The causal relationship between gastroesophageal reflux disease and constipation: a study utilizing bidirectional mendelian randomization combined with meta-analysis

doi:10.21203/rs.3.rs-4286883/v1

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The causal relationship between gastroesophageal reflux disease and constipation: a study utilizing bidirectional mendelian randomization combined with meta-analysis

https://doi.org/10.21203/rs.3.rs-4286883/v1

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Background Observational studies have revealed a correlation between gastroesophageal reflux disease (GERD) and constipation; however, such findings do not inherently establish causality. Comprehensive and detailed research is essential for ascertaining the direct causal links between these conditions.

Methods In this study, we integrated bidirectional two-sample Mendelian Randomization (MR) with meta-analysis to investigate the causal relationship between GERD and constipation. Pleiotropy assessments were conducted and the MR-PRESSO technique was applied to outlier data complemented by heterogeneity tests to enhance analytical precision. Leveraging data from various databases, we performed two rounds of MR analysis employing inverse variance weighting (IVW), MR-Egger regression, and the weighted median method. The choice between the IVW random effects and fixed effects models was determined by the data heterogeneity. Critical IVW results were further subjected to meta-analysis to validate their reliability and broad applicability. Additionally, a reverse Mendelian randomization analysis was performed. This comprehensive methodology enables detailed examination of the causal link, laying the foundation for future clinical research and intervention strategies.

Results We used the FinnGen R10 and GWAS catalog datasets to explore the causal link between GERD and constipation via MR analysis. Initially, with GERD as the exposure and constipation as the outcome, the FinnGen dataset revealed a positive correlation, as evidenced by an IVW Odds Ratio (OR) of 1.18 (95% Confidence Interval [CI]: 1.11-1.26, p=3.15×10^-7). Similarly, the GWAS catalog data affirmed a positive association, with an IVW OR of 1.56 (95% CI: 1.33-1.85, p=1.27×10^-7). A subsequent meta-analysis corroborated this positive correlation (OR = 1.35, 95% CI: 1.02-1.77, p = 0.035). Moreover, a reverse causation analysis, considering GERD as the outcome and constipation as the exposure, further indicated a positive correlation (OR=1.08, 95% CI=1.03-1.12, p=7.21×10^-4).

Conclusion Our study demonstrated that GERD and constipation are mutual risk factors and exhibit a bidirectional causal relationship, with exposure to GERD having a more substantial effect than constipation. These findings provide valuable insights for further studies on the biological mechanisms and clinical treatments.

Constipation

Gastroesophageal reflux disease

Causal inference

Mendelian randomization

Meta-analysis

Constipation is a prevalent gastrointestinal disorder characterized by difficulty in bowel movements, reduced defecation frequency, and hard stools [1]. Approximately 14% of the global population suffers from constipation, a proportion that increases with age [2]. Constipation not only significantly impairs quality of life [3] but also raises the risk of developing coronary heart disease and ischemic stroke, potentially leading to a 12% increase in all-cause mortality, thereby intensifying the societal burden of disease [4]. The etiology of constipation is complex, and its pathogenesis remains unclear, possibly involving gastrointestinal dysfunction, psychosocial factors, visceral hypersensitivity, autonomic nervous dysfunction, and a history of gastrointestinal infections [5]. Gastroesophageal reflux disease (GERD) is a pathological condition of the gastrointestinal tract [6] and is primarily attributed to dysfunction of the lower esophageal sphincter [7]. This dysfunction facilitates the retrograde movement of gastric acid and its contents into the esophageal lumen, manifesting clinically as pyroptosis, acid regurgitation, thoracic discomfort, and persistent cough[8]. In the absence of targeted therapeutic intervention, GERD may precipitate esophageal mucosal inflammation, ulceration, and luminal narrowing, and significantly elevate the risk of developing esophageal adenocarcinoma [9] [10].

Historically, GERD and constipation have been perceived as discrete clinical entities within a medical canon. Nevertheless, an emergent corpus of evidence from longitudinal and cross-sectional research paradigms has revealed a notable confluence of these maladies [11]. The REACTION-J2 study [12] in Japan, which analyzed a cohort of 10,000 subjects using a spectrum of diagnostic criteria for both constipation and GERD, deduced from a multifaceted analysis across nine distinct criteria sets that the prevalence of constipation among individuals diagnosed with GERD markedly exceeded that of their non-GERD counterparts, with patients afflicted by both conditions reporting a substantial degradation in quality of life. Concurrently, epidemiological data from the United States [13] indicate that an estimated 28.3% of patients with GERD concurrently experience constipation. Furthermore, an investigative study focusing on a pediatric cohort of 94 constipated subjects identified that 55 also presented with symptomatic manifestations of gastroesophageal reflux disease [14]. These empirical observations indicate a potentially intricate relationship between these two disorders. Nonetheless, the observational nature of these studies precludes definitive assertions regarding causality, underscoring the need for further rigorous scientific inquiry to unravel underlying pathophysiological interconnections.

Mendelian Randomization (MR), a causality inference method based on genetic principles, has been widely applied in clinical and epidemiological research [15]. This approach uses genetic variations randomly allocated to individuals during meiosis as instrumental variables (IVs) linked to specific exposures (such as lifestyle or disease risk factors) to infer potential causal relationships between exposures and outcomes [16]. This study harnessed datasets from divergent repositories by applying bidirectional Mendelian randomization and meta-analytical approaches to elucidate the putative causal nexus between GERD and constipation.

Study design

Our study meticulously integrated data from various databases to explore the potential causal relationship between GERD and constipation. Initially, we conducted an MR analysis of these data, followed by a meta-analysis [17] of the inverse variance weighting (IVW) results from the MR analysis. Furthermore, we performed reverse causation analysis to enhance the reliability of our results. MR analysis used selected genetic variants as proxies for potential risk factors. To compel causal inference, the IVs utilized must meet three core criteria [18]: first, there must be a direct association between the genetic variants and the exposure; second, the genetic variants must be independent of any confounders that could bias the relationship between the exposure and the outcome; and third, the impact of the genetic variants on the outcome should be exclusively through the exposure and not via alternative pathways ( Figure 1). Notably, the studies included in our analysis were approved by the relevant institutional review boards and the participants provided informed consent. These steps ensured the ethics and validity of this study.

GWAS summary data source

We analyzed two sets of GWAS data for constipation and GWAS summary statistics for GERD. The first set of GWAS data for constipation [19] was sourced from the GWAS catalog (accession number GCST90044172). This study included 4,781 cases of constipation in individuals of European ancestry and 451,567 control individuals of the same ancestry, analyzing approximately 11.84 million Single Nucleotide Polymorphisms (SNPs). The second set of GWAS data for constipation was obtained from the FinnGen database [20] accessible at https://r10.finngen.fi/. This study included 41,124 patients with constipation and 371,057 control individuals. GWAS summary statistics for GERD [21] were acquired from the GWAS catalog with the accession number GCST90000514. This study included 602,604 European individuals, comprising 129,080 GERD cases and 473,524 control individuals, analyzing approximately 2.32 million SNPs.

Selection of instrumental variables (IVs)

We used stringent criteria to identify SNPs that were closely associated with GERD. First, we set a significance threshold (p < 5.0×10^-8) to filter SNPs tightly linked to GERD. Subsequently, we calculated the F-statistic [22] for each SNP to ensure that the selected SNPs served as influential instrumental variables. The formula for the F-statistic is F= (β/Se)²,where 'β' represents the effect size of the SNP on the exposure (i.e., GERD), and 'Se' is the standard error. We retained only those SNPs with an F-statistic greater than 10 to exclude weak instrumental variables and ensure a strong association between the selected SNPs and GERD [23]. Furthermore, the Minor Allele Frequency (MAF) of each SNP was calculated. The MAF was computed as 1 - EAF if the effect allele frequency (EAF) was > 0.5, or EAF if the EAF was < 0.5. To exclude those linked to rare mutations, we eliminated SNPs with an MAF of less than 0.01 to exclude those linked to rare mutations. We applied stringent criteria to mitigate the effects of linkage disequilibrium (Kb = 10000, r² = 0.001) [24]. After these steps, the final filtered SNPs were used as instrumental variables (Supplementary Table S1).

Statistical analysis

Causal validation of GERD and constipation

Our study analyzed all data using the R software (version 4.2.1; details are available at https://www.r-project.org/). The first step in our analysis was to match SNPs between the outcome and exposure data, retaining only SNPs in the exposure data. Next, we excluded SNPs marked as MR_KEEP = FALSE and used the MR-Egger method [25] to test for horizontal pleiotropy; detailed results are shown in Supplementary Table S2. For datasets in which horizontal pleiotropy was detected (p < 0.05), we applied the MR-PRESSO method [26] to identify and remove outliers. In addition, we conducted tests for heterogeneity. For datasets exhibiting heterogeneity (Q, p < 0.05), we employed the IVW random-effects model; for datasets without heterogeneity, we used a fixed-effect model (Supplementary Table S3). Subsequently, we utilized five different MR analysis techniques to assess the causal link between GERD and constipation, including IVW [27], MR-Egger regression, and the weighted median approach [28], with detailed results in Supplementary Table S4. We visually represent these analysis findings through combined figures for intuitive visualization (Figures 2 and 3). Finally, we conducted a meta-analysis of IVW MR results from the two sets of outcome data (Supplementary Table S5).

Causal validation of GERD and constipation

During this process, we performed reverse analysis, treating the data on GERD as the outcome and the data on constipation as the exposure (Supplementary Table S6). This approach aligns with that of our previous forward analysis.

In our study, we used data from the FinnGen R10 and GWAS catalogs for MR analysis to explore the relationship between GERD and constipation. Initially, a forward Mendelian Randomization analysis was conducted with GERD as the exposure and constipation as the outcome. The MR analysis results using constipation data from FinnGen revealed a positive correlation, with the IVW method producing an Odds Ratio (OR) of 1.18 (95% Confidence Interval [CI]: 1.11-1.26, p=3.15×10^-7), and the weighted median approach yielding an OR of 1.17 (95% CI: 1.07-1.28, p=5.75×10^-4). Similarly, MR analysis using constipation data from the GWAS catalog confirmed this positive association, with the IVW method giving an OR of 1.56 (95% CI: 1.33-1.85, p=1.27×10^-7) and the weighted median method showing an OR of 1.54 (95% CI: 1.23-1.93, p=1.81×10^-4). Given the pivotal role of the IVW method within the MR framework, we conducted a meta-analysis of the IVW findings. This analysis unveiled a notable positive correlation between GERD and constipation, with an OR of 1.35 (95% CI: 1.02-1.77, p=0.035). Additionally, in a reverse causation analysis with GERD as the outcome and constipation as the exposure, MR analysis suggested a positive correlation (OR=1.08, 95% CI=1.03-1.12, p=7.21×10^-4), further supporting the bidirectional nature of the relationship.

These results suggest a bidirectional causal relationship between GERD and constipation. Thus, GERD may increase the risk of constipation, and constipation may also increase the risk of GERD. However, the effect of GERD on the risk of constipation was more pronounced.

Conventionally, it has been posited that GERD and constipation are two autonomous pathologies in gastroenterology. Nonetheless, an array of observational investigations[11] [12] [13] [14] [29] [30] has illuminated a potentially profound linkage between them, which is of paramount importance for devising nuanced diagnostic modalities and efficacious therapeutic interventions, thereby catalyzing extensive scholarly debate. However, the observational nature of these inquiries imposes constraints on our understanding of their relationship. In this study, we implemented bidirectional Mendelian randomization coupled with meta-analytical techniques by leveraging expansive GWAS datasets. The results revealed a bidirectional causal nexus between constipation and GERD, with the influence of GERD on augmenting constipation risk manifesting greater salience.

Empirical evidence delineates a significant augmentation in the risk of constipation attributable to GERD, corroborating findings from observational cohorts, such as the REACTION-J2 study [12]. However, the mechanistic underpinnings of this correlation remain unclear and alterations in the gut microbiome are speculated to be plausible mediators. Investigative efforts [31] [32] have elucidated pronounced microbiota disparities between patients with GERD and healthy cohorts. In a study conducted by Xiaolin Ye et al. [31], the gut microbiota of 30 patients with GERD was compared with that of 30 healthy controls using 16S rRNA sequencing. The results indicated significant differences in the gut microbiota composition between patients with GERD and healthy individuals, with a notable decrease in the genera Blautia, Lachnospira, Faecalibacterium, and Bifidobacterium in patients with GERD. These bacterial taxa are associated with the production of short-chain fatty acids (SCFAs) and lactic acid. Results from several animal studies have revealed the underlying mechanisms of SCFAs on intestinal motility, including activation of mucosal receptors linked to enteric or vagal nerves [33], direct modulation of colonic smooth muscle activity [34] [35], and elevation of intraluminal serotonin concentrations [36]. Consequently, it has been postulated that GERD exacerbates constipation through microbiome perturbations, leading to reduced SCFAs production. Additionally, the extensive presence of vagal nerve termini in the distal esophagus, subjected to chronic erosive and sensitizing stimuli in patients with GERD, suggests the potential for vagal neuropathy to disrupt gastrointestinal motility and acid secretion, culminating in constipation. Multiple randomized double-blind controlled trials [37–39] indicate that non-invasive electrical stimulation, such as transcutaneous electrical stimulation, by stimulating the vagus nerve, can not only alleviate the symptoms of GERD but also improve constipation, which supports our hypothesis. Furthermore, GERD-induced esophagitis may catalyze the release of inflammatory mediators such as cytokines and chemokines [40], potentially inducing constipation through mechanisms involving the gut-brain axis [41]. Nevertheless, a more profound inquiry into the causal dynamics of GERD's impact of GERD on constipation is imperative.

Reciprocal investigations have shown that constipation notably increases predisposition to GERD. Scholarly reports have posited that constipation-induced elevations in intra-abdominal pressure, along with potential gastric distension [42], may precipitate transient relaxation of the lower esophageal sphincter, a fundamental pathophysiological event in GERD development [43] [44]. A prospective study conducted by Baran et al. [14] involving 94 pediatric subjects, an initial 24-hour pH metry was performed on children presenting with constipation alongside symptoms indicative of GERD. This was succeeded by a conventional treatment regimen for constipation spanning three months, culminating in a follow-up 24-hour pH metry. The outcomes of this investigation highlight a notable enhancement in both the acid reflux index and the symptomatic manifestations of GERD after treatment for constipation. To complement these findings, a retrospective observational study by Mommad et al. [29] identified a significantly elevated prevalence of laxative utilization within the GERD cohort (38.1%) compared with the non-GERD group (21.3%), corroborating the results of our study. Nonetheless, the exploration of alternative mechanisms is imperative for a comprehensive understanding.

Our findings, derived from bidirectional Mendelian randomization, have several pivotal implications. Primarily, they augment our understanding of the intricate interplay between GERD and constipation, which are two prevalent conditions. Second, establishing bidirectional causality paves the way for exploring personalized therapeutic strategies that concurrently target both conditions and potentially enhance patient prognosis. Furthermore, these findings provide valuable insights for future clinical practice. Our findings offer a novel perspective for researchers investigating the biological underpinnings of GERD and constipation, thereby guiding future research in this domain.

This study has several strengths. Our conclusions were primarily based on genetic IVs and employed a diverse array of MR methods for robust causal inference. In addition, we conducted a comprehensive meta-analysis of pivotal IVW methods to ensure the reliability of our results. Secondly, the study used data from extensive GWAS cohorts for bidirectional two-sample MR analysis, ensuring the reliability of our findings, substantial sample sizes, and heightened statistical efficiency. Finally, our research methodology systematically mitigated the influence of the inevitable confounding factors and reverse causation.

Nonetheless, some limitations of this study warrant further investigation. First, the need for granular information for each sample in the database precludes further stratified analyses of the population. Second, the predominant representation of individuals of European ancestry in the dataset restricted the generalizability of our conclusions. Finally, adverse outcomes in MR studies do not conclusively negate causation, as genetically determined exposures may not fully encapsulate accurate exposures and a more stringent selection of IVs could yield negative results.

In summary, our study, employing a combination of MR analysis and meta-analysis, successfully revealed the potential role of GERD as a risk factor for constipation, revealing a causal relationship between them. Furthermore, our reverse causation analysis revealed a bidirectional causal link between constipation and GERD. These findings provide crucial scientific evidence for the early prevention and precise treatment of constipation. Additionally, these findings pave the way for researchers to explore the biological mechanisms underlying constipation. Through this research, we have enhanced our understanding of the interplay between these two conditions and charted a course for future clinical practice and scientific investigations.

Author contributions

Xingxing Wei and Xiangming Che contributed to the project conception, design, data analysis, and manuscript drafting. All authors approved the final publication, accepted responsibility for the work, and ensured thorough investigation and resolution of any accuracy- or integrity-related queries. All authors have read and agreed to the published manuscript.

Funding

There was no grant support for this study.

Data Availability

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding authors.

Ethics approval and consent to participate

Ethical approval was not required because this study retrieved and analyzed data from anonymized datasets of studies that were subjected to ethical approval.

Acknowledgement

We acknowledge the GWAS Catalog and FinnGen Database for sharing their GWAS datasets and the invaluable contributions of the participants.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Supplementary information

Supplementary table 1: Filtered instrumental variables

Supplementary table 2: Results of tests for horizontal pleiotropy

Supplementary table 3: Heterogeneity analysis results

Supplementary table 4: MR analysis results

Supplementary table 5: Meta-analysis results

Supplementary table 6: Results of reverse analysis

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No competing interests reported.

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The causal relationship between gastroesophageal reflux disease and constipation: a study utilizing bidirectional mendelian randomization combined with meta-analysis

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