Gastroesophageal reflux disease causes an increased risk of chronic obstructive pulmonary disease: a two-sample bidirectional Mendelian randomization study

Niu Xiaoya; Xiong Yajun; Cai Mengting; Chen Yu; Song Chunhua; Xu Aiguo

doi:10.13406/j.cnki.cyxb.003396

您当前的位置：

首页 >

文章列表页 >

Gastroesophageal reflux disease causes an increased risk of chronic obstructive pulmonary disease: a two-sample bidirectional Mendelian randomization study

Mendelianrandomization | 更新时间：2025-10-22

- Gastroesophageal reflux disease causes an increased risk of chronic obstructive pulmonary disease: a two-sample bidirectional Mendelian randomization study
- Journal of Chongqing Medical University Vol. 48, Issue 12, Pages: 1439-1445(2023)
- 作者机构：
  
  1.郑州大学第一附属医院呼吸与危重症医学科，郑州 450000
  2.郑州大学公共卫生学院流行病学教研室，郑州 450000
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003396
  CLC： R563
- Received：15 September 2023，
  
  Revised：2023-11-18，
  
  Accepted：21 November 2023，
  
  Published：28 December 2023
- 稿件说明：
移动端阅览
牛晓亚,熊雅俊,蔡梦婷,等.胃食管反流病增加慢性阻塞性肺疾病的患病风险：一项两样本双向孟德尔随机化研究[J].重庆医科大学学报,2023,48(12):1439-1445.

Niu Xiaoya,Xiong Yajun,Cai Mengting,et al.Gastroesophageal reflux disease causes an increased risk of chronic obstructive pulmonary disease: a two-sample bidirectional Mendelian randomization study[J].Journal of Chongqing Medical University,2023,48(12):1439-1445.
牛晓亚,熊雅俊,蔡梦婷,等.胃食管反流病增加慢性阻塞性肺疾病的患病风险：一项两样本双向孟德尔随机化研究[J].重庆医科大学学报,2023,48(12):1439-1445. DOI： 10.13406/j.cnki.cyxb.003396.

Niu Xiaoya,Xiong Yajun,Cai Mengting,et al.Gastroesophageal reflux disease causes an increased risk of chronic obstructive pulmonary disease: a two-sample bidirectional Mendelian randomization study[J].Journal of Chongqing Medical University,2023,48(12):1439-1445. DOI： 10.13406/j.cnki.cyxb.003396.

摘要

目的

采用两样本双向孟德尔随机化（Mendelian randomization，MR）方法研究胃食管反流病（gastroesophageal reflux disease，GERD）与慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）的因果关系。

方法

基于大规模全基因组关联研究（genome-wide association studies，GWAS）汇总数据，选择相互独立且与胃食管反流病及COPD高度相关的单核苷酸多态性（single nucleotide polymorphism，SNP）作为工具变量。采用逆方差加权法固定效应模型（inverse variance weighted-fixed effects，IVW-FE）为主要分析方法，简单中位数法、加权中位数法、MR Egger回归法进行结果验证和稳定性检验；采用

统计量、Cochran

检验、MR Egger截距测试、孟德尔随机多态性残差和离群值（mendelian randomization pleiotropy residual sum and outlier，MR-PRESSO）检验、“留一法”进行敏感性分析。以比值比（odds ratio，

）及95%置信区间（confidence interval，CI）作为效应指标对胃食管反流病及COPD的双向因果关系进行探讨。

结果

IVW-FE分析表明胃食管反流病可增加COPD的患病风险（

=1.757，95%CI=1.425~2.166，

=0.000），且在简单中位数法、加权中位数法中被证实。然而MR Egger回归法未显示出二者之间的因果关联。在反向MR分析中，IVW-FE分析显示没有证据表明COPD增加胃食管反流病的发病风险（

=0.999，95%CI=0.962~1.037，

=0.962），同样简单中位数法、加权中位数法、MR Egger回归法未发现二者存在因果关联。工具变量的

值均大于10，不存在弱工具变量；Cochran

检验、MR Egger截距测试、MR-PRESSO检验表明工具变量间不存在异质性或水平多效性；“留一法”分析显示没有单个SNP对整体结果有较大影响。

结论

胃食管反流病与COPD的风险增加有显著的因果关系，但是没有发现COPD导致胃食管反流病风险增加的证据。

Abstract

Objective

To investigate the causal relationship between gastroesophageal reflux disease（GERD） and chronic obstructive pulmonary disease（COPD） using two-sample bidirectional Mendelian randomization（MR）.

Methods

Based on the pooled data from large-scale genome-wide association studies（GWAS），single nucleotide polymorphisms（SNPs） which were independent of each other and highly correlated with GERD and COPD were selected as instrumental variables. The inverse-variance weighted fixed-effects（IVW-FE） model was used as the main analysis method，while simple median，weighted median，and MR-Egger regression methods were used to validate the results and test the stability. The

-statistic，Cochran’

s Q test，MR-Egger intercept test，Mendelian randomization pleiotropy residual sum and outlier（MR-PRESSO） test，and leave-one-out method were used for sensitivity analysis. The odds ratio（

） and 95% confidence interval（CI） were used as effect sizes for the bidirectional causal relationship between GERD and COPD.

Results

The IVW-FE analysis showed that GERD increased the risk of COPD（

=1.757，95%CI=1.425-2.166，

=0.000），which was confirmed by the simple median and weighted median methods. However，no causal relationship between the two factors was shown by the MR-Egger method. In the inverse MR analysis，there was no evidence of increased risk of GERD caused by COPD using IVW-FE（

=0.999，95%CI=0.962-1.037，

=0.962）. Similarly，no association between the two factors was found using the simple median，weighted median，and MR-Egger regression methods. The

F-

statistic of the instrumental variable was greater than 10，which showed that there was no weak instrumental variable. The Cochran’s Q test，MR-Egger intercept test，and MR-PRESSO test did not show heterogeneity or horizontal pleiotropy between instrumental variables. The leave-one-out analyses indicated that no single SNP had a significant effect on the overall outcome.

Conclusion

GERD is significantly and causally associated with an increased risk of COPD. However，there is no evidence suggesting that COPD causes an increased risk of GERD.

关键词

Keywords

references

Agustí A ， Celli BR ， Criner GJ ， et al . Global initiative for chronic obstructive lung disease 2023 report：gold executive summary [J ] . Eur Respir J ， 2023 ， 61 （ 4 ）： 2300239 ．

Christenson SA ， Smith BM ， Bafadhel M ， et al . Chronic obstructive pulmonary disease [J ] . Lancet ， 2022 ， 399 （ 10342 ）： 2227 - 2242 ．

Wu CT ， Li GH ， Huang CT ， et al . Acute exacerbation of a chronic obstructive pulmonary disease prediction system using wearable device data，machine learning，and deep learning：development and cohort study [J ] . JMIR Mhealth Uhealth ， 2021 ， 9 （ 5 ）： e22591 ．

Katz PO ， Dunbar KB ， Schnoll-Sussman FH ， et al . ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease [J ] . Am J Gastroenterol ， 2022 ， 117 （ 1 ）： 27 - 56 ．

Chapelle N ， Ben Ghezala I ， Barkun A ， et al . The pharmacotherapeutic management of gastroesophageal reflux disease（GERD） [J ] . Expert Opin Pharmacother ， 2021 ， 22 （ 2 ）： 219 - 227 ．

Chiu YC ， Chang WP ， Tang GJ ， et al . Chronic obstructive pulmonary disease is associated with a higher risk of functional gastrointestinal disorders [J ] . Respir Med ， 2022 ， 197 ： 106833 ．

Zou ML ， Zhang W ， Xu Y ， et al . Relationship between COPD and GERD：a bibliometrics analysis [J ] . Int J Chron Obstruct Pulmon Dis ， 2022 ， 17 ： 3045 - 3059 ．

Broers C ， Tack J ， Pauwels A . Review article：gastro-oesophageal reflux disease in asthma and chronic obstructive pulmonary disease [J ] . Aliment Pharmacol Ther ， 2018 ， 47 （ 2 ）： 176 - 191 ．

Griffiths TL ， Nassar M ， Soubani AO . Pulmonary manifestations of gastroesophageal reflux disease [J ] . Expert Rev Respir Med ， 2020 ， 14 （ 8 ）： 767 - 775 ．

Reynolds CJ ， Del Greco M F ， Allen RJ ， et al . The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis：a bidirectional two-sample Mendelian randomisation study [J ] . Eur Respir J ， 2023 ， 61 （ 5 ）： 2201585 ．

Wang YZ ， Shen HB . Challenges and factors that influencing causal inference and interpretation，based on Mendelian randomization studies [J ] . Zhonghua Liu Xing Bing Xue Za Zhi ， 2020 ， 41 （ 8 ）： 1231 - 1236 ．

Skrivankova VW ， Richmond RC ， Woolf BAR ， et al . Strengthening the reporting of observational studies in epidemiology using Mendelian randomization：the STROBE-MR statement [J ] . JAMA ， 2021 ， 326 （ 16 ）： 1614 - 1621 ．

An JY ， Gharahkhani P ， Law MH ， et al . Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases [J ] . Nat Commun ， 2019 ， 10 （ 1 ）： 4219 ．

Kurki MI ， Karjalainen J ， Palta P ， et al . FinnGen provides genetic insights from a well-phenotyped isolated population [J ] . Nature ， 2023 ， 613 （ 7944 ）： 508 - 518 ．

Yuan S ， Larsson SC . Adiposity，diabetes，lifestyle factors and risk of gastroesophageal reflux disease：a Mendelian randomization study [J ] . Eur J Epidemiol ， 2022 ， 37 （ 7 ）： 747 - 754 ．

Kamat MA ， Blackshaw JA ， Young R ， et al . PhenoScanner V2：an expanded tool for searching human genotype-phenotype associations [J ] . Bioinformatics ， 2019 ， 35 （ 22 ）： 4851 - 4853 ．

Zonneveld MH ， Trompet S ， Jukema JW ， et al . Exploring the possible causal effects of cardiac blood biomarkers in dementia and cognitive performance：a Mendelian randomization study [J ] . Geroscience ， 2023 ， 45 （ 6 ）： 3165 - 3174 ．

Bowden J ， Davey Smith G ， Haycock PC ， et al . Consistent estimation in mendelian randomization with some invalid instruments using a weighted Median estimator [J ] . Genet Epidemiol ， 2016 ， 40 （ 4 ）： 304 - 314 ．

Burgess S ， Thompson SG . Interpreting findings from Mendelian randomization using the MR-Egger method [J ] . Eur J Epidemiol ， 2017 ， 32 （ 5 ）： 377 - 389 ．

de Klerk JA ， Beulens JWJ ， Mei HL ， et al . Altered blood gene expression in the obesity-related type 2 diabetes cluster may be causally involved in lipid metabolism：a Mendelian randomisation study [J ] . Diabetologia ， 2023 ， 66 （ 6 ）： 1057 - 1070 ．

Carter AR ， Sanderson E ， Hammerton G ， et al . Mendelian randomisation for mediation analysis：current methods and challenges for implementation [J ] . Eur J Epidemiol ， 2021 ， 36 （ 5 ）： 465 - 478 ．

Greco M FD ， Minelli C ， Sheehan NA ， et al . Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome [J ] . Stat Med ， 2015 ， 34 （ 21 ）： 2926 - 2940 ．

Bowden J ， Davey Smith G ， Burgess S . Mendelian randomization with invalid instruments：effect estimation and bias detection through Egger regression [J ] . Int J Epidemiol ， 2015 ， 44 （ 2 ）： 512 - 525 ．

Verbanck M ， Chen CY ， Neale B ， et al . Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases [J ] . Nat Genet ， 2018 ， 50 （ 5 ）： 693 - 698 ．

唐　欢，陈贵华，李　琴，等 . 慢性阻塞性肺疾病病人胃食管反流发生率的系统评价 [J ] . 循证护理， 2022 ， 8 （ 19 ）： 2557 - 2563 ．

Tang H ， Chen GH ， Li Q ， et al . Systematic review of the incidence of gastroesophageal reflux in patients with chronic obstructive pulmonary disease [J ] . Chin Evid Based Nurs ， 2022 ， 8 （ 19 ）： 2557 - 2563 ．

Fu YS ， Kang N ， Yu YP ， et al . Polyphenols，flavonoids and inflammasomes：the role of cigarette smoke in COPD [J ] . Eur Respir Rev ， 2022 ， 31 （ 164 ）： 220028 ．

Larsson SC ， Burgess S . Appraising the causal role of smoking in multiple diseases：a systematic review and meta-analysis of Mendelian randomization studies [J ] . EBioMedicine ， 2022 ， 82 ： 104154 ．

Morehead RS . Gastro-oesophageal reflux disease and non-asthma lung disease [J ] . Eur Respir Rev ， 2009 ， 18 （ 114 ）： 233 - 243 ．

Müller I ， Alt P ， Rajan S ， et al . Transient receptor potential（TRP） channels in airway toxicity and disease：an update [J ] . Cells ， 2022 ， 11 （ 18 ）： 2907 ．

Wang XL ， Wright Z ， Wang JY ， et al . Elucidating the link：chronic obstructive pulmonary disease and the complex interplay of gastroesophageal reflux disease and reflux-related complications [J ] . Medicina ， 2023 ， 59 （ 7 ）： 1270 ．

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Ankylosing spondylitis may increase the risk of mental disorders: a two-sample Mendelian randomization study

Mendelian randomization-based exploration of bidirectional causal relationship between gastroesophageal reflux disease and interstitial lung disease

Correlation of neonatal birth weight with urinary microproteins and creatinine in adulthood

Three nutritional indices are effective predictors of all-cause mortality in patients with chronic obstructive pulmonary disease

Related Author

Zhou Xingyu

Cui Jiahe

Zhang Yufei

Wang Xinyi

Tian Yuansheng

Zhou Gengbiao

Zhang Jing

Li Fang

Related Institution

School of Acupuncture and Massage,Shanghai University of Traditional Chinese Medicine

Department of Pain and Rheumatology,Henan Integrative Medicine Hospital

The Second Clinical Medical College of Guangzhou University of Chinese Medicine

Department of Critical Care Medicine，The Second Affiliated Hospital of Guangzhou University of Chinese Medicine

Department of Pediatrics，Shanxi Medical University

⁰