反流性食管炎和中耳炎之间因果关系:一项基于欧洲人群的双样本孟德尔随机分析

doi:10.3969/j.issn.1004-583X.2024.12.005

摘要/Abstract

摘要：

目的观察性研究表明,中耳炎(otitis media, OM)与胃食管反流病(gastroesophageal reflux disease, GERD)之间存在相关性。然而,传统研究存在偏差,限制了我们对 GERD对OM影响的理解。方法采用一个双样本孟德尔随机化(mendelian randomization,MR)方法,以随机影响反方差加权模型(inverse variance weighting,IVW)为主要标准,从可公开访问的全基因组关系研究数据库中抽取一大批进行全基因组关联研究的欧洲人群作为样本,对 GERD和OM进行统计,以检测其因果相关性。同时采用 MR-Egger回归和加权中位数作为补充。通过Cochran Q、MR-PRESSO和MR-Egger截距实验进行敏感性分析,包括水平多向性和异质性检验,以保证研究结果的可靠性。结果根据IVW模型,发现 GERD与急性化脓性中耳炎之间的因果关系[ $O R$ =1.208,95% $C I$ (1.030-1.416),P=2.00e-2]似乎具有名义上的显著性, GERD患者与慢性化脓性中耳炎之间的因果关系得到了有力的证明[ $O R$ =2.085, 95% $C I$ (1.329-3.270),P=1.38e-3],但 GERD与非化脓性中耳炎之间没有因果关系[ $O R$ =1.151,95% $C I$ (0.970-1.366),P=2.50e-1],在一些MR模型中观察到一致的相关模式;此外,在敏感性分析中几乎没有发现偏倚的证据。结论 GERD人群对急性化脓性中耳炎、慢性化脓性中耳炎的遗传易感性有增加的趋势,提示在治疗OM时可以检查是否合并GERD并选择合适的治疗方法。

关键词: 胃食管反流, 中耳炎, 中耳炎, 化脓性, 伴渗出液中耳炎, 孟德尔随机试验

Abstract:

Objective Observational studies have shown an association between otitis media (OM) and gastroesophageal reflux disease (GERD). However, traditional studies have biases that limit our understanding of the impact of GERD on OM. Methods A two-sample Mendelian randomization (MR) approach with the random-effects inverse variance weighted model was adopted to analyze genome-wide association study (GWAS) data in the European population from the available online database. The causal relationship between GERD and OM in the European population was analyzed. MR-Egger regression and weighted median were also used as supplements. Sensitivity analysis was performed by Cochran's Q test, MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO) and Mendelian randomization-Egger (MR-Egger) intercept tests, including horizontal pleiotropy and heterogeneity tests, to ensure the reliability of the study results. Results According to the IVW model, a causal relationship was found between GERD and acute suppurative otitis media (ASOM) ( $O R$ =1.208; 95% $C I$ : 1.030-1.416, P=2.00e-2). A causal relationship between GERD and chronic suppurative otitis media (CSOM) was strongly demonstrated ( $O R$ =2.085, 95% $C I$ : 1.329-3.270, P=1.38e-3). However, there was no causal relationship between GERD and non-suppurative otitis media (NSOM) ( $O R$ =1.151, 95% $C I$ : 0.970-1.366, P=2.50e-1), and a consistent correlation pattern was observed in some MR models. In addition, little evidence of bias was found in the sensitivity analyses. Conclusion The genetic susceptibility of GERD to ASOM and CSOM tends to increase, suggesting that GERD should be checked, and appropriate treatment should be selected when treating OM.

Key words: gastroesophageal reflux, otitis media, suppurative otitis media, otitis media with effusion, Mendelian randomized trial

中图分类号:

R573.9

胡荣湫, 闫乐. 反流性食管炎和中耳炎之间因果关系:一项基于欧洲人群的双样本孟德尔随机分析[J]. 临床荟萃, 2024, 39(12): 1089-1094.

Hu Rongqiu, Yan Le. Causal relationship between reflux esophagitis and otitis media: a two-sample Mendelian randomization analysis in the European population[J]. Clinical Focus, 2024, 39(12): 1089-1094.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2024.12.005

https://huicui.hebmu.edu.cn/CN/Y2024/V39/I12/1089

图/表 4

表1 GWAS的详细信息

Tab.1 Details of GWAS

项目号	研究	样本量			地区
项目号	研究	试验组	对照组	合计	地区
ebi-a-GCST90000514	胃食管返流	129080	473524	602604	欧洲
finn-b-H8_SUP_ACUTE	ASOM	5232	205939	211171	欧洲
finn-b-H8_CHRON_SUPOTITIS	CSOM	594	205939	206533	欧洲
finn-b-H8_NONSUPPNAS	OME	4381	205939	210320	欧洲

图1 孟德尔分析森林图

Fig.1 A forest plot of mendelian randomization

图2 GERD对OM孟德尔分析散点图 a.GERD对ASOM; b.GERD对CSOM; c.GERD对OME

Fig.2 Scatter diagram of Mendelian analysis of GERD versus OM a.GERD versus ASOM; b. Geerd vs. CSOM; c.geo versus OME

表2 敏感性分析和水平多效性检验

Tab.2 Sensitivity analysis and horizontal pleiotropy test

结果	Cochran’s Q test (P)	Egger test (P)	MR PRESSO (P)
ASOM	0.457	0.308	0.433
CSOM	0.734	0.465	0.566
OME	0.879	0.562	0.876

参考文献 44

[1]	Fass R. Gastroesophageal reflux disease[J]. N Engl J Med, 2022, 387(13): 1207-1216.
[2]	Maret-Ouda J, Markar SR, Lagergren J. Gastroesophageal reflux disease[J]. JAMA, 2020, 324(24): 2565. doi: 10.1001/jama.2020.21573 pmid: 33351044
[3]	Delshad SD, Almario CV, Chey WD, et al. Prevalence of gastroesophageal reflux disease and proton pump inhibitor-refractory symptoms[J]. Gastroenterology, 2020, 158(5): 1250-1261.e1252. doi: S0016-5085(19)41941-0 pmid: 31866243
[4]	Richter JE, Rubenstein JH. Presentation and epidemiology of gastroesophageal reflux disease[J]. Gastroenterology, 2018, 154(2): 267-276. doi: S0016-5085(17)35977-2 pmid: 28780072
[5]	Zhang D, Liu S, Li Z, et al. Global, regional and national burden of gastroesophageal reflux disease, 1990-2019: Update from the GBD 2019 study[J]. Ann Med, 2022, 54(1): 1372-1384. doi: 10.1080/07853890.2022.2074535 pmid: 35579516
[6]	Lechien JR, Hans S, Simon F, et al. Association between laryngopharyngeal reflux and media otitis: A systematic review[J]. Otol Neurotol, 2021, 42(7): e801-e814.
[7]	Agirdir BV, Bozova S, Derin AT, et al. Chronic otitis media with effusion and Helicobacter pylori[J]. Int J Pediatr Otorhinolaryngo, 2006, 70(5): 829-834.
[8]	Melake NA, Shaker GH, Salama MA. Incidence of helicobacter pylori infection and their clarithromycin-resistant strains in otitis media with effusion regarding phenotypic and genotypic studies[J]. Saudi Pharm J, 2012, 20(4): 345-353. doi: 10.1016/j.jsps.2012.02.004 pmid: 23960809
[9]	Sone M, Kato T, Suzuki Y, et al. Relevance and characteristics of gastroesophageal reflux in adult patients with otitis media with effusion[J]. Auris Nasus Larynx, 2011, 38(2): 203-207. doi: 10.1016/j.anl.2010.08.004 pmid: 21035286
[10]	Abdel-aziz MM, El-Fattah AM, Abdalla AF. Clinical evaluation of pepsin for laryngopharyngeal reflux in children with otitis media with effusion[J]. Int J Pediatr Otorhinolaryngol, 2013, 77(10): 1765-1770.
[11]	Velepic M, Rozmanic V, Velepic M, et al. Gastroesophageal reflux, allergy and chronic tubotympanal disorders in children[J]. Int J Pediatr Otorhinolaryngol, 2000, 55(3): 187-190.
[12]	Yilmaz MD, Aktepe O, Cetinkol Y, et al. Does helicobacter pylori have role in development of otitis media with effusion?[J]. Int J Pediatr Otorhinolaryngol, 2005, 69(6): 745-749.
[13]	Sanderson E, Glymour MM, Holmes MV, et al. Mendelian randomization[J]. Nat Rev Methods Primers, 2022, 2:6.
[14]	Sanderson E, Richardson TG, Morris TT, et al. Estimation of causal effects of a time-varying exposure at multiple time points through multivariable Mendelian randomization[J]. PLoS Genet, 2022, 18(7): e1010290.
[15]	Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: A review[J]. Res Synth Methods, 2019, 10(4): 486-496. doi: 10.1002/jrsm.1346 pmid: 30861319
[16]	Ahn K, Penn RB, Rattan S, et al. Mendelian randomization analysis reveals a complex genetic interplay among atopic dermatitis, asthma, and gastroesophageal reflux disease[J]. Am J Respir Crit Care Med, 2023, 207(2): 130-137.
[17]	Freuer D, Linseisen J, Meisinger C. Asthma and the risk of gastrointestinal disorders: A Mendelian randomization study[J]. BMC Med, 2022, 20(1): 82. doi: 10.1186/s12916-022-02283-7 pmid: 35292014
[18]	Jiang S, Zheng L, Miao Z. Gastroesophageal reflux disease and oral symptoms: A two-sample Mendelian randomization study[J]. Front Genet, 2022, 13:1061550.
[19]	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. doi: 10.1007/s10654-022-00842-z pmid: 35119566
[20]	Ong JS, An J, Han X, et al. Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis[J]. Gut, 2022, 71(6): 1053-1061.
[21]	Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians[J]. BMJ, 2018, 362:k601.
[22]	Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies[J]. Int J Epidemiol, 2011, 40(3): 755-764. doi: 10.1093/ije/dyr036 pmid: 21414999
[23]	Ellervik C, Roselli C, Christophersen IE, et al. Assessment of the relationship between genetic determinants of thyroid function and atrial fibrillation: A Mendelian randomization study[J]. JAMA Cardiol, 2019, 4(2): 144-152. doi: 10.1001/jamacardio.2018.4635 pmid: 30673084
[24]	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epidemiol, 2013, 37(7): 658-665. doi: 10.1002/gepi.21758 pmid: 24114802
[25]	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. doi: 10.1093/ije/dyv080 pmid: 26050253
[26]	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. doi: 10.1002/gepi.21965 pmid: 27061298
[27]	Yang M, Wan X, Zheng H, et al. No evidence of a genetic causal relationship between ankylosing spondylitis and gut microbiota: A two-sample Mendelian randomization study[J]. Nutrients, 2023, 15(4):1057.
[28]	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. doi: 10.1038/s41588-018-0099-7 pmid: 29686387
[29]	Sone M, Kato T, Nakashima T. Current concepts of otitis media in adults as a reflux-related disease[J]. Otol Neurotol, 2013, 34(6): 1013-1017. doi: 10.1097/MAO.0b013e318299aa52 pmid: 23851353
[30]	Yüksel F, Doğan M, Karataş D, et al. Gastroesophageal reflux disease in children with chronic otitis media with effusion[J]. J Craniofac Surg, 2013, 24(2): 380-383. doi: 10.1097/SCS.0b013e31827feb08 pmid: 23524698
[31]	Elbeltagy R, Abdelhafeez M. Outcome of gastroesophageal reflux therapy in children with persistent otitis media with effusion[J]. Int Arch Otorhinolaryngol, 2022, 26(1): e058-e062.
[32]	Tasker A, Dettmar PW, Panetti M, et al. Reflux of gastric juice and glue ear in children[J]. Lancet, 2002, 359(9305): 493. pmid: 11853797
[33]	McCoul ED, Goldstein NA, Koliskor B, et al. A prospective study of the effect of gastroesophageal reflux disease treatment on children with otitis media[J]. Arch Otolaryngol Head Neck Surg, 2011, 137(1): 35-41.
[34]	Velagala NR, Velagala VR, Lamture Y. The spectrum of treatment Modalities for gastroesophageal reflux disease(GERD): A narrative review[J]. Cureus, 2022, 14(12): e32619.
[35]	Poelmans J, Tack J, Feenstra L. Prospective study on the incidence of chronic ear complaints related to gastroesophageal reflux and on the outcome of antireflux therapy[J]. Ann Otol Rhinol Laryngol, 2002, 111(10): 933-938.
[36]	Yeo CD, Kim JS, Lee EJ. Association of gastroesophageal reflux disease with increased risk of chronic otitis media with effusion in adults: A nationwide population-based cohort study[J]. Medicine (Baltimore), 2021, 100(29): e26727.
[37]	Boronat-Echeverría N, Aguirre-Mariscal H, Carmolinga-Ponce M, et al. Helicobacter pylori detection and clinical symptomatology of gastroesophageal reflux disease in pediatric patients with otitis media with effusion[J]. Int J Pediatr Otorhinolaryngol, 2016, 87:126-129.
[38]	Karyanta M, Satrowiyoto S, Wulandari DP. Prevalence ratio of otitis media with effusion in laryngopharyngeal reflux[J]. Int J Otolaryngol, 2019, 2019:7460891.
[39]	Doˇgru M, Kuran G, Haytoˇglu S, et al. Role of Laryngopharyngeal reflux in the pathogenesis of otitis media with effusion[J]. J Int Adv Otol, 2015, 11(1): 66-71. doi: 10.5152/iao.2015.642 pmid: 26223722
[40]	Habesoglu TE, Habesoglu M, Kalaycik C, et al. Gastroesophageal reflux disease and tympanoplasty surgical outcome: Is there a relationship?[J]. J Laryngol Otol, 2012, 126(6): 580-585. doi: 10.1017/S0022215112000461 pmid: 22494440
[41]	Luo HN, Yang QM, Sheng Y, et al. Role of pepsin and pepsinogen: Linking laryngopharyngeal reflux with otitis media with effusion in children[J]. Laryngoscope, 2014, 124(7): E294-300.
[42]	Pang K, Di Y, Li G, et al. Can reflux symptom index and reflux finding score be used to guide the treatment of secretory otitis media in adults?[J]. ORL J Otorhinolaryngol Relat Spec, 2020, 82(3): 130-138.
[43]	Miura MS, Mascaro M, Rosenfeld RM. Association between otitis media and gastroesophageal reflux: A systematic review[J]. Otolaryngol Head Neck Surg, 2012, 146(3): 345-352. doi: 10.1177/0194599811430809 pmid: 22157391
[44]	Górecka-Tuteja A, Jastrzębska I, Składzień J, et al. Laryngopharyngeal reflux in children with chronic otitis media with effusion[J]. J Neurogastroenterol Motil, 2016, 22(3): 452-458.