Causal associations between atrial fibrillation and esophageal cancer: a two-sample Mendelian randomization study
Original Article

Causal associations between atrial fibrillation and esophageal cancer: a two-sample Mendelian randomization study

Jinsong Lei1#, Longjun Yang2#, Gongming Wang1, Qianwen Liu1, Guangran Guo1

1Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China; 2Department of Thoracic Surgery, Cancer Hospital of Shandong First Medical University, Jinan, China

Contributions: (I) Conception and design: G Guo; (II) Administrative support: Q Liu; (III) Provision of study materials or patients: L Yang; (IV) Collection and assembly of data: G Wang; (V) Data analysis and interpretation: J Lei; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Qianwen Liu, PhD; Guangran Guo, PhD. Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Yuexiu District, Guangzhou 510060, China. Email: liuqw@sysucc.org.cn; guogr@sysucc.org.cn.

Background: Previous studies indicated that atrial fibrillation (AF) patients had a significantly higher esophageal cancer (EC) risk. However, influencing by confounding factors, the causal effect is uncertain. In this study, we aimed to validate the causal relationship between AF and EC by Mendelian randomization (MR) analysis.

Methods: An observational analysis was conducted using the data from the National Health and Nutrition Examination Survey (NHANES) and UK Biobank. Then a two-sample MR method was employed to assess the causal effect of AF on EC. The exposure of AF was collected from publicly available genome-wide association studies (GWASs). Meanwhile, the EC outcome data were derived from the UK Biobank and the FinnGen consortium. A set of 108 single-nucleotide polymorphisms (SNPs) served as instrumental variables (IVs). The effect estimates were calculated using the inverse variance weighted (IVW) method.

Results: Genetically predicted AF was associated with an increased risk of EC [odds ratio (OR), 1.73; 95% confidence interval (CI): 1.01–1.73; P=0.04]. The similar results could be found by sensitivity analyses and no any evidence of horizontal pleiotropy was observed.

Conclusions: This two-sample MR analysis suggested that AF was causally associated with an increased risk of EC.

Keywords: Atrial fibrillation (AF); esophageal cancer (EC); Mendelian randomization (MR)

Submitted Oct 28, 2024. Accepted for publication Jan 14, 2025. Published online Mar 10, 2025.

doi: 10.21037/tcr-24-2107

Highlight box

Key findings

• This study confirmed the causal relationship between atrial fibrillation (AF) and esophageal cancer (EC) by Mendelian randomization analysis.

What is known and what is new?

• Previous observational studies indicated that AF may increase the risk of EC.

• The causal associations those two diseases have been not elucidated yet.

What is the implication, and what should change now?

• AF patients need to pay attention to possible EC-related syndrome and consult for more medical help.

Introduction

The global prevalence of atrial fibrillation (AF) has increased substantially over the past three decades, concerning approximately 60 million cases (1). AF is associated to morbidity and mortality due to systemic embolic complications and heart failure (2). In addition to cardiovascular complications, cancer also accounts for approximately 11% of all deaths in AF patients (3). Owing to rapid population aging and the increasing global burden seen in both diseases, more work needs to answer whether AF is a risk factor for cancer.

A comprehensive nationwide cohort study revealed that individuals diagnosed with AF exhibited a markedly increased risk of developing cancer compared to the general population. Notably, patients with newly onset AF faced the greatest cancer risk during the initial year post-diagnosis, and this elevated risk continued to be evident even after 10 years (4). Recently, another research based on 25,964,447 Chinese patients revealed that AF was associated with 1.41-fold increased prevalence of esophageal cancer (EC) (5). However, it remains unclear whether AF and EC will interact and the causal relationship of AF and EC deserves further confirmation.

As a matter of fact, an increase of AF incidence among EC patients was also reported (6). Traditional observational studies, including well-designed prospective studies frequently encounter limitations due to residual confounding and reverse causality. Mendelian randomization (MR) is a method using genetic variants as instrumental variables (IVs) for exposures to evaluate the potential causality between various exposures and clinical outcomes. Since genetic variations are established at conception and occur before the development of disease, MR analysis can address reverse causation bias and minimize the impact of potential unmeasured confounders (7). In this research, we aimed to explore the potential causal link between AF and EC using the two-sample MR analysis. We present this article in accordance with the STROBE-MR reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2107/rc).

Methods

Study design and data sources

In our study, we used a two-sample MR approach to evaluate the causal relationship between AF and EC, with the study design depicted schematically in Figure 1. The rationale of our MR design is based on three specific criteria: firstly, the genetic variants are strongly associated with AF; secondly, the absence of associations between these genetic variants and other confounding variables; and thirdly, the genetic variants influence the clinical outcome exclusively through AF. For this analysis, we obtained genome-wide association study (GWAS) summary statistics for AF from the resource based on six contributing studies (8) to explore the association between AF and single-nucleotide polymorphisms (SNPs). The genetic data for EC (n=218,792) were obtained from the UK Biobank (https://www.ukbiobank.ac.uk) and the FinnGen consortium (https://www.finngen.fi/en). All GWAS statistics used were publicly available and ethical approval was not required for this study. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Figure 1 The schematic view of the study design with three assumptions: (I) the genetic variants are robustly associated with AF; (II) the genetic variants are not associated with other confounders; and (III) the genetic variants are associated with the clinical outcome only through AF. AF, atrial fibrillation; SNP, single-nucleotide polymorphism.

Two public databases were used to investigate the incidence correlation between AF and EC. We utilized data from the National Health and Nutrition Examination Survey (NHANES) for the years 1999 to 2023, with a total of 58,744 individuals aged 18 years and older, and data from the UK Biobank, which included 467,627 participants from 2006 to 2010, aged between 37 and 73 years. Data on age, gender, education, smoking, alcohol consumption, and the status of EC and AF were extracted from the two databases.

Selection and validation of SNPs

We pinpointed 108 independent SNPs linked to AF by adhering to three criteria. Firstly, SNPs were chosen based on a genome-wide significance threshold, where P values were less than 5×10−8. The second criterion involved using paired linkage disequilibrium to ensure the independence of selected SNPs. SNPs with r2>0.001 within a clumping window of 10,000 kb were discarded if they were correlated with more SNPs or had higher P values. Lastly, we confirmed the strength of individual SNPs using the F statistic, considering SNPs as sufficiently strong to reduce potential bias if their F-statistics exceeded ten. Aata-harmonization steps were also conducted before performing the MR analysis.

Statistical analysis

For the primary analysis, we utilized random effect inverse variance weighted (IVW) MR methods, which presumes that all SNPs serve as valid instruments and calculates the effect of each variant using first-order weights. To assess horizontal pleiotropy among the selected SNPs, we subsequently applied the MR-Egger method and weighted median analysis. MR-Egger method allows for directional pleiotropy and the MR-Egger intercept estimates the average pleiotropic effect across all SNPs. If the MR Egger intercept deviates from zero, directional pleiotropy is present. Similarly, funnel plots can also identify directional pleiotropy if there is asymmetry. The Q statistic was employed to test for heterogeneity among SNPs in the IVW analysis. We also performed a leave-one-out sensitivity analysis to determine if any single SNP disproportionately influenced the overall estimates. The effects of AF on EC were reported as odds ratios (ORs) with 95% confidence intervals (CIs). All statistics were carried out using the “Two-Sample MR” package in R 4.2.0. For the significant causal associations in the univariable MR analysis, the multivariable MR (MVMR) analysis was performed using the MVMR-IVW method, aiming to adjust for potential confounding factors including smoking, alcohol, education (9) as well as obesity (Table S1).

Results

Firstly, we compared the incidence rate of EC between AF patients and normal people. The incidence was higher in AF patients compared with the general population (Table 1). To confirm the causal relationship between the two diseases, we selected SNPs and then estimated the effect of genetically predicted AF on EC.

Table 1

Characteristics of the cohort studies

Variables NHANES UK Biobank
AF (n=1,525) Control (n=57,219) AF (n=8,356) Control (n=459,271)
Age (years) 67 [60–79] 49 [34–64] 64 [59–67] 57 [49–63]
Gender
   Female 815 [53] 29,679 [52] 2,530 [30] 257,218 [56]
   Male 710 [47] 27,540 [48] 5,826 [70] 202,053 [44]
Education
   College degree 645 [42] 28,561 [50] 2,312 [27.7] 149,955 [32.7]
   Others 880 [58] 28,658 [50] 6,044 [72.3] 309,316 [67.3]
Smoke
   Yes 747 [49] 24,489 [43] 4,512 [54] 202,597 [44.1]
   No 34 [2.2] 1,128 [2.0] 3,844 [46.0] 256,674 [55.9]
   Unknown 744 [49] 31,602 [55] – –
Drink
   Yes 169 [11] 7,066 [12] 7,985 [95.6] 438,662 [95.5]
   No 12 [0.8] 730 [1.3] 371 [4.4] 20,509 [4.5]
   Unknown 1,344 [88] 49,423 [86] – –
EC 3 [0.2] 33 [<0.1] 33 [0.4] 983 [0.2]

Data are presented as median [IQR] or n [%]. AF, atrial fibrillation; EC, esophageal cancer; IQR, interquartile range; NHANES, National Health and Nutrition Examination Survey.

We identified 108 independent SNPs associated with AF (Table S2). Then we applied random-effects IVW models, and the two-sample MR analyses based on these SNPs demonstrated a causal effect of genetically predicted AF on the risk of EC (OR, 1.32; 95% CI, 1.01–1.73; P=0.04). Even after adjusting for smoking, alcohol, education as well as obesity, the causal effect of AF on EC still existed (Figure 2). The results of MR-Egger and weighted median are consistent with the IVW models but of low precision. No evidence of directional pleiotropy and heterogeneity were detected (Table 2).

Figure 2 Associations of AF with EC. AF, atrial fibrillation; CI, confidence interval; EC, esophageal cancer; nSNP, number of SNP; OR, odds ratio; SNP, single-nucleotide polymorphism.

Table 2

Sensitivity analyses of the genetic association between AF and EC risk

Sensitivity analyses Value P value
MR-Egger
   OR (95% CI) 1.24 (0.74–2.07) 0.41
Weight median
   OR (95% CI) 1.21 (0.72–2.03) 0.47
Heterogeneity test
   Cochrane Q 96.26 0.72
Pleiotropy test
   Intercept 0.006 0.77

AF, atrial fibrillation; CI, confidence interval; EC, esophageal cancer; MR, Mendelian randomization; OR, odds ratio.

The funnel plots in Figure 3 revealed no evidence of directional pleiotropy. The scatter plots illustrating the association between AF and EC are presented in Figure S1, revealing similar results. The leave-one-out sensitivity analysis confirmed that the association was not significantly driven by any individual SNP (Figure S2). In addition, Figure S3 provides details on the associations of each variant with AF and the risk of EC.

Figure 3 Funnel plot of the associations between AF and EC. AF, atrial fibrillation; EC, esophageal cancer; IV, instrumental variable; MR, Mendelian randomization; SE, single equation.

Discussion

Given the lengthened life expectancy in the general population, the coexistence of AF and cancer has also increased pervasively, and AF may present an additional factor affecting the prognosis of malignant diseases (10). A large initially healthy cohort showed that women with new-onset AF had an elevated cancer risk beyond 1 year of AF diagnosis (11). Yet, limited research has been done to confirm the potential causality relationship between AF and EC. To our knowledge, this is the first MR analysis to reveal the causal relationship between AF and EC.

Previous studies have indicated a close association between AF and EC. Firstly, postoperative AF is frequently observed in EC patients undergoing esophagectomy with an increased risk of death (12). For EC therapy, radiation (13) and anticancer agent like fluorouracil (14) also increases AF risk. Even for cancer patients without active treatment are still associated with a 20% increased risk of AF (15). One nationwide population-based study revealed that AF risk varies depending on the cancer type, and EC patients show the highest AF risk among all the solid cancers (16). In addition, patients with cancer and new-onset AF showed a 2-fold increased risk of thromboembolism and a 6-fold increased risk of heart failure (17). However, the potential causality role of AF on EC still remains unknown. Few studies showed that AF patients had a higher risk of EC (5) and suggested that AF may be a risk and predictor of EC (4). If the causal relationship is established, AF patients need to pay attention to possible EC-related syndrome.

In our study, we uncovered the causal effect of AF on EC by two-sample MR analysis using large-scale GWAS data, inferring the higher risk of EC among AF patients comparing to the normal people.

It remains unclear why AF patients are associated with increased prevalence of EC, and some factors may be responsible for the increased risk. First, some common risk factors such as smoking, alcohol use, and obesity are shared by both diseases (18). It has also been reported that higher educational attainment has a protective effect on EC (19). However, causality relationship between AF and EC still existed based on MR analysis even after adjustment for these factors, suggesting that another mechanism may involve. Considering that inflammation promotes the progress of the two diseases, inflammation may be another possible mechanism. Indeed, remodeling and increased energy demand during AF lead to oxidative stress (20), which could cause the esophageal injury indirectly (21). It has been proven that during the Barrett’s esophagus-dysplasia-EC sequence, esophageal cells are under a tremendous burden of accumulating reactive oxygen species oxidative stress (22). In addition, the STAT3/NF-κB signaling increases AF vulnerability (23) as well as involvement in tumorigenesis (24). NF-κB modulates EC tumor microenvironment and is linked to poor prognosis (25). Furthermore, remodeling of the extracellular matrix (ECM) has been identified as a significant factor contributing to the pathophysiology of both AF and EC. Fibroblasts control the composition and structure of ECM and play a central role in stabilizing the reentrant drivers that maintain the arrhythmia (26). In EC, cancer-associated fibroblasts can also promote tumorigenesis, metastatic dissemination, and therapeutic resistance (27).

Recent study has shown that EC-related gene-4 (ECRG4) is implicated in the pathogenesis of AF. Downregulation of ECRG4 expression level correlates with myocardial injuries and arrhythmias as well as EC (28). ECRG4 may be used in the treatment of arrhythmias and tumors in this regard. However, there are some unique challenges for therapeutic decision-making in AF patients with cancer. As a matter of fact, the use of anticoagulants for reducing the high risk of AF-associated thromboembolism may increase the risk of bleeding in EC, especially for those who have received treatment (29). Considering the heterogeneity in cancer patients, risk assessments should also take into account cancer stage, treatment response, and overall prognosis (30). Furthermore, the immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for EC (31), while ICI-associated myocarditis may contribute to higher risk of atrial arrhythmias (32). Understanding the relationship between AF and EC may result in improved prevention and treatment strategies for both diseases.

This study is the first MR analysis to uncover the causal effects of AF on EC. Comparing to traditional observational studies, MR analyses are well suited to overcome confounding by unmeasured factors. Additionally, the role of inflammation among AF on EC and their potential mechanism deserve further study. Despite the findings, there are several limitations to consider. Firstly, the GWAS data were derived from individuals of European ancestry, potentially limiting the generalization of our results to other population. Then, in the period following AF diagnosis, there are more interactions with healthcare, and thus providing more opportunities to find asymptomatic EC. Moreover, children are susceptible to AF but have a low probability of suffering EC, the age-specific relationships between AF and EC should be further clarified in the future.

Conclusions

In conclusion, this two-sample MR analysis identified causal relationships between AF and EC. Furthermore, additional research is necessary to clarify the underlying mechanisms that mediate the association between these two diseases.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE-MR reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2107/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2107/prf

Funding: The study was supported by the Guangzhou Science and Technology Program (No. 2024A04J4411).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2107/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Lei J, Yang L, Wang G, Liu Q, Guo G. Causal associations between atrial fibrillation and esophageal cancer: a two-sample Mendelian randomization study. Transl Cancer Res 2025;14(3):1849-1856. doi: 10.21037/tcr-24-2107

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