the results showed a bidirectional causal relationship. Our MR study has several strengths. Firstly, to the best of our knowledge, this study is the first to use MR methods to assess the causal effects between H.pylori infection and SS. Secondly, MR explores the causal relationship between exposure and outcome through genetic data, unaffected by causal inversion and confounding factors. Thirdly, MR uses genetic variation as IVs to mimic the design of randomized controlled trials. It falls between observational studies and intervention trials, providing information on public health interventions in situations where randomized controlled trials may not be feasible.

However, this analysis also has several limitations. Firstly, the majority of samples used are from the European population, so the findings of this study may not be applicable to other populations. Secondly, the diagnosis of H.pylori infection was based on serum IgG antibodies testing in the datasets. Lastly, in order to incorporate a certain number of SNPs that contributed to H.pylori infection, the P-value limits were adjusted.

This study is a genetic-based causal study exploring the causal relationship between H.pylori infection and SS at the genetic level through two-sample MR analysis utilizing publicly available databases and large-scale GWAS studies. The results support that H.pylori infection increases the risk of developing SS, and SS can lead to a higher risk of H.pylori infection. However, the underlying mechanisms of H.pylori infection and SS are not clear. Data from genome-wide association studies with larger sample sizes are still needed to validate this relationship in the future. Most importantly, this study provides novel approaches for continued research and therapy of H.pylori and SS by evaluating the genetic relationship between H.pylori infection and SS.

SS: Sjogren's syndrome

H.pylori: helicobacter pylori

MALT: mucosa associated lymphoid tissue

SLE: systemic lupus erythematosus

RA: rheumatoid arthritis

MR: mendelian randomization

IV: instrumental variable

GWAS: genome-wide association studies

SNPs: single nucleotide polymorphisms

EBI: European Bioinformatics Institute

LD: linkage disequilibrium

PRESSO: pleiotropy residual sum and outlier

IVW: inverse variance weighted

OR: odds ratio

CI: confidence interval

HSP: human heat shock protein

CRP: C-reactive protein

Th1: helper T cell 1

IL-2: interleukin-2

IFN-γ: interferon-γ

pDCs: plasmacytoid dendritic cells

Data availability statement

The datasets generated during analysis in the current study are available in the European Bioinformatics Institute (EBI) database[https://gwas.mrcieu.ac.uk/], and the FinnGen consortium[https://r9.finngen.fi/].

Ethics statement

Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements.

Author contributions

Dinglu Cui: Data curation, Software, Writing – original draft. Rongxian An: Writing – original draft. Lei Li: Writing – original draft. Long Jiang: Writing – original draft. Chunshan Jiang: Writing – review & editing. Jingchun Jin: Supervision, Writing – review & editing.

Funding

This study was supported by the National Natural Science Foundation of China (NO. 82360441), projects funded by the Science and Technology Department of Jilin Province (No.20200201492JC and YDZJ202201ZYTS161).

Acknowledgments

We want to acknowledge the European Bioinformatics Institute and FinnGen consortium for providing related GWAS summary data.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author details

1.Department of Rheumatology, The Affiliated Hospital of Yanbian University, 1327 Juzi Street, Yanji 133000, China.

2.The Affiliated Hospital of Yanbian University, 1327 Juzi Street, Yanji 133000, China.

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No competing interests reported.

Causal association between helicobacter Pylori infection and Sjogren’s syndrome: a bi-directional Mendelian randomization analysis

Status:

Journal Publication

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Abstract

Figures

Introduction

1. MATERIALS AND METHODS

2. Results

3. Discussion

4.Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1