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Wilson AC, Rocco A, Chiles J, Srinivasasainagendra V, Labaki W, Meyers D, Hidalgo B, Irvin MR, Bhatt SP, Tiwari H, McDonald ML. Novel risk loci encompassing genes influencing STAT3, GPCR, and oxidative stress signaling are associated with co-morbid GERD and COPD. PLoS Genet 2025; 21:e1011531. [PMID: 39919125 PMCID: PMC11805425 DOI: 10.1371/journal.pgen.1011531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 12/05/2024] [Indexed: 02/09/2025] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of death globally. Gastroesophageal reflux disease (GERD) is a common comorbidity in COPD associated with worse pulmonary symptoms, reduced quality of life, and increased exacerbations and hospitalizations. GERD treatment in COPD is associated with a lower risk of exacerbations and mortality; however, it is not clear whether these findings can be attributed to aging populations where both diseases are likely to co-occur or reflect shared etiology. To test for the influence of common etiology in both diseases, we aimed to identify shared genetic etiology between GERD and COPD. We performed the first whole-genome sequence association analysis of comorbid GERD and COPD in 12,438 multi-ancestry participants. The co-heritability of GERD and COPD was 39.7% (h2 = 0.397, SE = 0.074) and we identified several ancestry-independent loci associated with co-morbid GERD and COPD (within LINC02493 and FRYL) known to be involved in oxidative stress and G protein-coupled receptor (GPCR) signaling mechanisms. We found several loci associated with co-morbid GERD and COPD previously associated with GERD or COPD individually, including HCG17, which plays a role in oxidative stress mechanisms. Gene set enrichment identified GPCR signaling pathways in co-morbid GERD and COPD loci. Rare variants in ZFP42, encoding key regulators of the IL6/STAT3 pathway, have been previously implicated with GI disorders and were associated with co-morbid GERD and COPD. We identified common genetic etiology for GERD in COPD which begins to provide a mechanistic foundation for the potential therapeutic utility of STAT3, oxidation, and GPCR signaling pathway modulators in both GERD and COPD.
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Affiliation(s)
- Ava C. Wilson
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, United States of America
| | - Alison Rocco
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Joe Chiles
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Vinodh Srinivasasainagendra
- Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Wassim Labaki
- Division of Pulmonary and Critical Care Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Deborah Meyers
- Division of Genetics, Genomics, and Precision Medicine, University of Arizona, Tucson, Arizona, United States of America
| | - Bertha Hidalgo
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Marguerite R. Irvin
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Surya P. Bhatt
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Hemant Tiwari
- Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Merry-Lynn McDonald
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
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Essa A, Nasser A, Noureldeen IM, Ebeid I, Ebeid A, Ahmed B, Allam HK, Shehab-Eldeen S, Essa A. Gastroesophageal Reflux Disease Among Undergraduate Medical Students in Egypt: Prevalence and Risk Factors. Int J Gen Med 2024; 17:6037-6046. [PMID: 39678676 PMCID: PMC11646440 DOI: 10.2147/ijgm.s503049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 11/29/2024] [Indexed: 12/17/2024] Open
Abstract
Background Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal condition that has a detrimental impact on one's quality of life because of acid reflux causing damage to the esophagus. Primary symptoms consist of heartburn and regurgitation, although patients may also encounter chest pain, nausea, and dysphagia. Medical students may be particularly susceptible due to stressful lifestyles and unhealthy habits. This study investigates the prevalence of GERD among medical students in Egypt and explores associated risk factors. Subjects and Methods This is a cross-sectional observational study that was conducted among undergraduate medical students at 21 medical schools across Egypt. The study included 602 participants from medical schools. The study utilized a pre-designed, self-administered questionnaire that includes questions about sociodemographic and lifestyle attributes, accompanied by the GERDQ questionnaire used to diagnose gastroesophageal reflux disease. Results A total of 602 undergraduate medical students completed the questionnaire. The prevalence of GERD was found to be 28.4%, with heartburn and regurgitation being the most prevalent symptoms among participants. Univariate and multivariate logistic regression revealed family history of GERD and stress after medical school enrollment as significant predictors of GERD symptoms (p=0.043 and p=0.044, respectively). Conclusion GERD has become increasingly common among medical students in Egypt. Contributing factors include medical students' stressful lifestyles and familial predispositions. To address this, it is essential to implement counseling programs and raise awareness as initial steps toward reducing GERD prevalence.
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Affiliation(s)
- Ali Essa
- Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
| | - Ahmed Nasser
- Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
| | | | - Ibrahim Ebeid
- Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
| | - Ahmed Ebeid
- Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
| | - Baraa Ahmed
- Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Heba Khodary Allam
- Public Health and Community Medicine Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
| | - Somaia Shehab-Eldeen
- Internal Medicine Department, College of Medicine, King Faisal University, Al-Ahsa, Kingdom of Saudi Arabia
| | - Abdallah Essa
- Internal Medicine Department, College of Medicine, King Faisal University, Al-Ahsa, Kingdom of Saudi Arabia
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Ong JS, An J, Han X, Law MH, Nandakumar P, Schumacher J, Gockel I, Bohmer A, Jankowski J, Palles C, Olsen CM, Neale RE, Fitzgerald R, Thrift AP, Vaughan TL, Buas MF, Hinds DA, Gharahkhani P, Kendall BJ, MacGregor S. 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; 71:1053-1061. [PMID: 34187846 PMCID: PMC9120377 DOI: 10.1136/gutjnl-2020-323906] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 06/13/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. DESIGN We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). RESULTS We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. CONCLUSION Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.
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Affiliation(s)
- Jue-Sheng Ong
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Jiyuan An
- School of Biology & Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Xikun Han
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Matthew H Law
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
| | | | - Johannes Schumacher
- Institute of Human Genetics, Philipps University of Marburg, Marburg, Germany
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Anne Bohmer
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Janusz Jankowski
- Centre for Medicine and Health Sciences, University of United Arab Emirates, Al Ain, Abu Dhabi, UAE
- UCL Medical School, University College London, London, UK
| | - Claire Palles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Catherine M Olsen
- Department of Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia
| | - Rachel E Neale
- Department of Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | | | - Aaron P Thrift
- Department of Medicine, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Thomas L Vaughan
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA
| | - Matthew F Buas
- Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | | | - Puya Gharahkhani
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Bradley J Kendall
- Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Stuart MacGregor
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
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Maev IV, Andreev DN, Ovsepyan MA, Barkalova EV. Gastroesophageal reflux disease: risk factors, current possibilities of diagnosis and treatment optimisation. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2022:16-26. [DOI: 10.21518/2079-701x-2022-16-7-16-26] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Gastroesophageal reflux disease (GERD) is one of the most common causes of health care seeking at the primary care level in many countries. At an epidemiological level, GERD has been shown to be associated with a number of risk factors: obesity, tobacco smoking, alcohol abuse, certain patterns of eating behaviour, and the use of several medications. GERD is now regarded as a heterogeneous disease and includes different phenotypes (erosive reflux disease, non-erosive reflux disease, hypersensitive oesophagus, functional heartburn), the proper diagnosis of which improves the effectiveness of therapy in patients with heartburn symptoms. Daily impedance–pH monitoring is known to be an integral part of the diagnostic algorithm for GERD and is a functional diagnostic method to record all types of refluxes entering the oesophagus regardless of pH, to assess their association with symptoms, and to determine whether patients with heartburn symptoms belong to a particular phenotype. Esophageal manometry plays a key role in the evaluation of patients with heartburn symptoms, as it helps to rule out other conditions that may mimic GERD: achalasia cardia and scleroderma esophagus. This technique is used to assess thoracic esophageal motility and sphincter function and in the assessment of patients prior to antireflux surgery or in the refractory course of GERD. The article describes in detail GERD risk factors (triggers of heartburn), as well as diagnostic aspects, taking into account a differentiated approach to patients with heartburn based on daily impedance–pH monitoring data in accordance with the current guidelines and recommendations.
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Affiliation(s)
- I. V. Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - D. N. Andreev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - M. A. Ovsepyan
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - E. V. Barkalova
- Yevdokimov Moscow State University of Medicine and Dentistry
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Helle K, Bálint L, Szekeres V, Ollé G, Rosztóczy A. Prevalence of reflux-related symptoms in South-Hungarian blood donor volunteers. PLoS One 2022; 17:e0265152. [PMID: 35290403 PMCID: PMC8923446 DOI: 10.1371/journal.pone.0265152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 02/23/2022] [Indexed: 11/25/2022] Open
Abstract
Background/Aim Population-based studies on the prevalence of GERD-related symptoms are still missing in Eastern Europe, therefore, we aimed to obtain such data in South-East Hungarian subjects. Methods A total of 2,002 apparently healthy blood donor volunteers were consecutively enrolled and completed detailed questionnaires related to general factors, demographic data, socioeconomical factors, and the presence and frequency of typical and atypical GERD-related symptoms. Results Among 2,002 study participants, 56.5% were completely asymptomatic. The prevalence of typical GERD symptoms appearing at least monthly or weekly was 16.5% and 6.8%, respectively. Two-thirds (209/330) of the patients experienced at least monthly occurring typical GERD symptoms and also had associated atypical symptoms and this was even more pronounced when comparing subgroups with higher symptom frequencies. Significant correlations were found between monthly GERD-related complaints and height, body mass index (BMI), coffee consumption, and smoking. Positive family history was another significant factor in all the symptom-frequency categories. GERD-related symptom frequency showed a linear association with sex (R2 = 0.75, P = 0.0049). Typical and atypical GERD symptoms were significantly more common in those with chronic diseases than those without. Heartburn was observed in 12.5% and 4.4% (P<0.05) and acid regurgitation was seen in 6.9% and 1.8% (P<0.05), respectively. Conclusion The prevalence of GERD-related symptoms in South Hungary was significantly lower than that in Western countries and was closer to Eastern values. The presence of mild, non-exclusionary chronic diseases significantly increased the prevalence of GERD-related symptoms, as well as positive family history of GERD, height, BMI, coffee consumption, and smoking.
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Affiliation(s)
- Krisztina Helle
- Division of Gastroenterology, First Department of Internal Medicine, University of Szeged, Szeged, Hungary
- * E-mail:
| | - Lenke Bálint
- Division of Gastroenterology, First Department of Internal Medicine, University of Szeged, Szeged, Hungary
| | | | - Georgina Ollé
- Division of Gastroenterology, First Department of Internal Medicine, University of Szeged, Szeged, Hungary
| | - András Rosztóczy
- Division of Gastroenterology, First Department of Internal Medicine, University of Szeged, Szeged, Hungary
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Matoshina IV, Livzan MA, Fedorin MM, Lapteva IV. Clinically significant stigmas of the severity of GERD and dissociation with the degree of damage to the esophageal mucosa — the obligatory esophagoprotection? EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021; 1:5-11. [DOI: 10.31146/1682-8658-ecg-190-6-5-11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
Study goal: Identify clinically significant stigmas of reduced esophageal mucosal resistance.Materials and methods: The study included 181 patients aged 18–70 years with gastroesophageal refl ux disease (GERD).Complaints, age, sex, history of the disease, life history, physical examination data, results of laboratory and instrumental examinations, data on medication intake at the time of enrollment of the patient for the main disease and concomitant pathology were noted in the individual registration card (IRC).Results: The study demonstrated the presence of features suggesting with a higher degree of probability a reduced esophageal mucosal resistance in a certain group of patients with GERD. Individuals with early- onset GERD, males, young adults, smokers, and individuals with a high body mass index (BMI) have a higher risk of esophageal mucosal erosions. The presence of esophageal hernia of the diaphragm (EVD), intake of acetylsalicylic acid (ASA), calcium channel blockers (CCBs), or nonsteroidal anti-inflammatory drugs (NSAIDs) are factors that reduce esophageal mucosal resistance. The formation of erosive esophagitis is not associated with the subjective perception of GERD symptoms and does not affect the patient’s complaints.Conclusion: Clinical manifestations of GERD are not associated with the degree of esophageal mucosal damage and cannot be a phenotypic sign of erosive esophagitis requiring mandatory prescription of an esophagoprotector. Clinically significant stigmas of decreased esophageal mucosal resistance were revealed. The need in research of expediency and efficacy of prescription of esophagoprotector in patients with GERD, having GVHD or regularly taking BCA, ASA and other NSAIDs, including obligatory estimation of therapy effi cacy taking into account patient gender and age, has been established.
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Affiliation(s)
- I. V. Matoshina
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
| | - M. A. Livzan
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
| | - M. M. Fedorin
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
| | - I. V. Lapteva
- Healthcare institution of the Omsk region City Hospital No. 3
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Andreev DN, Zaborovsky AV, Lobanova EG. Gastroesophageal reflux disease: new approaches to optimizing pharmacotherapy. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2021:30-37. [DOI: 10.21518/2079-701x-2021-5-30-37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Proton pump inhibitors (PPIs) are baseline drugs for induction and maintenance of remission in gastroesophageal reflux disease (GERD). PPIs have proven to be highly effective in healing esophageal mucosal lesions and relieving the symptoms of the disease in most cases. However, according to the literature data, the incidence rate of clinical ineffectiveness of PPIs in the form of partial or complete persistence of current symptoms during administration of standard doses of PPIs ranges from 10 to 40%. Optimization of GERD therapy in PPI refractory patients is a significant challenge. In most cases, experts advise to increase a dose / dosage frequency of PPIs, switch to CYP2C19-independent PPIs (rabeprazole, esomeprazole, dexlansoprazole), add an esophagoprotective or promotility agents to therapy. At the same time, these recommendations have a limited effect in some patients, which opens up opportunities for looking for new solutions related to the optimization of GERD therapy. Today there is growing evidence of the relevance of the role of disruption of the cytoprotective and barrier properties of the esophageal mucosa in the genesis of GERD and the formation of refractoriness. Intercellular contacts ensure the integrity of the barrier function of the esophageal mucosa to protect it from various exogenous intraluminal substances with detergent properties. Acid-peptic attack in patients with GERD leads to alteration of the expression of some tight junction proteins in epithelial cells of the esophageal mucosa. The latter leads to increased mucosal permeability, which facilitates the penetration of hydrogen ions and other substances into the submucosal layer, where they stimulate the terminals of nerve fibers playing a role in the induction and persistence of the symptoms of the disease. The above evidence brought up to date the effectiveness study of the cytoprotective drugs with tropism to the gastrointestinal tract, as part of the combination therapy of GERD.
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Affiliation(s)
- D. N. Andreev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | | | - E. G. Lobanova
- Yevdokimov Moscow State University of Medicine and Dentistry
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Wu Y, Murray GK, Byrne EM, Sidorenko J, Visscher PM, Wray NR. GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression. Nat Commun 2021; 12:1146. [PMID: 33608531 PMCID: PMC7895976 DOI: 10.1038/s41467-021-21280-7] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 01/06/2021] [Indexed: 01/31/2023] Open
Abstract
Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) individuals identify 8 independent and significant loci for PUD at, or near, genes MUC1, MUC6, FUT2, PSCA, ABO, CDX2, GAST and CCKBR. There are previously established roles in susceptibility to Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder.
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Affiliation(s)
- Yeda Wu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
| | - Graham K Murray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
- Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Enda M Byrne
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Julia Sidorenko
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Peter M Visscher
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Naomi R Wray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
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An J, Gharahkhani P, Law MH, Ong JS, Han X, Olsen CM, Neale RE, Lai J, Vaughan TL, Gockel I, Thieme R, Böhmer AC, Jankowski J, Fitzgerald RC, Schumacher J, Palles C, Whiteman DC, MacGregor S. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases. Nat Commun 2019; 10:4219. [PMID: 31527586 PMCID: PMC6746768 DOI: 10.1038/s41467-019-11968-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 07/25/2019] [Indexed: 02/07/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett's esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.
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Affiliation(s)
- Jiyuan An
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Puya Gharahkhani
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Matthew H Law
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Jue-Sheng Ong
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Xikun Han
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Catherine M Olsen
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Rachel E Neale
- Cancer Aetiology and Prevention, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- School of Public Health, The University of Queensland, Brisbane, QLD, Australia
- School of Public Health and Social Work, the Queensland University of Technology, Brisbane, QLD, Australia
| | - John Lai
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, Australia
| | - Tom L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Anne C Böhmer
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | | | - Rebecca C Fitzgerald
- Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge, UK
| | - Johannes Schumacher
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Claire Palles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - David C Whiteman
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Stuart MacGregor
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
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10
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Atta MM, Sayed MH, Zayed MA, Alsulami SA, Al-Maghrabi AT, Kelantan AY. Gastro-oesophageal reflux disease symptoms and associated risk factors among medical students, Saudi Arabia. Int J Gen Med 2019; 12:293-298. [PMID: 31692498 PMCID: PMC6707933 DOI: 10.2147/ijgm.s206995] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 06/25/2019] [Indexed: 12/20/2022] Open
Abstract
Background and aims Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal disease worldwide that is associated with impaired quality of life and higher risk of complications. The identification of risk factors is necessary for preventive measures. The aim of this study is to evaluate the prevalence of GERD symptoms as well as its relation to body mass index (BMI) and other risk factors among medical students of Jeddah and Rabigh branches, King Abdul-Aziz University, Saudi Arabia. Subjects and methods A cross-sectional study was conducted at the Faculty of Medicine in Rabigh, King Abdul-Aziz University, Saudi Arabia. The study included 197 medical students from Rabigh and Jeddah branches of the university. The study employed a Gastroesophageal Reflux Disease Questionnaire which is derived from a self-administered validated GERD questionnaire (GerdQ). Results The prevalence of GERD symptoms was 25.9%. The most frequent symptoms were regurgitation and burning sensation. High BMI, family history, energy drinks and fried food were found to be statistically significant risk factors (p<0.05) by univariate analysis. However, the logistic regression for the prediction of GERD symptoms among medical students showed that only family history had a significant correlation (p<0.05). Conclusion GERD symptoms were common in medical students of King Abdulaziz University, Saudi Arabia. Family history was found to be a significant predictor of GERD symptoms. Effective educational strategies for groups with significant risk factors of GERD need to be implemented.
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Affiliation(s)
- Mohamed Magdi Atta
- Department of Medicine, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.,Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University, Benha, Egypt
| | - Mohamed Hisham Sayed
- Department of Pediatrics, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.,Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed A Zayed
- Department of Physiology, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.,Department of Physiology, Faculty of Medicine, Menoufia University, Shibīn Al Koum, Egypt
| | - Sultan A Alsulami
- Department of Medicine, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Ahmed T Al-Maghrabi
- Department of Medicine, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Abdulhfeez Y Kelantan
- Department of Medicine, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
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11
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Maev IV, Andreev DN, Kucheryavyy YA, Shaburov RI. [Current advances in the treatment of gastroesophageal reflux disease: a focus on esophageal protection]. TERAPEVT ARKH 2019; 91:4-11. [PMID: 32598747 DOI: 10.26442/00403660.2019.08.000387] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Indexed: 02/07/2023]
Abstract
Gastroesophageal reflux disease (GERD) is characterized by high morbidity and a significant decrease in the quality of life of patients, and is a major risk factor for esophageal adenocarcinoma. Nowadays, antisecretory therapy with proton pump inhibitors (PPI) is the "gold standard" of conservative treatment of GERD, but in some cases this therapy is unsuccessful. According to various studies, the prevalence of refractory GERD can reach 30-40%. The latest scientific data in the field of genetics and pathophysiology of GERD demonstrate that a disruption of the barrier function of the esophageal mucosa and an increase of its permeability can be the leading causes of refractoriness. Thus, the optimal therapy for patients with GERD should not only suppress the secretion of hydrochloric acid, but also restore the barrier function of the mucous membrane, providing an esophagoprotective effect. To achieve these goals, Alfasoxx was developed, which consists of a mixture of low molecular weight hyaluronic acid and low molecular weight chondroitin sulfate dissolved in a bioadhesive carrier (poloxamer 407). The clinical efficacy of this product has been confirmed by three prospective, randomized, placebo - controlled trials. Alfasoxx has a healing and restorative effect towards the esophageal epithelium and due to high ability for bioadhesion provides long - term protection of the mucous membrane of the esophagus. Combination therapy for GERD with the use of PPI and an esophagoprotector offers new perspectives for the treatment of patients with GERD.
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Affiliation(s)
- I V Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - D N Andreev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - Y A Kucheryavyy
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - R I Shaburov
- Yevdokimov Moscow State University of Medicine and Dentistry
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12
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Argyrou A, Legaki E, Koutserimpas C, Gazouli M, Papaconstantinou I, Gkiokas G, Karamanolis G. Polymorphisms of the BARX1 and ADAMTS17 Locus Genes in Individuals With Gastroesophageal Reflux Disease. J Neurogastroenterol Motil 2019; 25:436-441. [PMID: 31048564 PMCID: PMC6657930 DOI: 10.5056/jnm18183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/01/2019] [Accepted: 04/07/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Gastroesophageal reflux disease (GERD) represents a common condition having a substantial impact on the patients' quality of life, as well as the health system. According to many studies, the BARX1 and ADAMTS17 genes have been suggested as genetic risk loci for the development of GERD and its complications. The purpose of this study is to investigate the potential association between GERD and BARX1 and ADAMTS17 polymorphisms. METHODS The present is a prospective cohort study of 160 GERD patients and 180 healthy control subjects of Greek origin, examined for BARX1 and ADAMTS17 polymorphisms (rs11789015 and rs4965272) and a potential correlation to GERD. RESULTS The rs11789015 AG and GG genotypes were found to be significantly associated with GERD (P= 0.032; OR, 1.65; 95% CI, 1.062.57 and P= 0.033; OR, 3.00; 95% CI, 1.15-7.82, respectively), as well as the G allele (P= 0.007; OR, 1.60; 95% CI, 1.14- 2.24). Concerning the rs4965272, only the GG genotype was significantly associated with GERD (P= 0.035; OR, 3.42; 95% CI, 1.06-11.05). CONCLUSIONS This is a study investigating the potential correlation between BARX1 and ADAMTS17 polymorphisms and the development of GERD, showing a considerable association between both polymorphisms and the disease. This finding suggests that esophageal differentiation or altered regulation on microfibrils in the cell environment could be implicated as possible mechanisms in the pathogenesis of GERD.
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Affiliation(s)
- Alexandra Argyrou
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - Evangelia Legaki
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - Christos Koutserimpas
- 2nd Department of General Surgery, “Sismanoglio General Hospital of Athens, Athens,
Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - Ioannis Papaconstantinou
- 2nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - George Gkiokas
- 2nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - George Karamanolis
- Gastroenterology Unit, 2nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
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13
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Chatila AT, Nguyen MTT, Krill T, Roark R, Bilal M, Reep G. Natural history, pathophysiology and evaluation of gastroesophageal reflux disease. Dis Mon 2019; 66:100848. [PMID: 30803725 DOI: 10.1016/j.disamonth.2019.02.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gastroesophageal reflux disease (GERD) is one of the most common diseases encountered by both internists and gastroenterologists. GERD can cause a wide variety of symptoms ranging from heartburn and regurgitation to more atypical symptoms such as cough, chest pain, and hoarseness. The diagnosis is often times made on the basis of history and clinical symptomatology. The prevalence of GERD is currently estimated to be 8-33% with the incidence of disease only expected to increase over time. Although most cases of GERD can be diagnosed based on symptoms and clinical presentation, the diagnosis of GERD can be challenging when symptoms are atypical. In this review, we provide a comprehensive summary of the epidemiology, pathophysiology, evaluation and diagnosis of gastroesophageal reflux disease.
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Affiliation(s)
- Ahmed T Chatila
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX, United States
| | - Minh Thu T Nguyen
- The University of Texas Medical Branch School of Medicine, Galveston, TX, United States
| | - Timothy Krill
- Division of Gastroenterology & Hepatology, The University of Texas Medical Branch, Galveston, TX, United States
| | - Russell Roark
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX, United States
| | - Mohammad Bilal
- Division of Gastroenterology & Hepatology, The University of Texas Medical Branch, Galveston, TX, United States.
| | - Gabriel Reep
- Division of Gastroenterology & Hepatology, The University of Texas Medical Branch, Galveston, TX, United States
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14
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Argyrou A, Legaki E, Koutserimpas C, Gazouli M, Papaconstantinou I, Gkiokas G, Karamanolis G. Risk factors for gastroesophageal reflux disease and analysis of genetic contributors. World J Clin Cases 2018; 6:176-182. [PMID: 30148145 PMCID: PMC6107529 DOI: 10.12998/wjcc.v6.i8.176] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 05/31/2018] [Accepted: 06/08/2018] [Indexed: 02/05/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder with an increasing prevalence. GERD develops when the reflux of stomach contents causes troublesome typical and atypical symptoms and/or complications. Several risk factors of GERD have been identified and evaluated over the years, including a considerable amount of genetic factors. Multiple mechanisms are involved in the pathogenesis of GERD including: (1) motor abnormalities, such as impaired lower esophageal sphincter (LES) resting tone, transient LES relaxations, impaired esophageal acid clearance and delayed gastric emptying; and (2) anatomical factors, such as hiatal hernia and obesity. Genetic contribution seems to play a major role in GERD and GERD- related disorders development such Barrett's esophagus and esophageal adenocarcinoma. Twin and family studies have revealed an about 31% heritability of the disease. Numerous single-nucleotide polymorphisms in various genes like FOXF1, MHC, CCND1, anti-inflammatory cytokine and DNA repair genes have been strongly associated with increased GERD risk. GERD, Barrett's esophagus and esophageal adenocarcinoma share several genetic loci. Despite GERD polygenic basis, specific genetic loci such as rs10419226 on chromosome 19, rs2687201 on chromosome 3, rs10852151 on chromosome 15 and rs520525 on the paired related homeobox 1 gene have been mentioned as potential risk factors. Further investigation on the risk genes may elucidate their exact function and role and demonstrate new therapeutic approaches to this increasingly common disease.
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Affiliation(s)
- Alexandra Argyrou
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Evangelia Legaki
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Christos Koutserimpas
- 2nd Department of General Surgery, “Sismanoglion” General Hospital of Athens, Athens 11527, Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Ioannis Papaconstantinou
- 2nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - George Gkiokas
- 2nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - George Karamanolis
- Gastroenterology Unit, 2nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
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15
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Patel A, Hasak S, Nix BD, Sayuk GS, Newberry RD, Gyawali CP. Genetic risk factors for perception of symptoms in GERD: an observational cohort study. Aliment Pharmacol Ther 2018; 47:289-297. [PMID: 29148080 PMCID: PMC6278933 DOI: 10.1111/apt.14414] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 10/16/2017] [Accepted: 10/22/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Genetic polymorphisms in G-protein beta-3 subunit (GNβ3) and beta-2 adrenergic receptor (ADRB2) are associated with pain and gut hypersensitivity, which can overlap with gastroesophageal reflux disease (GERD). AIM To evaluate relationships between single nucleotide polymorphisms (SNPs) within GNβ3 and ADRB2 systems, and reflux symptom burden, GERD phenotypes from ambulatory reflux monitoring, and quality of life. METHODS Symptomatic adults undergoing ambulatory reflux testing were recruited and phenotyped based on acid burden and symptom reflux association; major oesophageal motor disorders and prior foregut surgery were exclusions. A comparison asymptomatic control cohort was also identified. Subjects and controls completed questionnaires assessing symptom burden on visual analog scales, short-form health survey-36 (SF-36), and Beck Anxiety and Depression Inventories (BAI and BDI). Genotyping was performed from saliva samples; 6 SNPs selected from each of the two genes of interest were compared. RESULTS Saliva from 151 study subjects (55.3 ± 1.2 years, 63.6% F) and 60 control subjects (50.9 ± 2.2 years, 66.7%) had sufficient genetic material for genotyping. Study subjects had higher symptom burden, worse total and physical health, and higher anxiety scores compared to controls (P ≤ .002). Tested SNPs within ADRB2 were similar between study subjects and controls (P > .09). Study subjects with recessive alleles in 3 GNβ3 SNPs (Rs2301339, Rs5443, and Rs5446) had worse symptom severity (P = .011), worse mental health (P = .03), and higher depression scores (P = .005) despite no associations with GERD phenotypes or reflux metrics. CONCLUSIONS Genetic variation within GNβ3 predicts oesophageal symptom burden and affect, but not oesophageal acid burden or symptom association with reflux episodes.
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Affiliation(s)
- A. Patel
- Duke University School of Medicine, Durham VA Medical Center, Durham, NC, USA
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - S. Hasak
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - B. D. Nix
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - G. S. Sayuk
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - R. D. Newberry
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - C. P. Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
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16
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Böhmer AC, Schumacher J. Insights into the genetics of gastroesophageal reflux disease (GERD) and GERD-related disorders. Neurogastroenterol Motil 2017; 29. [PMID: 28132438 DOI: 10.1111/nmo.13017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 11/30/2016] [Indexed: 12/31/2022]
Abstract
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.
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Affiliation(s)
- 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
| | - J Schumacher
- Institute of Human Genetics, University of Bonn, Bonn, Germany
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