Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Dec 15, 2023; 15(12): 2169-2184
Published online Dec 15, 2023. doi: 10.4251/wjgo.v15.i12.2169
Evaluating the causal relationship between human blood metabolites and gastroesophageal reflux disease
Jia-Yan Hu, Mi Lv, Kun-Li Zhang, Xi-Yun Qiao, Yu-Xi Wang, Feng-Yun Wang
Jia-Yan Hu, Mi Lv, Kun-Li Zhang, Xi-Yun Qiao, Yu-Xi Wang, Feng-Yun Wang, Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
Author contributions: Hu JY and Lv M designed the research; Hu JY, Zhang KL, Qiao XY collected and analyzed the data; Hu JY, Lv M and Zhang KL drafted the manuscript; Qiao XY, Wang YX and Wang FY revised the manuscript; Wang FY for the entire text; all authors contributed to the article and approved the submitted version.
Supported by National Natural Science Foundation of China, No. 82174363.
Institutional review board statement: Only publicly available genome-wide association study (GWAS) data were used in this study, and the Ethics approval and consent to participate could be available in the original GWAS study.
Conflict-of-interest statement: The authors report no conflicts of interest.
Data sharing statement: All data generated or during this study are included in this published article and the supplementary materials. genome-wide association study (GWAS) summary statistics for human blood metabolites were publicly available at https://metabolomics.helmholtz-muenchen.de/gwas/. GWAS summary statistics for gastroesophageal reflux disease can be found here: https://cnsgenomics.com/content/data and https://gwas.mrcieu.ac.uk/.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Feng-Yun Wang, PhD, Chief Doctor, Professor, Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, No. 1 Courtyard, Xiyuan Playground, Haidian District, Beijing 100091, China. wfy811@163.com
Received: July 29, 2023
Peer-review started: July 29, 2023
First decision: September 23, 2023
Revised: October 1, 2023
Accepted: October 30, 2023
Article in press: October 30, 2023
Published online: December 15, 2023
Processing time: 138 Days and 0.7 Hours
Abstract
BACKGROUND

Gastroesophageal reflux disease (GERD) affects approximately 13% of the global population. However, the pathogenesis of GERD has not been fully elucidated. The development of metabolomics as a branch of systems biology in recent years has opened up new avenues for the investigation of disease processes. As a powerful statistical tool, Mendelian randomization (MR) is widely used to explore the causal relationship between exposure and outcome.

AIM

To analyze of the relationship between 486 blood metabolites and GERD.

METHODS

Two-sample MR analysis was used to assess the causal relationship between blood metabolites and GERD. A genome-wide association study (GWAS) of 486 metabolites was the exposure, and two different GWAS datasets of GERD were used as endpoints for the base analysis and replication and meta-analysis. Bonferroni correction is used to determine causal correlation features (P < 1.03 × 10-4). The results were subjected to sensitivity analysis to assess heterogeneity and pleiotropy. Using the MR Steiger filtration method to detect whether there is a reverse causal relationship between metabolites and GERD. In addition, metabolic pathway analysis was conducted using the online database based MetaboAnalyst 5.0 software.

RESULTS

In MR analysis, four blood metabolites are negatively correlated with GERD: Levulinate (4-oxovalerate), stearate (18:0), adrenate (22:4n6) and p-acetamidophenylglucuronide. However, we also found a positive correlation between four blood metabolites and GERD: Kynurenine, 1-linoleoylglycerophosphoethanolamine, butyrylcarnitine and guanosine. And bonferroni correction showed that butyrylcarnitine (odd ratio 1.10, 95% confidence interval: 1.05-1.16, P = 7.71 × 10-5) was the most reliable causal metabolite. In addition, one significant pathways, the “glycerophospholipid metabolism” pathway, can be involved in the pathogenesis of GERD.

CONCLUSION

Our study found through the integration of genomics and metabolomics that butyrylcarnitine may be a potential biomarker for GERD, which will help further elucidate the pathogenesis of GERD and better guide its treatment. At the same time, this also contributes to early screening and prevention of GERD. However, the results of this study require further confirmation from both basic and clinical real-world studies.

Keywords: Blood metabolites; Gastroesophageal reflux disease; Mendelian randomization; Causality; Pathogenesis; Biomarkers; Metabolic pathway

Core Tip: At present, there is no study on blood metabolomics of gastroesophageal reflux disease (GERD). This may be the first study combining metabolomics and genomics to explore the causal relationship between serum metabolites and GERD. We found that there was a significant correlation between eight metabolites and GERD, among which butyrylcarnitine was the most reliable pathogenic metabolite (odd ratio 1.10, 95% confidence interval: 1.05-1.16). Glycerophospholipid metabolism may be involved in the pathogenesis of GERD. The results provide a reference direction for the early screening, prevention and treatment of GERD and the design of future clinical research.