Association between gastroesophageal reflux disease and obstructive sleep apnea: a Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

JIAO Xin ^1,2 , SHAO Axue ^1,2 , HE Qingqing ^1,2 , WU Wenyu ^1,2 , LIU Jianbo ^1,2 ,  WANG Kai ^1,2

1. The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, P. R. China;
2. The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, P. R. China;

Corresponding author：

WANG Kai, Email: 827108327@qq.com

Keywords：

Gastroesophageal reflux disease; Obstructive sleep apnea; Snoring; Daytime sleepiness; Mendelian randomization; Causal relationship

DOI：

10.7507/1672-2531.202312062

Video：

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Objective To investigate the causal relationship between gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) with its typical symptoms (snoring and daytime sleepiness) by using Mendelian randomization (MR). Methods The inverse-variance weighted method was used as the main analysis method to assess the causal effect. Sensitivity and pleiotropy analyses were carried out using leave-one-out and MR-Egger analysis, and then heterogeneity tests were conducted. Results In the MR analysis, genetically predicted GERD was associated with a greater risk of OSA (IVW: OR=1.528, 95%CI 1.374 to 1.699, P=5.315E‒15). Additional MR results were consistent with the IVW results, and no pleiotropy or heterogeneity was found. We also discovered a significant causal relationship between GRED and snoring (IVW: OR=0.959, 95%CI 0.949 to 0.969, P=1.507E‒15), and daytime sleepiness (IVW: OR=1.024, 95%CI 1.021 to 1.036, P=4.580E‒5), with no evidence of pleiotropy. Conclusion The MR study supports a causal effect between GERD and OSA with its typical symptoms (daytime sleepiness and snoring).

Citation： JIAO Xin, SHAO Axue, HE Qingqing, WU Wenyu, LIU Jianbo, WANG Kai. Association between gastroesophageal reflux disease and obstructive sleep apnea: a Mendelian randomization study. Chinese Journal of Evidence-Based Medicine, 2024, 24(9): 1004-1010. doi: 10.7507/1672-2531.202312062 Copy

1.	Sasankan P, Thota PN. Evaluation and management of gastroesophageal reflux disease: a brief look at the updated guidelines. Cleve Clin J Med, 2022, 89(12): 700-703.
2.	Richter JE, Rubenstein JH. Presentation and epidemiology of gastroesophageal reflux disease. Gastroenterology, 2018, 154(2): 267-276.
3.	Maret-Ouda J, Markar SR, Lagergren J. Gastroesophageal reflux disease: a review. JAMA, 2020, 324(24): 2536-2547.
4.	Oh JH. Gastroesophageal reflux disease: recent advances and its association with sleep. Ann N Y Acad Sci, 2016, 1380(1): 195-203.
5.	Jaimchariyatam N, Tantipornsinchai W, Desudchit T, et al. Association between respiratory events and nocturnal gastroesophageal reflux events in patients with coexisting obstructive sleep apnea and gastroesophageal reflux disease. Sleep Med, 2016, 22: 33-38.
6.	Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet, 2014, 383(9918): 736-747.
7.	Philip P, Bailly S, Benmerad M, et al. Self-reported sleepiness and not the apnoea hypopnoea index is the best predictor of sleepiness-related accidents in obstructive sleep apnoea. Sci Rep, 2020, 10(1): 16267.
8.	Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the lyon consensus. Gut, 2018, 67(7): 1351-1362.
9.	Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med, 2019, 7(8): 687-698.
10.	Demeter P, Pap A. The relationship between gastroesophageal reflux disease and obstructive sleep apnea. J Gastroenterol, 2004, 39(9): 815-820.
11.	Chen MJ, Wu MS, Lin JT, et al. Gastroesophageal reflux disease and sleep quality in a Chinese population. J Formos Med Assoc, 2009, 108(1): 53-60.
12.	Pilakasiri A, Mahakit P. Prospective study of the prevalence and co-morbidities of obstructive sleep apnea in active-duty army personnel in the three southernmost provinces of Thailand using questionnaire screening. Mil Med Res, 2018, 5(1): 39.
13.	Eusebi LH, Ratnakumaran R, Yuan Y, et al. Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis. Gut, 2018, 67(3): 430-440.
14.	Kim Y, Lee YJ, Park JS, et al. Associations between obstructive sleep apnea severity and endoscopically proven gastroesophageal reflux disease. Sleep Breath, 2018, 22(1): 85-90.
15.	Lindam A, Ness-Jensen E, Jansson C, et al. Gastroesophageal reflux and sleep disturbances: a bidirectional association in a population-based cohort study, the HUNT study. Sleep, 2016, 39(7): 1421-1427.
16.	Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res, 2023, 4: 186.
17.	Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
18.	Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA, 2021, 326(16): 1614-1621.
19.	Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
20.	Sanderson E, Glymour MM, Holmes MV, et al. Mendelian randomization. Nat Rev Methods Primers, 2022, 2: 6.
21.	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. Gut, 2022, 71(6): 1053-1061.
22.	Strausz S, Ruotsalainen S, Ollila HM, et al. Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health. Eur Respir J, 2021, 57(5): 2003091.
23.	Haworth S, Mitchell R, Corbin L, et al. Apparent latent structure within the UK Biobank sample has implications for epidemiological analysis. Nat Commun, 2019, 10(1): 333.
24.	Wu F, Huang Y, Hu J, et al. Mendelian randomization study of inflammatory bowel disease and bone mineral density. BMC Med, 2020, 18(1): 312.
25.	Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol, 2011, 40(3): 740-752.
26.	Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods. Stat Med, 2016, 35(11): 1880-1906.
27.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
28.	Nazarzadeh M, Pinho-Gomes AC, Bidel Z, et al. Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study. Eur Heart J, 2020, 41(40): 3913-3920.
29.	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. Nat Genet, 2018, 50(5): 693-698.
30.	Hemani G, Zheng J, Elsworth B, et al. The MR-base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
31.	El-Serag HB, Sweet S, Winchester CC, et al. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut, 2014, 63(6): 871-880.
32.	Basoglu OK, Vardar R, Tasbakan MS, et al. Obstructive sleep apnea syndrome and gastroesophageal reflux disease: the importance of obesity and gender. Sleep Breath, 2015, 19(2): 585-592.
33.	Morse CA, Quan SF, Mays MZ, et al. Is there a relationship between obstructive sleep apnea and gastroesophageal reflux disease. Clin Gastroenterol Hepatol, 2004, 2(9): 761-768.
34.	Mahfouz R, Barchuk A, Obeidat AE, et al. The relationship between obstructive sleep apnea (OSA) and gastroesophageal reflux disease (GERD) in inpatient settings: a nationwide study. Cureus, 2022, 14(3): e22810.
35.	Gilani S, Quan SF, Pynnonen MA, et al. Obstructive sleep apnea and gastroesophageal reflux: a multivariate population-level analysis. Otolaryngol Head Neck Surg, 2016, 154(2): 390-395.
36.	Su J, Fang Y, Meng Y, et al. Effect of continuous positive airway pressure on chronic cough in patients with obstructive sleep apnea and concomitant gastroesophageal reflux. Nat Sci Sleep, 2022, 14: 13-23.
37.	Senior BA, Khan M, Schwimmer C, et al. Gastroesophageal reflux and obstructive sleep apnea. Laryngoscope, 2001, 111(12): 2144-2146.
38.	Regenbogen E, Helkin A, Georgopoulos R, et al. Esophageal reflux disease proton pump inhibitor therapy impact on sleep disturbance: a systematic review. Otolaryngol Head Neck Surg, 2012, 146(4): 524-532.
39.	Bortolotti M, Gentilini L, Morselli C, et al. Obstructive sleep apnoea is improved by a prolonged treatment of gastrooesophageal reflux with omeprazole. Dig Liver Dis, 2006, 38(2): 78-81.
40.	Rassameehiran S, Klomjit S, Hosiriluck N, et al. Meta-analysis of the effect of proton pump inhibitors on obstructive sleep apnea symptoms and indices in patients with gastroesophageal reflux disease. Proc (Bayl Univ Med Cent), 2016, 29(1): 3-6.
41.	Dunai A, Keszei AP, Kopp MS, et al. Cardiovascular disease and health-care utilization in snorers: a population survey. Sleep, 2008, 31(3): 411-416.
42.	El Hangouche AJ, Jniene A, Aboudrar S, et al. Relationship between poor quality sleep, excessive daytime sleepiness and low academic performance in medical students. Adv Med Educ Pract, 2018, 9: 631-638.
43.	Fass R, Quan SF, O'Connor GT, et al. Predictors of heartburn during sleep in a large prospective cohort study. Chest, 2005, 127(5): 1658-1666.
44.	Emilsson ÖI, Benediktsdóttir B, Ólafsson Í, et al. Respiratory symptoms, sleep-disordered breathing and biomarkers in nocturnal gastroesophageal reflux. Respir Res, 2016, 17(1): 115.
45.	Hägg SA, Emilsson ÖI, Franklin K, et al. Nocturnal gastroesophageal reflux increases the risk of daytime sleepiness in women. Sleep Med, 2019, 53: 94-100.
46.	Kang HH, Lim CH, Oh JH, et al. The influence of gastroesophageal reflux disease on daytime sleepiness and depressive symptom in patients with obstructive sleep apnea. J Neurogastroenterol Motil, 2021, 27(2): 215-222.
47.	Sutherland K, Lee RWW, Chan TO, et al. Craniofacial phenotyping in Chinese and caucasian patients with sleep apnea: influence of ethnicity and sex. J Clin Sleep Med, 2018, 14(7): 1143-1151.
48.	Dudley KA, Patel SR. Disparities and genetic risk factors in obstructive sleep apnea. Sleep Med, 2016, 18: 96-102.

1. Sasankan P, Thota PN. Evaluation and management of gastroesophageal reflux disease: a brief look at the updated guidelines. Cleve Clin J Med, 2022, 89(12): 700-703.
2. Richter JE, Rubenstein JH. Presentation and epidemiology of gastroesophageal reflux disease. Gastroenterology, 2018, 154(2): 267-276.
3. Maret-Ouda J, Markar SR, Lagergren J. Gastroesophageal reflux disease: a review. JAMA, 2020, 324(24): 2536-2547.
4. Oh JH. Gastroesophageal reflux disease: recent advances and its association with sleep. Ann N Y Acad Sci, 2016, 1380(1): 195-203.
5. Jaimchariyatam N, Tantipornsinchai W, Desudchit T, et al. Association between respiratory events and nocturnal gastroesophageal reflux events in patients with coexisting obstructive sleep apnea and gastroesophageal reflux disease. Sleep Med, 2016, 22: 33-38.
6. Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet, 2014, 383(9918): 736-747.
7. Philip P, Bailly S, Benmerad M, et al. Self-reported sleepiness and not the apnoea hypopnoea index is the best predictor of sleepiness-related accidents in obstructive sleep apnoea. Sci Rep, 2020, 10(1): 16267.
8. Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the lyon consensus. Gut, 2018, 67(7): 1351-1362.
9. Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med, 2019, 7(8): 687-698.
10. Demeter P, Pap A. The relationship between gastroesophageal reflux disease and obstructive sleep apnea. J Gastroenterol, 2004, 39(9): 815-820.
11. Chen MJ, Wu MS, Lin JT, et al. Gastroesophageal reflux disease and sleep quality in a Chinese population. J Formos Med Assoc, 2009, 108(1): 53-60.
12. Pilakasiri A, Mahakit P. Prospective study of the prevalence and co-morbidities of obstructive sleep apnea in active-duty army personnel in the three southernmost provinces of Thailand using questionnaire screening. Mil Med Res, 2018, 5(1): 39.
13. Eusebi LH, Ratnakumaran R, Yuan Y, et al. Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis. Gut, 2018, 67(3): 430-440.
14. Kim Y, Lee YJ, Park JS, et al. Associations between obstructive sleep apnea severity and endoscopically proven gastroesophageal reflux disease. Sleep Breath, 2018, 22(1): 85-90.
15. Lindam A, Ness-Jensen E, Jansson C, et al. Gastroesophageal reflux and sleep disturbances: a bidirectional association in a population-based cohort study, the HUNT study. Sleep, 2016, 39(7): 1421-1427.
16. Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res, 2023, 4: 186.
17. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
18. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA, 2021, 326(16): 1614-1621.
19. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
20. Sanderson E, Glymour MM, Holmes MV, et al. Mendelian randomization. Nat Rev Methods Primers, 2022, 2: 6.
21. 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. Gut, 2022, 71(6): 1053-1061.
22. Strausz S, Ruotsalainen S, Ollila HM, et al. Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health. Eur Respir J, 2021, 57(5): 2003091.
23. Haworth S, Mitchell R, Corbin L, et al. Apparent latent structure within the UK Biobank sample has implications for epidemiological analysis. Nat Commun, 2019, 10(1): 333.
24. Wu F, Huang Y, Hu J, et al. Mendelian randomization study of inflammatory bowel disease and bone mineral density. BMC Med, 2020, 18(1): 312.
25. Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol, 2011, 40(3): 740-752.
26. Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods. Stat Med, 2016, 35(11): 1880-1906.
27. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
28. Nazarzadeh M, Pinho-Gomes AC, Bidel Z, et al. Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study. Eur Heart J, 2020, 41(40): 3913-3920.
29. 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. Nat Genet, 2018, 50(5): 693-698.
30. Hemani G, Zheng J, Elsworth B, et al. The MR-base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
31. El-Serag HB, Sweet S, Winchester CC, et al. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut, 2014, 63(6): 871-880.
32. Basoglu OK, Vardar R, Tasbakan MS, et al. Obstructive sleep apnea syndrome and gastroesophageal reflux disease: the importance of obesity and gender. Sleep Breath, 2015, 19(2): 585-592.
33. Morse CA, Quan SF, Mays MZ, et al. Is there a relationship between obstructive sleep apnea and gastroesophageal reflux disease. Clin Gastroenterol Hepatol, 2004, 2(9): 761-768.
34. Mahfouz R, Barchuk A, Obeidat AE, et al. The relationship between obstructive sleep apnea (OSA) and gastroesophageal reflux disease (GERD) in inpatient settings: a nationwide study. Cureus, 2022, 14(3): e22810.
35. Gilani S, Quan SF, Pynnonen MA, et al. Obstructive sleep apnea and gastroesophageal reflux: a multivariate population-level analysis. Otolaryngol Head Neck Surg, 2016, 154(2): 390-395.
36. Su J, Fang Y, Meng Y, et al. Effect of continuous positive airway pressure on chronic cough in patients with obstructive sleep apnea and concomitant gastroesophageal reflux. Nat Sci Sleep, 2022, 14: 13-23.
37. Senior BA, Khan M, Schwimmer C, et al. Gastroesophageal reflux and obstructive sleep apnea. Laryngoscope, 2001, 111(12): 2144-2146.
38. Regenbogen E, Helkin A, Georgopoulos R, et al. Esophageal reflux disease proton pump inhibitor therapy impact on sleep disturbance: a systematic review. Otolaryngol Head Neck Surg, 2012, 146(4): 524-532.
39. Bortolotti M, Gentilini L, Morselli C, et al. Obstructive sleep apnoea is improved by a prolonged treatment of gastrooesophageal reflux with omeprazole. Dig Liver Dis, 2006, 38(2): 78-81.
40. Rassameehiran S, Klomjit S, Hosiriluck N, et al. Meta-analysis of the effect of proton pump inhibitors on obstructive sleep apnea symptoms and indices in patients with gastroesophageal reflux disease. Proc (Bayl Univ Med Cent), 2016, 29(1): 3-6.
41. Dunai A, Keszei AP, Kopp MS, et al. Cardiovascular disease and health-care utilization in snorers: a population survey. Sleep, 2008, 31(3): 411-416.
42. El Hangouche AJ, Jniene A, Aboudrar S, et al. Relationship between poor quality sleep, excessive daytime sleepiness and low academic performance in medical students. Adv Med Educ Pract, 2018, 9: 631-638.
43. Fass R, Quan SF, O'Connor GT, et al. Predictors of heartburn during sleep in a large prospective cohort study. Chest, 2005, 127(5): 1658-1666.
44. Emilsson ÖI, Benediktsdóttir B, Ólafsson Í, et al. Respiratory symptoms, sleep-disordered breathing and biomarkers in nocturnal gastroesophageal reflux. Respir Res, 2016, 17(1): 115.
45. Hägg SA, Emilsson ÖI, Franklin K, et al. Nocturnal gastroesophageal reflux increases the risk of daytime sleepiness in women. Sleep Med, 2019, 53: 94-100.
46. Kang HH, Lim CH, Oh JH, et al. The influence of gastroesophageal reflux disease on daytime sleepiness and depressive symptom in patients with obstructive sleep apnea. J Neurogastroenterol Motil, 2021, 27(2): 215-222.
47. Sutherland K, Lee RWW, Chan TO, et al. Craniofacial phenotyping in Chinese and caucasian patients with sleep apnea: influence of ethnicity and sex. J Clin Sleep Med, 2018, 14(7): 1143-1151.
48. Dudley KA, Patel SR. Disparities and genetic risk factors in obstructive sleep apnea. Sleep Med, 2016, 18: 96-102.

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