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      Risk factors for gastroesophageal reflux disease and analysis of genetic contributors

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          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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          Epidemiology of gastro-oesophageal reflux disease: a systematic review.

          J. Dent, H B El-Serag, M.-A. Wallander … (2005)
          A systematic review of the epidemiology of gastro-oesophageal reflux disease (GORD) has been performed, applying strict criteria for quality of studies and the disease definition used. The prevalence and incidence of GORD was estimated from 15 studies which defined GORD as at least weekly heartburn and/or acid regurgitation and met criteria concerning sample size, response rate, and recall period. Data on factors associated with GORD were also evaluated. An approximate prevalence of 10-20% was identified for GORD, defined by at least weekly heartburn and/or acid regurgitation in the Western world while in Asia this was lower, at less than 5%. The incidence in the Western world was approximately 5 per 1000 person years. A number of potential risk factors (for example, an immediate family history and obesity) and comorbidities (for example, respiratory diseases and chest pain) associated with GORD were identified. Data reported in this systematic review can be interpreted with confidence as reflecting the epidemiology of "true" GORD. The disease is more common in the Western world than in Asia, and the low rate of incidence relative to prevalence reflects its chronicity. The small number of studies eligible for inclusion in this review highlights the need for global consensus on a symptom based definition of GORD.
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            Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.

            Howard Hampel, Neena Abraham, Hashem El-Serag (2005)
            The association of body mass index and gastroesophageal reflux disease (GERD), including its complications (esophagitis, Barrett esophagus, and esophageal adenocarcinoma), is unclear. To conduct a systematic review and meta-analysis to estimate the magnitude and determinants of an association between obesity and GERD symptoms, erosive esophagitis, Barrett esophagus, and adenocarcinoma of the esophagus and of the gastric cardia. MEDLINE search between 1966 and October 2004 for published full studies. Studies that provided risk estimates and met criteria on defining exposure and reporting outcomes and sample size. Two investigators independently performed standardized search and data abstraction. Unadjusted and adjusted odds ratios for individual outcomes were obtained or calculated for each study and were pooled by using a random-effects model. Nine studies examined the association of body mass index (BMI) with GERD symptoms. Six of these studies found statistically significant associations. Six of 7 studies found significant associations of BMI with erosive esophagitis, 6 of 7 found significant associations with esophageal adenocarcinoma, and 4 of 6 found significant associations with gastric cardia adenocarcinoma. In data from 8 studies, there was a trend toward a dose-response relationship with an increase in the pooled adjusted odds ratios for GERD symptoms of 1.43 (95% CI, 1.158 to 1.774) for BMI of 25 kg/m2 to 30 kg/m2 and 1.94 (CI, 1.468 to 2.566) for BMI greater than 30 kg/m2. Similarly, the pooled adjusted odds ratios for esophageal adenocarcinoma for BMI of 25 kg/m2 to 30 kg/m2 and BMI greater than 30 kg/m2 were 1.52 (CI, 1.147 to 2.009) and 2.78 (CI, 1.850 to 4.164), respectively. Heterogeneity in the findings was present, although it was mostly in the magnitude of statistically significant positive associations. No studies in this review examined the association between Barrett esophagus and obesity. Obesity is associated with a statistically significant increase in the risk for GERD symptoms, erosive esophagitis, and esophageal adenocarcinoma. The risk for these disorders seems to progressively increase with increasing weight.
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              Body-mass index and symptoms of gastroesophageal reflux in women.

              Ciarán Kelly, Gabriela A C G Camargo, E Somers … (2006)
              Overweight and obese persons are at increased risk for gastroesophageal reflux disease. An association between body-mass index (BMI)--the weight in kilograms divided by the square of the height in meters - and symptoms of gastroesophageal reflux disease in persons of normal weight has not been demonstrated. In 2000, we used a supplemental questionnaire to determine the frequency, severity, and duration of symptoms of gastroesophageal reflux disease among randomly selected participants in the Nurses' Health Study. After categorizing women according to BMI as measured in 1998, we used logistic-regression models to study the association between BMI and symptoms of gastroesophageal reflux disease. Of 10,545 women who completed the questionnaire (response rate, 86 percent), 2310 (22 percent) reported having symptoms at least once a week, and 3419 (55 percent of those who had any symptoms) described their symptoms as moderate in severity. We observed a dose-dependent relationship between increasing BMI and frequent reflux symptoms (multivariate P for trend <0.001). As compared with women who had a BMI of 20.0 to 22.4, the multivariate odds ratios for frequent symptoms were 0.67 (95 percent confidence interval, 0.48 to 0.93) for a BMI of less than 20.0, 1.38 (95 percent confidence interval, 1.13 to 1.67) for a BMI of 22.5 to 24.9, 2.20 (95 percent confidence interval, 1.81 to 2.66) for a BMI of 25.0 to 27.4, 2.43 (95 percent confidence interval, 1.96 to 3.01) for a BMI of 27.5 to 29.9, 2.92 (95 percent confidence interval, 2.35 to 3.62) for a BMI of 30.0 to 34.9, and 2.93 (95 percent confidence interval, 2.24 to 3.85) for a BMI of 35.0 or more. Even in women with a normal baseline BMI, an increase in BMI of more than 3.5, as compared with no weight changes, was associated with an increased risk of frequent symptoms of reflux (odds ratio, 2.80; 95 percent confidence interval, 1.63 to 4.82). BMI is associated with symptoms of gastroesophageal reflux disease in both normal-weight and overweight women. Even moderate weight gain among persons of normal weight may cause or exacerbate symptoms of reflux. Copyright 2006 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Alexandra Argyrou
                Evangelia Legaki
                Christos Koutserimpas
                Maria Gazouli
                Ioannis Papaconstantinou
                George Gkiokas
                George Karamanolis
                Journal
                Journal ID (nlm-ta): World J Clin Cases
                Journal ID (publisher-id): WJCC
                Title: World Journal of Clinical Cases
                Publisher: Baishideng Publishing Group Inc
                ISSN (Electronic): 2307-8960
                Publication date (Print): 16 August 2018
                Publication date (Electronic): 16 August 2018
                Volume: 6
                Issue: 8
                Pages: 176-182
                Affiliations
                Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
                Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
                2 nd Department of General Surgery, “Sismanoglion” General Hospital of Athens, Athens 11527, Greece
                Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece. mgazouli@ 123456med.uoa.gr
                2 nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
                2 nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
                Gastroenterology Unit, 2 nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
                Author notes

                Author contributions: All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.

                Correspondence to: Maria Gazouli, PhD, Associate Professor, Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Michalakopoulou 176, Athens 11527, Greece. mgazouli@ 123456med.uoa.gr

                Telephone: +30-210-7462231

                Article
                Other ID: jWJCC.v6.i8.pg176
                DOI: 10.12998/wjcc.v6.i8.176
                PMC ID: 6107529
                PubMed ID: 30148145
                SO-VID: d051461f-723c-494f-ba48-2c34cdea6639
                Copyright © ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
                License:

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                Date received : 3 May 2018
                Date revision received : 31 May 2018
                Date accepted : 8 June 2018
                Categories
                Subject: Minireviews

                Keywords: single nucleotide polymorphisms,genetic risk loci,risk factors,gastroesophageal reflux disease,gastroesophageal reflux disease development
                Data availability:
                Keywords: single nucleotide polymorphisms, genetic risk loci, risk factors, gastroesophageal reflux disease, gastroesophageal reflux disease development

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