Causal relationship between gastroesophageal reflux disease and pneumoconiosis: Evidence from a clinical retrospective study and two-sample Mendelian randomization
Year: 2025
Type: article
Study design: Observational Study
Abstract: To the Editor: Gastroesophageal reflux disease (GERD) has been implicated in a range of respiratory conditions.[1] However, its relationship with pneumoconiosis has received less attention. In this study, we conducted a case-control study, in addition to a two-sample Mendelian randomization (MR) analysis, to investigate the potential causal relationship between GERD and pneumoconiosis [Figure 1].Figure 1: The abstract graphic of the study design. The integration of a retrospective case-control study and MR analysis suggested that GERD as a risk factor for pneumoconiosis. MR: Mendelian randomization; GERD: Gastroesophageal reflux disease; SNP: Single-nucleotide polymorphism.Case-control study: Patients were recruited from Shandong Provincial Research Institute for Occupational Health and Occupational Disease Prevention between August 1, 2021, and July 31, 2024. This study was approved by the Ethics Committee of the Shandong Provincial Research Institute for Occupational Health and Occupational Disease Prevention (SDZFY-EC-H-2021-05). Informed consent was obtained from all participants. All patients were diagnosed with pneumoconiosis based on the guidelines. Patients with unclear diagnosis or classification and those without complete clinical data were excluded. Clinical data, including age, gender, ethnicity, duration of exposure, protective measures, smoking, alcohol use, daily working hours, and daily sleep duration, were extracted from medical records. GERD Q was employed as the diagnostic tool for GERD in this study. Statistical analyses were conducted using SPSS version 29.0 (SPSS Inc., USA). Continuous data are expressed as mean ± standard deviation, and comparisons between groups were made using the independent sample t-test. Categorical data are presented as frequencies and percentages, with comparisons between groups conducted using the chi-squared test. Covariables with statistical significance in univariable analysis were included in the multivariable logistic regression model. Multivariable logistic regression was employed to identify the factors involved in the development of pneumoconiosis. A P-value of <0.05 was considered statistically significant. The characteristics of 53 patients with pneumoconiosis and 56 healthy controls are summarized in Supplementary Table 1, https://links.lww.com/CM9/C583. There were significant differences between the two groups in terms of age, exposure duration, and positive outcomes of GERD Q (all P <0.05). No significant differences were found between the two groups in terms of protective measures, smoking status, alcohol use, daily working hours, or daily sleep duration (all P >0.05). The variables used for multivariable logistic regression are presented in Supplementary Table 2, https://links.lww.com/CM9/C583. Exposure duration ≥15 years (odds ratio [OR] = 5.274, 95% confidence interval [CI] 2.182–12.747) and positive outcomes of GERD Q (OR = 5.899, 95% CI 1.656–21.010) were identified as independent risk factors of pneumoconiosis (both P <0.05) [Supplementary Table 3, https://links.lww.com/CM9/C583]. Mendelian randomization: Summary data for GERD were obtained from a large-scale genome-wide association study (GWAS) with 602,604 participants. The summary data for pneumoconiosis included 479,040 participants. Details of the GWAS summary-level data are shown in Supplementary Table 4, https://links.lww.com/CM9/C583. These data are publicly available in the IEU Open GWAS Project database (https://gwas.mrcieu.ac.uk). All data used in this study are publicly accessible and were derived from GWAS summary statistics; therefore, ethics approval and informed consent were not required. We used the published single-nucleotide polymorphisms (SNPs) with a strong relationship (P <5.0 × 10–8) and independent inheritance (r2 <0.01) for GERD as an instrumental variable in MR analysis. Subsequently, data related to these instrumental variables in the context of the outcome (pneumoconiosis) were extracted. In total, 49 independent SNPs were identified as genetic markers. The inverse-variance weighted (IVW) analysis revealed a significant association between GERD and pneumoconiosis (OR = 2.981; 95% CI 1.530–5.808; P = 0.001). Furthermore, the results of MR-Egger, weighted median, simple mode, and weighted mode were consistent with those of the IVW, although some methods mentioned above (MR-Egger, simple mode, and weighted mode) did not exhibit statistical significance (P >0.05). The OR values for each method are summarized in Supplementary Table 5, https://links.lww.com/CM9/C583, demonstrating a robust causal relationship between GERD and pneumoconiosis based on the IVW method, with supportive evidence from alternative MR approaches. We employed multiple statistical approaches to mitigate potential limitations and enhance the causal inference validity of MR analysis. During SNP selection, we systematically excluded SNPs directly associated with confounders or outcomes using linkage disequilibrium-link to minimize biological pleiotropy. A clustering distance threshold of 10,000 kb was considered to avoid pleiotropy caused by linkage disequilibrium. MR-pleiotropy RESidual sum and outlier (MR-PRESSO) analysis for horizontal pleiotropy among instrumental variables yielded a P-value of 0.898 (P >0.05), confirming the absence of significant horizontal pleiotropy and validating the MR assumptions. Stringent quality control was performed on the selected SNPs, with an F-statistic (calculated by the formula: F = beta2/se2) >10 threshold to prevent weak instrument bias. Subsequent sensitivity analyses evaluated potential pleiotropy and genetic outliers. Cochran’s Q test, based on MR-Egger and IVW calculations, showed Q statistics of 54.59 and 54.61 with corresponding P-values of 0.20 and 0.23, respectively. These non-significant results (P >0.10) indicated no genetic heterogeneity among instrumental variables, resolving the need for heterogeneity adjustment. The robustness of instrumental variables was also confirmed using the leave-one-out test, showing that no single SNP disproportionately affected the outcome [Supplementary Figure 1A, https://links.lww.com/CM9/C583]. The effects of individual SNPs and the combined MR method were visualized using a scatter plot [Supplementary Figure 1B, https://links.lww.com/CM9/C583]. Collectively, these analyses provide robust evidence supporting a positive association between GERD and the development of pneumoconiosis. In this study, we integrated a retrospective case-control analysis with a two-sample MR approach to investigate the association between GERD and pneumoconiosis. This study provides genetic evidence linking GERD to pneumoconiosis, offering new insights into the clinical management of pneumoconiosis. In patients with pneumoconiosis and risk factors of GERD, such as alcoholism and obesity, the symptoms of GERD should be taken seriously. We recommend initiating GERD screening for patients with symptomatic pneumoconiosis. In occupational health settings with limited resources, a more cost-effective stepped intervention combining questionnaires and symptom-oriented approaches can be adopted. From a diagnostic perspective, since GERD can trigger esophageal-bronchial cough reflux, it is important to differentiate whether cough in patients with pneumoconiosis and comorbid GERD is caused by GERD or by pneumoconiosis itself. Regarding treatment, the involvement of GERD in the progression of pneumoconiosis suggests that some GERD medications, such as proton pump inhibitors and H2-receptor blockers, may help patients with pneumoconiosis and comorbid GERD. Nevertheless, our study has certain limitations. First, the relatively small sample size may have limited the statistical power of this study to detect subtle inter-group differences, necessitating large-scale prospective studies to investigate the relationship between GERD and pneumoconiosis. Second, since all the SNP data were derived from European populations, and despite the positive findings in a small-scale Chinese case-control study, the substantial differences in ORs suggest potential differences in susceptibility to pneumoconiosis across ethnic groups. Therefore, these results should be extrapolated with caution. Finally, the lack of strongly associated SNPs when considering pneumoconiosis as the exposure precluded the analysis of reverse causality. Large-scale prospective studies are needed to investigate the relationship between GERD and pneumoconiosis, thereby providing higher-level epidemiological evidence, improving GWAS across different populations, and offering cross-ethnic genetic data. Future studies should prioritize three interconnected objectives: First, elucidating the specific pathogenic mechanisms through which gastric components (e.g., gastric acid, proteases, and bile acids) damage pulmonary tissue,[2,3] while establishing dose-response thresholds for the activation of pro-fibrotic pathways, including toll-like receptor (TLR)-mediated inflammation, transforming growth factor β (TGF-β)/Smad3 signaling, and farnesoid X receptor (FXR).[4] Second, deciphering core regulatory nodes in the inflammation-fibrosis cascade, particularly tumor necrosis factor α (TNF-α)/interleukin 6 (IL-6)-driven immune cell recruitment dynamics and matrix metalloproteinase-9 (MMP-9)-mediated airway remodeling. Third and most critically, investigating synergistic interactions between GERD-induced oxidative stress, pulmonary dysbiosis,[5] and occupational dust exposure. Such studies can establish a mechanistic foundation for developing early preventive interventions and targeted therapeutics for pneumoconiosis. Randomized controlled trials are necessary to determine the actual effect of GERD management on the prognosis of pneumoconiosis. In conclusion, the integration of case-control studies and MR analysis suggested that GERD could be a potential risk factor for pneumoconiosis. This finding can help understand the mechanisms by which GERD increases the risk of pneumoconiosis, helping identify patients who may benefit from existing interventions and providing novel insights into the prevention and treatment of pneumoconiosis. Funding This work was supported by grants from the National Natural Science Foundation of China (No. 82170650) and the Natural Science Foundation of Shandong Province (No. ZH2021MH178). Conflicts of interest None.
Source: Chinese Medical Journal
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,000
OpenAlex ID: W4413279502