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. 2024 Feb 16;103(7):e37054. doi: 10.1097/MD.0000000000037054

Identifying causal relationships between gastroesophageal reflux and extraesophageal diseases: A Mendelian randomization study

Peishan Yao a, Xiaomin Liao b, Junming Huang c, Yi Dang d, Haixing Jiang a,*
PMCID: PMC10869099  PMID: 38363933

Abstract

Traditional observational and in vivo studies have suggested an etiological link between gastroesophageal reflux disease (GERD) and the development of extraesophageal diseases (EEDs), such as noncardiac chest pain. However, evidence demonstrating potential causal relationships is lacking. This study evaluated the potential causal relationship between GERD and EEDs, including throat and chest pain, asthma, bronchitis, chronic rhinitis, nasopharyngitis and pharyngitis, gingivitis and periodontal disease, cough, using multiple Mendelian randomization (MR) methods, and sensitivity analysis was performed. The Mendelian randomization Pleiotropy RESidual Sum and Outlier and PhenoScanner tools were used to further check for heterogeneous results and remove outliers. MR with inverse-variance weighted (IVW) showed a significant causal relationship between GERD and EEDs after Bonferroni correction. IVW results indicated that GERD increased the risk of chronic rhinitis, nasopharyngitis and pharyngitis (odds ratio [OR] = 1.482, 95% confidence interval [CI] = 1.267–1.734, P < .001], gingivitis and periodontal disease (OR = 1.166, 95% CI = 1.046–1.190, P = .001), throat and chest pain (OR = 1.585, 95% CI = 1.455–1.726, P < .001), asthma (OR = 1.539, 95% CI = 1.379–1.717, P < .001), and bronchitis (OR = 1.249, 95% CI = 1.168–1.335, P < .001). Sensitivity analysis did not detect pleiotropy. Leave-one-out analysis shows that MR results were not affected by individual single nucleotide polymorphisms. The funnel plot considers the genetic instrumental variables to be almost symmetrically distributed. This MR supports a causal relationship among GERD and EEDs. Precise moderation based on causality and active promotion of collaboration among multidisciplinary physicians ensure high-quality diagnostic and treatment recommendations and maximize patient benefit.

Keywords: cause–effect, extraesophageal disease, gastroesophageal reflux disease, genetics, Mendelian randomization analysis

Introduction

Gastroesophageal reflux disease (GERD) is a disease connected with valve-like dysfunction of the lower esophageal sphincter. The morbidity of GERD varies globally and is increasing worldwide, with a combined global prevalence of 13.98%. In addition to undermining individual health, GERD imposes a significant economic burden on society through healthcare monitoring and acid suppression medication.[1] Approximately one-third of patients with GERD also suffer from extraesophageal diseases (EEDs) such as chest pain and asthma, making it challenging to determine the underlying cause.[2]

Based on regurgitant fluid microaspiration and vagal reflexes leading to upper esophageal sphincter relaxation, ultimately causes chronic inflammation in the oral cavity and upper respiratory tract and is currently the main etiological perspective.[3] However, no multicenter, double-blind, placebo, randomized controlled trials have investigated the improvement of respiratory symptoms with aggressive acid-suppressing drugs, even if some of the observational results are contradictory and inconsistent.[4–7] The incidence of GERD is higher in people over 30 years of age than in those under 30 years of age, with a peak age of 50 to 69 years. Reduced salivary secretion, decreased chemical clearance, decreased submucosal capillary blood flow, and decreased respiratory, digestive, or masticatory physiological functions due to aging appear to be an explanation for the impaired defense against reflux.[8] In the absence of classic heartburn and reflux symptoms, it is difficult to correctly diagnose EED involved in GERD.[9] The causal relationship between cough and GERD is controversial, as they may be triggered by one another.[10] Data from studies on the etiology of periodontal disease suggest a strong association between periodontal disease and GERD.[11,12] The saliva is rich in mucins, which covers the adjacent teeth and periodontal tissue surfaces via infiltration, and forms a natural protective barrier against external microbiological, chemical, and mechanical damage.[13] However, in a trial of patients with and without GERD, no statistical differences have been reported in salivary flow rate, buffering capacity, oral clinical examination, or palatal mucosal histopathology.[14] These controversial findings are often influenced by different and unavoidable confounding factors, such as the oral flora. Positive results of 24-hour pH monitoring, upper gastrointestinal endoscopy, and contrast examination only confirm the coexistence of pathological GERD and EEDs, but the association index is not sufficient to derive a chronological order to establish a cause-and-effect relationship. An analysis of a retrospective cohort study showed that treatment failures associated with misdiagnosis accounted for 7% of medically induced adverse events.[15] In clinical work, physicians who have been exposed to or dealt with certain diseases for a long time tend to develop a certain empirical mindset and rarely consider diseases outside their department. Failure to accurately identify the cause can delay treatment and increase the incidence of adverse drug reactions and the economic burden of care.

In recent years, many observational studies have shown an association between GERD and a number of risk factors.[16–18] However, observational studies do not allow for artificially controlled trials and inevitably have unobservable background variables that are susceptible to confounding factors and reverse causality, which in turn can change over time and in the strength of their effect on outcome indicators, thus reducing their credibility.[19] Although randomized controlled trials can provide higher levels of evidence, high costs, weak external validity, and implementation difficulties limit their widespread use.[20] Mendelian randomization (MR) is an epidemiological method that uses genetic variation as instrumental variables to make causal inferences based on 3 main assumptions.[21,22] These assumptions are: the instrumental variable is closely associated with the exposure factor; the instrumental variable is independent of confounding factors; and the instrumental variable is used solely to infer the relationship between exposure and outcome. MR has also been widely used for causal associations between various modifiable exposure factors and GERD,[23] as well as between GERD and related disease, such as atopic dermatitis, asthma, and anxiety disorders.[24–26] These existing MR research findings provide important theoretical support for further exploring the association between GERD and EEDs.

When gastric contents reflux through the upper esophageal sphincter, the reflux may change from liquid to aerosol and enter the pharynx, nasal cavity, and lungs due to anatomical and pressure changes. The observation that reflux events are often temporally associated with cough in up to 50% of patients may only indicate a high probability that GERD is the underlying cause, but not enough to elucidate a causal relationship between these 2 clinical manifestations.[27] Considering the inconsistent conclusions reached by previous observational studies on the relationship between GERD and risk of EEDs, the aim of the present study was to apply a 2-sample MR approach to reveal a potential causal relationship between GERD and EEDs.

Methods

Study design

We have carried out a 2-sample MR analysis of the relationship between GERD and EEDS (throat and chest pain, asthma, bronchitis, chronic rhinitis, nasopharyngitis and pharyngitis, gingivitis and periodontal diseases, and cough on most days) through the genome-wide association study (GWAS) database to reveal a causal relationship. The MR analysis had to satisfy 3 major assumptions: genetic variation is strongly associated with exposure (GERD), exposure can only affect outcomes through genetic variation and not through other biological pathways, and genetic variation is independent of outcome related confounders. The research design is outlined in Figure 1.

Figure 1.

Figure 1.

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Flowchart of the current MR design. GERD = gastroesophageal reflux disease, GWAS = genome-wide association study, MR = Mendelian randomization, MR-PRESSO = Mendelian randomization pleiotropy residual sum, SNP = single nucleotide polymorphism.

GERD data sources

The multitrait analysis of GWAS summary data on GERD (study accession GCST90000514) were obtained from the IEU Open GWAS.[28] The GWAS study included 602,604 European ancestry individuals (129,080 cases and 473,524 controls).

EEDs data sources

The GWAS summary data for EEDs were derived from the finngen consortium. EEDs including throat and chest pain (37,984 cases and 223,726 controls), asthma (32,351 cases and 180,942 controls), bronchitis (42,119 cases and 267,035 controls), chronic rhinitis, nasopharyngitis and pharyngitis (8140 cases and 234,924 controls), gingivitis and periodontal diseases (64,311 cases and 220,537 controls), and cough (11,791 cases and 223,726 controls). The data sources for this study are detailed in Table S1, Supplemental Digital Content, http://links.lww.com/MD/L520.

Genetic instruments selection

Genetic instruments were selected as significantly associated with GERD (P < 5 × 10−8) by clumping single nucleotide polymorphisms (SNPs) in linkage disequilibrium (r2 < 0.001 and within 10,000 kb). We then retrieved each SNP from the outcome GWAS summary data. Exposure-outcome datasets were harmonized to remove strand-ambiguous and palindromic SNPs (detailed in Table S2, Supplemental Digital Content, http://links.lww.com/MD/L522). F-statistics were used to explain the strength of instrumental variables and SNPs with F-statistics > 10 were deemed strong instrumental variables. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and PhenoScanner were also used to identify and remove SNPs with potential pleiotropy and to correct for horizontal.[29]

MR estimates

The random-effects inverse-variance weighted (IVW) was the main method used to measure the overall causal relationship between GERD and EEDs.[30] In considering the variability among SNPs, the variance of the random-effects model was relatively large. IVW combined the Wald ratio of individual SNP on the outcome and used a meta-analysis approach to obtain a pooled causal estimate.[31] MR-Egger regression and weighted median were executed as a complement to IVW approach.[32,33] MR-Egger regression assumes that instrumental variables are not too weak to also provide unbiased causal estimates. The weighted median is the case where more than half of the instrumental variables are valid to provide unbiased estimates of causal effects. If the results of the MR method in our study were in a different direction, a more stringent P-value threshold was set and MR analysis redone.[34] Outlier SNPs were removed and MR analysis was re-performed in 2 cases: 1 removed SNPs with P < .05 if the MR-PRESSO test P-value was <.05 and outliers were detected. The other case removed SNPs with P < 1 from the MR-PRESSO test if the P-value was <.05 and no outliers were detected but heterogeneity remained statistically significant (Cochran Q test).[35] We also searched and removed SNPs on PhenoScanner for recognized risk factors associated with EEDS, including the risk of obesity, cigarettes, alcohol consumption, diabetes, hyperglycemia, hypertension, and hyperlipidemia, before recomputing the MR estimates.[36]

Sensitivity analysis

Cochran Q test, MR-Egger intercept test, Leave-one-out tests, and funnel plot were used to assess potential heterogeneity and pleiotropy in MR analysis. The MR-Egger intercept test of the intercept and Cochran Q test (P < .05) indicate heterogeneity. The leave-one-out test refers to whether the results change dramatically after excluding a single SNP. P < .0083 (0.05/(exposure * outcome), Bonferroni multiple comparisons) is considered a statistically significant result, and P < .05 indicates a nominally significant result. All analysis were performed by the TwoSampleMR package for the R program.

Results

After the rigorous screening process described above, the F-statistics of the genetic variables varied from 29 to 96 (Table S2, Supplemental Digital Content, http://links.lww.com/MD/L522). Primary IVW and sensitivity correlation analyses between GERD and EEDs are shown (Fig. 2). Overall, it was determined that GERD was significantly associated with an increased risk of EEDs. However, heterogeneity was found in asthma, gingivitis and periodontal disease, and throat and chest pain using Cochran Q test, and since the MR-PRESSO results showed no significant outliers, we relaxed the instrumental P-value threshold of SNP to 1 in MR-PRESSO test and removed outlier. When cough was used as the outcome, the β-values of the 3 MR analysis methods were not in the same direction, and the P-value of the limited exposure was <5e−11 before reapplied the MR analysis.

Figure 2.

Figure 2.

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MR results of the causal relationship between GERD and EEDs after the use of MR-PRESSO and PhenoScanner. CI = confidence interval, OR = odds ratio, MR = Mendelian randomization, MR-PRESSO = Mendelian randomization pleiotropy residual sum.

Based on 1 of the 3 main assumptions of MR estimation, genetic variables were searched in PhenoScanner. rs13107325, rs9940128 are linked to obesity, alcohol, and hypertension. rs215614 is affiliated with smoking and obesity. In addition, rs2240326, rs7685686, rs903959, and rs9372625 were associated with alcohol, rs13107325 and rs2744961 with cholesterol, rs329122 and rs9940128 with diabetes. As shown in Figure 2, after removing the above SNPs, causal relationship remains solid.

GERD significantly increased the risk of bronchitis (odds ratio [OR] = 1.249, 95% confidence interval [CI] = 1.168–1.335, P < .001), gingivitis and periodontal disease (OR = 1.116, 95% CI = 1.046–1.190, P = .001), throat and chest pain (OR = 1.585, 95% CI = 1.455–1.726, P < .001), chronic rhinitis, nasopharyngitis and pharyngitis (OR = 1.482, 95% CI = 1.267–1.734, P < .001), and asthma (OR = 1.539, 95% CI = 1.379–1.717, P < .001) in the IVW analysis. No causal relationship between GERD and cough (OR = 1.269, 95% CI = 0.955–1.685, P = .100). EEDs causal estimates similar to IVW were acquired from the weighted median approach and MR-Egger regression. Heterogeneity is no longer detected in bronchitis, chronic rhinitis, nasopharyngitis and pharyngitis, gingivitis and periodontal disease, and throat and chest pain. P-values was >.05 and intercepts close to 0 in the MR-Egger intercept test indicate no significant horizontal polymorphism bias (Fig. 3). MR results of the causal relationship between GERD and EEDs before the use of MR-PRESSO and PhenoScanner are shown in Figure S1, Supplemental Digital Content, http://links.lww.com/MD/L533. The results of the sensitivity analysis leaving out the leave-one-out showed that the association between GERD and EEDs was not significantly driven by a single SNP and that the causality was robust (Fig. S2, Supplemental Digital Content, http://links.lww.com/MD/L524). The funnel plot is symmetrical, suggesting no evidence of pleiotropy (Fig. S3, Supplemental Digital Content, http://links.lww.com/MD/L526).

Figure 3.

Figure 3.

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Scatter plots for MR analyses of the causal effect of GERD on EEDs in replicative practice. (A) Pain in throat and chest. (B) Asthma. (C) Bronchitis. (D) Chronic rhinitis, nasopharyngitis and pharyngitis. (E) Gingivitis and periodontal diseases. (F) Cough. Analyses were conducted using the conventional IVW, weighted median, and MR-Egger. The slope of each line corresponding to the estimated MR effect per method. EEDs = extraesophageal diseases, GERD = gastroesophageal reflux disease, IVW = inverse-variance weighted, MR = Mendelian randomization, SNP = single nucleotide polymorphism.

Discussion

Ours the first study to systematically investigate the causal relationship between GERD and EEDs using multiple MR methods, and a clear causal relationship has significant implications for the prevention of EEDs. Our results suggest that the estimated effect size of GERD on EEDs remained significant after Bonferroni correction and also supported the results from meta-analyses incorporating multiple cross-sectional and longitudinal studies.[37–41] The relationship between GERD and EEDs has been extensively discussed in the literature, and retrospective epidemiological studies and animal studies have indicated that GERD is independently related with an increased incidence and severity of asthma, noncardiac chest pain, dental erosion, and tooth loss.[37–41]

Relationships between GERD and EEDs in observational studies may be biased by drug exposure, colorectal cancer screening, or residual confounding factors, in which case clinical evidence of causality would be extremely difficult or likely to be spuriously associated. Despite considerable progress in the potential mechanisms underlying the association of GERD with EEDs, data from randomized controlled trials treatment-induced changes in GERD have sometimes been inconsistent and conflicting. Adjusted for minimal differences in oral microbiology in GERD patients with long-term proton pump inhibitors (PPIs) use compared to healthy controls without PPI use.[42] A recent double-blinded, randomized clinical trial using PPIs or placebo reported that esomeprazole may transiently inhibit the progression of GERD-related dental erosion.[43] PPIs combined with pro-gastrointestinal motility drugs are common clinical treatments, and effectively inhibiting gastric acid secretion and improving reflux symptoms, which in turn improve asthma symptoms. The distal esophagus defines a highly complex bacterial biota[44] and studies have often overlooked the fact that changes in the oral microenvironment in patients with GERD may alter colonizing bacterial populations.[45,46] Long-term use of PPIs alters the pH of the gastrointestinal and respiratory tracts, making it easier for bacteria to colonize; PPIs may inhibit the activity of neutrophils, cytotoxic T lymphocytes, and natural killer cells, increasing susceptibility to GERD-related disease.

GERD is closely related to other systemic diseases and requires multidisciplinary attention. If GERD is causally related to these diseases, there is an urgent need to develop a multidisciplinary treatment model to improve the effectiveness of disease management. However, atypical clinical manifestations of GERD are easily overlooked by nongastroenterologists, thus affecting the outcome of treatment. The results of our study are consistent with previous reports, Highly acid stomach environments may exert self-protection mechanisms in the body and on gastrointestinal tract mucosa to prevent damage, however, mucosa above the esophagus lacks this mechanism, and once substances such as gastric juice and pepsin break through the reflux barrier to reach other tissues and organs, they may cause extensive damage and induce harmful symptoms.[47] Pathological reflux directly irritates the mucous membrane of the throat and damages esophageal nerve endings leading to throat diseases,[48] while acidification of the esophagus increases sensitivity to coughing.[49] The mechanism of chest pain caused by gastroesophageal reflux is unclear. Considering that both the heart and digestive organs are innervated by vegetative nerves, the nerve conduction processes of both may converge in neurons in the same spinal cord segment and share conduction pathways, thus, the central system may misinterprets pain information from visceral afferents as coming from superficial body tissues and manifests as chest pain.[50] GERD can also alter coronary blood flow.[51] Direct stimulation of bronchoconstriction or activation of the vagal reflex by pharyngeal reflux aerosols, leading to asthma and tracheospasm.[52]

Long-term untreated GERD may cause chronic inflammation of the oral mucosa and periodontal tissues. Periodontal disease is a combination of host response and bacterial infection that destroys the bone and connective tissue that support the teeth.[42] Decreased salivary flow and function is one of the plausible explanations, and saliva may act as an endogenous antacid and antimicrobial agent to protect teeth.[46,53] Patients with GERD have reduced salivary flow and reduced swallowing function, reduced salivary production may not effectively neutralize the acid formed, and exposure of tooth enamel to acidic stomach contents may lead to irreversible dental and periodontal erosion.[54] Tooth loss and severe erosion and impairment of oral function, aesthetics, and other oral health-related quality of life in patients. Another study failed to confirm an association between GERD and dental erosion.[55] For unavoidable reasons, such as retrospective studies, the level of evidence for some results is low, so high-quality evidence is needed to ensure the accuracy of the results.

The etiology of the coexistence of extraintestinal diseases in GERD patients, whether it is attributable to the disease itself, medication treatments, or a combination thereof, remains unknown. Due to ethical constraints in human medicine and limitations of many trial designs, observational studies cannot draw conclusions about causality or even overestimate associations between diseases. Firstly, systemic disease initiators may be overlooked because early disease is usually asymptomatic and disease progression is only observed after prolonged exposure to endogenous acid substances. Secondly, the proposed role of infection and inflammation mechanisms causing EEDs may originate from sites outside the gastrointestinal tract. Therefore, the causal relationship between GERD and EEDs to be verified with high quality.

MR can be understood as an extension of instrumental variables in epidemiology and biomedicine. While traditional epidemiological research methods obtain exposure through experimental or observational methods, genes or epigenetics are born following the law of free association and are born independent of confounding factors such as external environment and social behavior, and are stable exposure factors over time with a clear causal time series, so that associations obtained through MR are not affected or distorted by causal inversions. Multiple MR estimations were performed after obtaining GWAS summary data on exposure and outcome to strengthen the reliability of our findings. Multiple sensitivity analyses were performed to assess and minimize potential heterogeneity and pleiotropy. Although the statistically significant causal relationship between GERD and EEDs passed the Bonferroni correction, the clinical significance of MR estimates should be cautiously treated. Additionally, the heterogeneity was further narrowed by MR-PRESSO. In our study, causality outside of bias was largely excluded by applying MR methods due to a better study design.

Inevitably, there are inevitable limitations of our study. First, we restricted the study population to European populations to reduce bias due to ethnic differences, thus our study does not represent the global population, so it may be prudent to generalize the causal results of this study to other ethnic populations. Second, it was difficult to analyze the impact of different types of GERD types on EEDs in a stratified manner using GWAS summary data. The biological mechanisms of the SNPs chosen for the MR analysis remain unclear.

Our results support observational studies that there is a causal relationship between GERD and EED, which should be identified in detail during clinical consultations, which is important for long-term disease prevention and management. Only by fully understanding the extraesophageal manifestations of GERD, making the correct diagnosis and treatment, and reducing the incidence of misdiagnosis and mismanagement can we further achieve optimal outcomes and reduce the psychological, physical, and social burden of the disease.

Acknowledgments

The authors acknowledge the efforts and selfless contributions of all researchers for whom GWAS summary data are publicly available.

Author contributions

Conceptualization: Peishan Yao, Junming Huang.

Data curation: Peishan Yao.

Funding acquisition: Haixing Jiang.

Investigation: Junming Huang.

Methodology: Xiaomin Liao.

Resources: Peishan Yao.

Software: Yi Dang.

Supervision: Haixing Jiang.

Writing – original draft: Peishan Yao, Xiaomin Liao, Yi Dang.

Supplementary Material

medi-103-e37054-s001.xlsx (10.7KB, xlsx)
medi-103-e37054-s002.xlsx (141.8KB, xlsx)
medi-103-e37054-s003.jpg (64.8KB, jpg)

Abbreviations:

CI
confidence interval
EEDs
extraesophageal diseases
GERD
gastroesophageal reflux disease
GWAS
genome-wide association study
IVW
inverse-variance weighted
MR
Mendelian randomization
MR-PRESSO
mendelian randomization pleiotropy residual sum
OR
odds ratio
PPI
proton pump inhibitor
SNP
single nucleotide polymorphism.

This work was supported by the National Natural Science Foundation of China (81960119), the Guangxi Natural Science Foundation (2018GXNSFAA281221), and the Scientific Research Project of Guangxi Health Commission (No. Z20190717).

All data used in this study were retrieved from publicly available data and therefore did not require additional medical ethics review consent or ethics approval or declaration.

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are publicly available.

Supplemental Digital Content is available for this article.

How to cite this article: Yao P, Liao X, Huang J, Dang Y, Jiang H. Identifying causal relationships between gastroesophageal reflux and extraesophageal diseases: A Mendelian randomization study. Medicine 2024;103:7(e37054).

Contributor Information

Peishan Yao, Email: peishanyao@sr.gxmu.edu.cn.

Xiaomin Liao, Email: liaoxiaomin@stu.gxmu.edu.cn.

Junming Huang, Email: hunjunming@163.com.

Yi Dang, Email: 202280006@sr.gxmu.edu.cn.

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