MINI-REVIEW
Free to Read
Insights into the genetics of gastroesophageal reflux disease (GERD) and GERD-related disorders
A. C. Böhmer,
J. Schumacher,
Corresponding Author
A. C. Böhmer
Institute of Human Genetics, University of Bonn, Bonn, Germany
Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn, Germany
Correspondence
Dr. Anne C. Böhmer, Institute of Human Genetics, University of Bonn, Bonn, Germany.
Email: [email protected]
Search for more papers by this authorJ. Schumacher
Institute of Human Genetics, University of Bonn, Bonn, Germany
Search for more papers by this authorA. C. Böhmer,
J. Schumacher,
Corresponding Author
A. C. Böhmer
Institute of Human Genetics, University of Bonn, Bonn, Germany
Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn, Germany
Correspondence
Dr. Anne C. Böhmer, Institute of Human Genetics, University of Bonn, Bonn, Germany.
Email: [email protected]
Search for more papers by this authorJ. Schumacher
Institute of Human Genetics, University of Bonn, Bonn, Germany
Search for more papers by this authorAbstract
Gastroesophageal reflux disease (GERD) is associated with obesity and hiatal hernia, and often precedes the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EA). Epidemiological studies show that the global prevalence of GERD is increasing. GERD is a multifactorial disease with a complex genetic architecture. Genome-wide association studies (GWAS) have provided initial insights into the genetic background of GERD. The present review summarizes current knowledge of the genetics of GERD and a possible genetic overlap between GERD and BE and EA. The review discusses genes and cellular pathways that have been implicated through GWAS, and provides an outlook on how future molecular research will enhance understanding of GERD pathophysiology.
References
- 1Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, and Global Consensus G. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006; 101: 1900–1920; quiz 1943.
- 2Bonfiglio F, Hysi PG, Ek W, et al. A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population. Neurogastroenterol Motil. 2016; 29: e12923.
- 3Dent J, Vakil N, Jones R, et al. Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study. Gut. 2010; 59: 714–721.
- 4El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014; 63: 871–880.
- 5Reid BJ, Li X, Galipeau PC, Vaughan TL. Barrett's oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat Rev Cancer. 2010; 10: 87–101.
- 6Holmes RS, Vaughan TL. Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol. 2007; 17: 2–9.
- 7Cook MB, Chow WH, Devesa SS. Oesophageal cancer incidence in the United States by race, sex, and histologic type, 1977–2005. Br J Cancer. 2009; 101: 855–859.
- 8Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med. 2005; 143: 199–211.
- 9El-Serag H. Role of obesity in GORD-related disorders. Gut. 2008; 57: 281–284.
- 10Corley DA, Kubo A, Zhao W. Abdominal obesity, ethnicity and gastro-oesophageal reflux symptoms. Gut. 2007; 56: 756–762.
- 11Singh S, Sharma AN, Murad MH, et al. Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2013; 11: 1399–1412 e1397.
- 12Boeckxstaens G, El-Serag HB, Smout AJ, Kahrilas PJ. Symptomatic reflux disease: the present, the past and the future. Gut. 2014; 63: 1185–1193.
- 13Nadaleto BF, Herbella FA, Patti MG. Gastroesophageal reflux disease in the obese: pathophysiology and treatment. Surgery. 2016; 159: 475–486.
- 14Dent J. Recent views on the pathogenesis of gastro-oesophageal reflux disease. Baillieres Clin Gastroenterol. 1987; 1: 727–745.
- 15Meneghetti AT, Tedesco P, Damani T, Patti MG. Esophageal mucosal damage may promote dysmotility and worsen esophageal acid exposure. J Gastrointest Surg. 2005; 9: 1313–1317.
- 16Gordon C, Kang JY, Neild PJ, Maxwell JD. The role of the hiatus hernia in gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2004; 20: 719–732.
- 17Patti MG, Goldberg HI, Arcerito M, Bortolasi L, Tong J, Way LW. Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of mucosal injury. Am J Surg. 1996; 171: 182–186.
- 18Bredenoord AJ, Draaisma WA, Weusten BL, Gooszen HG, Smout AJ. Mechanisms of acid, weakly acidic and gas reflux after anti-reflux surgery. Gut. 2008; 57: 161–166.
- 19Pandolfino JE, El-Serag HB, Zhang Q, Shah N, Ghosh SK, Kahrilas PJ. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology. 2006; 130: 639–649.
- 20Roman S, Pandolfino JE. Environmental—lifestyle related factors. Best Pract Res Clin Gastroenterol. 2010; 24: 847–859.
- 21El-Serag H, Hill C, Jones R. Systematic review: the epidemiology of gastro-oesophageal reflux disease in primary care, using the UK General Practice Research Database. Aliment Pharmacol Ther. 2009; 29: 470–480.
- 22Li YM, Du J, Zhang H, Yu CH. Epidemiological investigation in outpatients with symptomatic gastroesophageal reflux from the Department of Medicine in Zhejiang Province, east China. J Gastroenterol Hepatol. 2008; 23: 283–289.
- 23Fujimoto K, Iwakiri R, Okamoto K, et al. Characteristics of gastroesophageal reflux disease in Japan: increased prevalence in elderly women. J Gastroenterol. 2003; 38(Suppl. 15): 3–6.
- 24Lee J, Anggiansah A, Anggiansah R, Young A, Wong T, Fox M. Effects of age on the gastroesophageal junction, esophageal motility, and reflux disease. Clin Gastroenterol Hepatol. 2007; 5: 1392–1398.
- 25Achem AC, Achem SR, Stark ME, DeVault KR. Failure of esophageal peristalsis in older patients: association with esophageal acid exposure. Am J Gastroenterol. 2003; 98: 35–39.
- 26Fischbach LA, Nordenstedt H, Kramer JR, et al. The association between Barrett's esophagus and Helicobacter pylori infection: a meta-analysis. Helicobacter. 2012; 17: 163–175.
- 27Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prev Res (Phila). 2008; 1: 329–338.
- 28El-Serag HB, Sonnenberg A, Jamal MM, Inadomi JM, Crooks LA, Feddersen RM. Corpus gastritis is protective against reflux oesophagitis. Gut. 1999; 45: 181–185.
- 29Fischbach LA, Graham DY, Kramer JR, et al. Association between Helicobacter pylori and Barrett's esophagus: a case-control study. Am J Gastroenterol. 2014; 109: 357–368.
- 30Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ. Genetic influences in gastro-oesophageal reflux disease: a twin study. Gut. 2003; 52: 1085–1089.
- 31Cameron AJ, Lagergren J, Henriksson C, Nyren O, Locke GR 3rd, Pedersen NL. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology. 2002; 122: 55–59.
- 32Ghoshal UC, Chourasia D. Genetic factors in the pathogenesis of gastroesophageal reflux disease. Indian J Gastroenterol. 2011; 30: 55–62.
- 33Panagiotou OA, Ioannidis JP, Genome-Wide Significance P. What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations. Int J Epidemiol. 2012; 41: 273–286.
- 34Jovov B, Que J, Tobey NA, Djukic Z, Hogan BL, Orlando RC. Role of E-cadherin in the pathogenesis of gastroesophageal reflux disease. Am J Gastroenterol. 2011; 106: 1039–1047.
- 35Whiteman DC, Sadeghi S, Pandeya N, et al. , Australian Cancer S. Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus. Gut. 2008; 57: 173–180.
- 36Anderson LA, Watson RG, Murphy SJ, et al. Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study. World J Gastroenterol. 2007; 13: 1585–1594.
- 37Wu AH, Tseng CC, Bernstein L. Hiatal hernia, reflux symptoms, body size, and risk of esophageal and gastric adenocarcinoma. Cancer. 2003; 98: 940–948.
- 38Chak A, Lee T, Kinnard MF, et al. Familial aggregation of Barrett's oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut. 2002; 51: 323–328.
- 39Munitiz V, Parrilla P, Ortiz A, Martinez-de-Haro LF, Yelamos J, Molina J. High risk of malignancy in familial Barrett's esophagus: presentation of one family. J Clin Gastroenterol. 2008; 42: 806–809.
- 40Groves C, Jankowski J, Barker F, Holdstock G. A family history of Barrett's oesophagus: another risk factor? Scand J Gastroenterol. 2005; 40: 1127–1128.
- 41Gharahkhani P, Tung J, Hinds D, Mishra A, Barrett's, Esophageal Adenocarcinoma C, Vaughan TL, Whiteman DC, MacGregor S, and investigators B.s. (2016). Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett's esophagus. Hum Mol Genet 25, 828–835.
- 42Gharahkhani P, Fitzgerald RC, Vaughan TL, et al. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis. Lancet Oncol. 2016; 17: 1363–1373.
- 43Chambers LA, Rollins BM, Tarran R. Liquid movement across the surface epithelium of large airways. Respir Physiol Neurobiol. 2007; 159: 256–270.
- 44Robinson NB, DiMango E. Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease. Ann Am Thorac Soc. 2014; 11: 964–968.
- 45Maisonneuve P, Marshall BC, Knapp EA, Lowenfels AB. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J Natl Cancer Inst. 2013; 105: 122–129.
Citing Literature
