In this study, we established a causal relationship between GERD and IPF using a large-scale GWAS data analysis. Our findings indicate that GERD is significantly associated with an increase in IPF risk, and that GERD can slightly increase the risk of IPF. To the best of our knowledge, this is the first study to explore the causal relationship between GERD and IPF from a genetic perspective, which contributes to a better understanding of the relationship between these two conditions.
Many studies have been conducted to investigate the relationship between GERD and IPF [29–31], the majority of which have provided support for the close relationship between the two [32–33]. Some previous guidelines conditionally recommend the application of anti-reflux therapy in IPF [34].
However, some studies have suggested that confounding factors may be the cause of the association [13]. The latest guidelines do not recommend the use of anti-reflux therapy to improve the respiratory outcomes of patients with IPF [35]. The inconsistent research results may be attributed to variations in research definition, methodology, sample size, and confounding factors.
The high prevalence of GERD and IPF is well-established [36, 37]. However, there is currently a lack of convincing evidence to determine whether the two are associated or causally linked [38]. In addition, due to the limitations of observational research, the understanding of the causal relationship between them is limited. The advantages of MR could potentially address these issues. The results of this study, based on verified GWAS data and incorporating a series of sensitivity analyses, provide the strongest evidence for clarifying the relationship between GERD and IPF. These results enhance the reliability and robustness of the findings.
This study also sought to identify potential confounding factors in the GERD-IPF pathway. The preliminary results suggest that BMI, smoking, and type 2 diabetes may play a role in promoting the GERD-IPF pathway. Obesity is a common and important risk factor for both GERD and IPF. Previous MR studies have evaluated the impact of BMI on GERD and IPF, indicating that higher BMI may increase the risk of both [39, 40]. To account for the influence of confounding factors, we further employed the MVMR. The aforementioned confounding factors were found to have no significant causal relationship with IPF. Notably, GERD plays an important role in IPF even after accounting for the influence of confounding factors.
It is complex and challenging to clarify the pathogenesis of IPF [41]. Similarly, the mechanism by which GERD increases the risk of IPF is not clear. Possible mechanisms by which GERD may contribute to IPF include inflammatory reactions caused by reflux content [42]. Studies have shown that prolonged chronic micro-inhalation of reflux contents can damage alveolar epithelium, induce macrophage- and T-cell-mediated inflammatory responses, and lead to the formation of abnormal tissues [43–45]. Additionally, persistently high acid levels in the esophagus can lead to increased excitability of the vagus nerve, bronchial and laryngeal hyper-reactive contraction, and the aggravation of respiratory system symptoms, ultimately leading to IPF [46]. Additionally, bile acid has been shown to participate in IPF. Cell experiments have confirmed that bile acid induces transforming growth factor by activating p38 mitogen-activated protein kinase-β and its downstream target, connective tissue growth factor expression [47]. In addition, pepsin has been shown to participate in inflammatory response and airway remodeling [48–50].
Although MR research reduces the interference of reverse causality and confounding factors, it has some limitations. First, some cases in the GERD database were diagnosed using scales rather than objective examination tools. Second, the databases used in this study were from European populations; therefore, the results may not be generalizable to other populations. Finally, the results of this study may only partially explain the causal effect of GERD on IPF, as the occurrence of IPF is also determined by genetic and environmental factors. Therefore, the results of this study should be interpreted with these limitations in mind.