FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2087680442> ?p ?o ?g. }

• W2087680442 endingPage "510" @default.
• W2087680442 startingPage "506" @default.
• W2087680442 abstract "In the past few years, attention has focused on the possibility that gastroesophageal reflux disease (GERD) may have a genetic basis. A specific locus associated with pediatric GERD has been identified on chromosome 13. This article reviews the literature to date that supports a familial or genetic basis for GERD, examines evidence for a specific locus for pediatric GERD at 13q14, and analyzes the rationale for suspecting genetic heterogeneity within pediatric GERD. The suspicion that GERD might have a familial component is not a new one. The first reports of familial hiatal hernia were published nearly forty years ago. In the subsequent decades, two dozen publications have identified familial segregation of hiatal hernia (HH), Barrett's esophagus (BE), esophageal adenocarcinoma, and GERD. Differences between adult and pediatric GERD (1) prompt one to be somewhat cautious in extrapolating data from one to the other. However, as a genetic basis has been considered in the literature for both ends of the age spectrum recently, it is worthwhile to reflect on the literature as a whole, particularly given our own cadre of families containing both infants and adults with significant GERD. Nonetheless, it may be that distinct genetic predispositions will be identified for different presentations, including presentations in different age groups. HIATAL HERNIA One of the earliest publications on the impact of genetics on the prevalence of HH was a `negative' epidemiologic report. In 1964, Kim cited a lower incidence of HH in Korea (1.4% of 1000 fluoroscopies) than had been reported in the western literature (2.3%–50%) (2). The significance of this finding is uncertain. There is a huge variability in the frequency with which HH is identified in fluoroscopic studies, which probably depends more on the fluoroscopic technique and the interest of the radiologist than it does on the genetic background of the population. In 1965, Carre published the first of several reports on the familial clustering of hiatus hernia (which he called “partial thoracic stomach”) in a large group of young children with GERD (3). Carre's dependence upon the x-ray as the definitive diagnostic tool for HH and GERD makes his studies difficult to interpret today, when diagnostic standards are so different. In this study he screened the relatives of children with reflux and hiatal hernia for evidence of these same disorders. Siblings were examined fluoroscopically regardless of presence or absence of symptoms, and other relatives (parents, grandparents, uncles, aunts, and cousins) were examined if they acknowledged symptoms. He identified 31 families in which multiple members had hiatus herniae. In 1970 he also described a family in which HH was identified in 8 individuals from three generations (4). Twenty-one years later, Carre and a colleague evaluated 406 of the younger siblings of 465 probands with HH (5). Inquiring for GERD symptoms in these younger siblings, they identified what they defined as definite symptoms in 7% and suggestive symptoms in 8%, a total of 15% in toto. They advised fluoroscopic evaluation of all 61 of these symptomatic younger siblings, and the parents of all of them agreed. Additionally, they offered fluoroscopic screening to the other 345 younger siblings, and parents of 210 of them agreed to the testing. The provocative fluoroscopic protocol specified rolling the child to the right side and to the supine position multiple times, and also manual abdominal pressure during the barium meal. Eleven percent of the siblings who were negative for HH on their initial fluoroscopic examination underwent a repeat examination during subsequent months. The authors detected HH in 9 (3%) of the 271 siblings tested, which is comparable to the 2.3 to 50% reported incidence of HH in all fluoroscopic examinations cited by Kim (2), and may be considered to argue against a familial incidence. Thirty-nine (14%) of the 271 siblings experienced gastroesophageal reflux during the fluoroscopic examination, which is also probably within the expected incidence for normal children during fluoroscopy. Several other small reports of familial HH have been published. In 1966, Sidd et al., described four siblings, including a pair of twins, with sliding hiatal hernia (6). In 1968, Chaiken described four families with multiple cases of HH (7). The following year, Goodman et al., published a four-generation pedigree of a kindred with HHs in six members and diabetes mellitus in seven (8). BARRETT'S ESOPHAGUS AND ADENOCARCINOMA As endoscopy began to supersede fluoroscopy as the principal diagnostic modality for pathologic reflux, it became clear that hiatal herniation was not a very sensitive or specific method for detecting the mucosal manifestations of GERD. In recent years, the studies on familial manifestations of GERD have focused on Barrett's esophagus (BE) and esophageal adenocarcinoma. The first report, by Lehman in 1979, described BE and GERD in five children whose father had BE and whose mother had HH (9). Four years later, Everhart et al. described a father and two sons, age 14 and 16, with BE (10). In the 1980s two papers described two pairs of sisters (one a set of twins) presenting with BE in their seventh decade (11,12). Between 1985 and 1993, there were four more reports of families with BE in multiple members (13–16). Three of them identified two- or three-generation pedigrees in which there were four to seven members with BE, including a number who had progressed to adenocarcinoma (13–15). The fourth article diagrammed four families with a total of 10 affected individuals (16). Taken together, as summarized in an editorial by Romero and Locke, these families comprise 88 individuals, of whom 28% had BE and 42% had esophagitis or heartburn (17). In 1996 a further publication described three families with six individuals having either BE or esophageal adenocarcinoma (18). In the past several years, the evidence suggesting a familial tendency in BE prompted the first prospective examination of the issue. In a study from the Mayo Clinic, a questionnaire was used to evaluate the prevalence of reflux symptoms in the relatives of 55 probands with reflux esophagitis, 40 probands with BE, and 27 probands with esophageal adenocarcinoma (19). The authors evaluated reflux symptoms in a total of 243 parents and siblings. The survey responses of these first-degree relatives were compared to those from a group of controls made up of all 122 spouses of the probands, and 230 of the spouses' parents and siblings. The authors found that reflux symptoms occurred with similar frequency among the first-degree relatives (33%) and spousal relatives (29%) of probands with reflux esophagitis. However, the prevalence of reflux symptoms was greater in the first-degree relatives of probands with BE than in the spousal relatives (46% vs. 27%, P = 0.013, adjusted odds ratio 2.23). Similar differences in reflux symptom prevalence were found between first-degree relatives and spousal relatives of the probands with esophageal adenocarcinoma (43% vs. 23%, P = 0.034, adjusted odds ratio 2.80). (In addition to genetic influences, including male gender, the authors identified instigation of GERD by obesity, smoking, and gender, adjusting for those factors in their analysis.) GERD AND GERD SYMPTOMS Several studies have investigated the familial occurrence of GERD using reflux symptoms or esophagitis as indicators rather than HH or BE. Two early studies simply described symptoms or esophagitis in pairs of siblings or twins, the latter a report in children (20–21). Recently two studies have explored the epidemiology of reflux symptoms. A cross-sectional study by Locke et al. from the Mayo Clinic extended their earlier work on the reflux symptoms of relatives of BE and esophageal adenocarcinoma patients (19) with a broadened examination of risk factors associated with reflux symptoms (22). They used a validated questionnaire mailed to residents of Olmsted County. Of the 2118 residents to whom questionnaires were mailed, 1524 (72%) returned them. Odds ratios with 95% confidence intervals indicated that heartburn and gastric and esophageal disease were significantly increased in the immediate family members of individuals who reported reflux symptoms at least once a week. As in their earlier study, they again identified obesity and smoking as risk factors for reflux symptoms; additional risk factors were alcohol consumption more than seven times a week and increased psychosomatic symptom checklist scores. Trudgill et al. used a prospective questionnaire to examine the prevalence of reflux symptoms and the use of anti-reflux medications in first-degree relatives of six equal groups of patients, 30 with no reflux symptoms; 30 with reflux symptoms but no objective evidence for increased esophageal acid exposure; 30 with reflux symptoms, abnormal pH probe study and normal lower esophageal sphincter pressure; 30 with reflux symptoms, abnormal pH probe study, and lower esophageal sphincter pressure h10 mm Hg; 30 with Barrett's esophagus; and 30 with esophageal strictures (23). Responses were obtained from 418 (78%) of the first-degree relatives of these 180 probands. Interestingly, significantly increased symptoms and medication use occurred only in relatives of the two groups with objective evidence of GERD and in those with BE. Increases in symptoms and medication use among relatives of those with symptomatic reflux (but without abnormal pH probe studies or endoscopies) and in those with strictures did not reach significance. Two very recent studies examined symptomatic reflux in large cohorts of twins. One evaluated 3000 randomly selected pairs from the approximately 8000 twin pairs in the Minnesota twin registry born between 1936 and 1963 (i.e., aged 38 to 65 in 2001 when the study was published in abstract form), using a questionnaire for regurgitation and heartburn (24). That study defined reflux as presence of heartburn or regurgitation more than once per week during the preceding year, and found reflux in 14% of the individuals in the 498 monozygotic (MZ) and 517 dyzygotic (DZ) pairs (an MZ:DZ ratio of 0.96) who completed the questionnaire. Concordance was 19% in the MZ and 4% in the DZ twins (P = 0.0011), which remained significant after controlling for obesity or smoking, two potential confounders. The second study evaluated 8401 pairs of twins over 55 years of age from the Swedish Twin Registry via a computer-assisted telephone interview (25), using the same definition of reflux as the Minnesota study. This Swedish study defined MZ by affirmative responses of both twins in a pair to the question, “During childhood, were you and your twin partner as alike as `two peas in a pod'...?” Overall, the authors found reflux in 15.3% of the individuals, who were subdivided into 2178 MZ, 3219 same-sex DZ, and 3014 unlike-sex DZ pairs (a ratio of MZ:DZ of 0.35). Concordance was 31% (29% in men and 33% in women) for the MZ pairs, and 13%, 14%, and 6% for the male, female, and mixed sex DZ pairs. Further analysis excluded confounding by genetic effects for obesity and alcohol, and partially liability to GERD is caused by genetic influences. However, the much larger proportion of individuals with GERD in this study, and the 16% loss of test-retest reliability for reflux diagnoses in a sub-set re-interviewed only two weeks later, raise questions about the reliability of the telephone interview technique. The disparate MZ:DZ ratios in the two studies also might prompt questions regarding accuracy of zygosity assignment, although these authors cite a 98% accuracy rate for their method. LOCUS AT 13q14 IN “SEVERE PEDIATRIC GERD” PHENOTYPE Responding to the accumulation of data suggesting a genetic determinant for GERD, in 2000 Hu et al. found a locus on chromosome 13 linked with a phenotype they identified as `severe pediatric GERD' (26). They surveyed more than 1000 members of a large parent GERD support group and received return surveys from 80 families. They thus identified twenty families that had a multigenerational history of GERD, and selected five families with 26 affected members for study. Using linkage analysis, they found a 21-centiMorgan (cM) region of chromosome 13 to be strongly linked to their reflux phenotype. The maximum 2-point LOD (logarithm of odds) score of 5.58 signifies a likelihood of >100,000:1 that the phenotype and genetic locus are linked, and their multipoint LOD score of 7.15 signifies a likelihood of >10,000,000:1 that the phenotype and locus are linked. Seeking to identify a specific gene associated with GERD, Hu et al. followed up their initial study by assessing the association of the gene encoding the 5-hydroxytryptamine receptor 2A (HTR2A) with the GERD phenotype. This gene, located in the 21 cM locus on chromosome 13, codes for a serotonin receptor that affects smooth muscle function and myogenesis (27). The analysis of linkage excluded this candidate gene in the five study families. Evaluations of other candidate genes in this locus have not been reported. The strength of the genetic association found by Hu et al. and the clinical importance of GERD itself make it important to confirm and extend these observations in more carefully defined patient groups. We recently performed linkage analysis in five families with infant probands under 5 months of age in whom there was a history of other similarly affected infant family members (28). We had clinically evaluated and comprehensively phenotyped five probands and five of the affected siblings. These 10 subjects had esophageal biopsies, which confirmed reflux esophagitis (29) and excluded eosinophilic esophagitis (30). The five probands and three of the siblings were evaluated by a validated Infant Gastroesophageal Reflux Questionnaire (I-GERQ), the results of which supported the diagnosis of infantile GERD (31). All probands and four of the siblings had barium fluoroscopy that excluded anatomic abnormalities. The three-generation pedigrees of the five probands contained 127 individuals who consented to representation in pedigrees. Included among these were 54 children in the proband generation (including the previously described 5 probands and their five affected siblings). The 49 non-probands from the proband generation (i.e., siblings and cousins), as well as the five probands, were also characterized as to phenotype (affected or not) via a shortened version of the I-GERQ, finding 21 of the 54 (39%) from that generation to be affected. Linkage analysis to the four most closely linked markers from the Hu study was performed on DNA extracted from blood of 45 members of the five families. This analysis excluded linkage of the 13q14 locus to the infantile GERD phenotype in our families, with LOD scores h-2 (odds greater than 100:1 against linkage) for multipoint linkage to all of the four markers (26). Why do these two studies differ in their findings regarding the 13q14 locus in pediatric GERD? The answer may lie in phenotypic disparity between the subjects of the two studies, in genetic heterogeneity of GERD itself, or both. While each study evaluated five families multiply affected by symptoms associated with pediatric GERD, the studies contain notable differences. The most important of these differences are probably the age of the affected children and the symptomatic presentations. In our study the phenotype was by definition typical infantile GERD with esophagitis, whereas in the study by Hu et al. no children were included whose GERD was limited to infancy. The symptoms in these patients were variable but there was a preponderance of otolaryngologic complications of GERD. The question has been raised as to whether the affected phenotype of the patients evaluated by Hu et al. might be linked to a chromosomal locus related to allergy, rather than to one related to GERD (32,33). Even if the locus on chromosome 13 is indeed one that determines a GERD phenotype, it is likely that a disorder as phenotypically and pathophysiologically diverse as GERD is determined or modified by more than one genetic locus. It is compelling to consider that there may be different molecular underpinnings of the various pathophysiologic determinants of GERD in different families. Some of the most direct, or `primary' pathophysiologic determinants of GERD that might be controlled genetically are shown in Table 1. In addition to molecular mechanisms responsible for these various pathophysiologic mechanisms, such as those in patients with familial gastric stasis and GERD (20), there also may be molecular mechanisms that cause reflux indirectly (e.g., those causing obesity (22), spasticity (34), or cough (35,36)) which might indirectly increase abdominal pressure and thereby reflux). Finally, molecular mechanisms (such as those underlying familial tendencies to allergy (32,33)) might also provoke symptoms identical with those produced by GERD without being due to primary pathologic GERD.TABLE 1: Pathophysiologic determinants of GERDThe resolution of these disparate results, and the identification of the molecular mechanisms underlying familial pediatric GERD, will have important consequences, both for our understanding of the pathophysiology of this common and costly disorder, and for our ability to more accurately target treatments at those mechanisms." @default.
• W2087680442 created "2016-06-24" @default.
• W2087680442 creator A5008781173 @default.
• W2087680442 creator A5017218711 @default.
• W2087680442 creator A5021037951 @default.
• W2087680442 creator A5081928695 @default.
• W2087680442 date "2002-05-01" @default.
• W2087680442 modified "2023-09-28" @default.
• W2087680442 title "Genetics of Gastroesophageal Reflux Disease: A Review" @default.
• W2087680442 cites W1498177643 @default.
• W2087680442 cites W1862195153 @default.
• W2087680442 cites W1976612198 @default.
• W2087680442 cites W2004117822 @default.
• W2087680442 cites W2007097175 @default.
• W2087680442 cites W2011049774 @default.
• W2087680442 cites W2023125172 @default.
• W2087680442 cites W2024545905 @default.
• W2087680442 cites W2026451621 @default.
• W2087680442 cites W2036007533 @default.
• W2087680442 cites W2036960887 @default.
• W2087680442 cites W2044246400 @default.
• W2087680442 cites W2057773316 @default.
• W2087680442 cites W2079659934 @default.
• W2087680442 cites W2083946850 @default.
• W2087680442 cites W2091123967 @default.
• W2087680442 cites W2115007875 @default.
• W2087680442 cites W2118346482 @default.
• W2087680442 cites W2123481206 @default.
• W2087680442 cites W2128388535 @default.
• W2087680442 cites W2132131061 @default.
• W2087680442 cites W2134207741 @default.
• W2087680442 cites W2135189410 @default.
• W2087680442 cites W2139031591 @default.
• W2087680442 cites W2312689970 @default.
• W2087680442 cites W2314765816 @default.
• W2087680442 cites W2324366054 @default.
• W2087680442 cites W79506128 @default.
• W2087680442 doi "https://doi.org/10.1097/00005176-200205000-00005" @default.
• W2087680442 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/12050574" @default.
• W2087680442 hasPublicationYear "2002" @default.
• W2087680442 type Work @default.
• W2087680442 sameAs 2087680442 @default.
• W2087680442 citedByCount "42" @default.
• W2087680442 countsByYear W20876804422012 @default.
• W2087680442 countsByYear W20876804422014 @default.
• W2087680442 countsByYear W20876804422015 @default.
• W2087680442 countsByYear W20876804422016 @default.
• W2087680442 countsByYear W20876804422017 @default.
• W2087680442 countsByYear W20876804422018 @default.
• W2087680442 countsByYear W20876804422019 @default.
• W2087680442 countsByYear W20876804422021 @default.
• W2087680442 crossrefType "journal-article" @default.
• W2087680442 hasAuthorship W2087680442A5008781173 @default.
• W2087680442 hasAuthorship W2087680442A5017218711 @default.
• W2087680442 hasAuthorship W2087680442A5021037951 @default.
• W2087680442 hasAuthorship W2087680442A5081928695 @default.
• W2087680442 hasBestOaLocation W20876804421 @default.
• W2087680442 hasConcept C126322002 @default.
• W2087680442 hasConcept C2777819096 @default.
• W2087680442 hasConcept C2779134260 @default.
• W2087680442 hasConcept C2780323790 @default.
• W2087680442 hasConcept C43270747 @default.
• W2087680442 hasConcept C71924100 @default.
• W2087680442 hasConcept C90924648 @default.
• W2087680442 hasConceptScore W2087680442C126322002 @default.
• W2087680442 hasConceptScore W2087680442C2777819096 @default.
• W2087680442 hasConceptScore W2087680442C2779134260 @default.
• W2087680442 hasConceptScore W2087680442C2780323790 @default.
• W2087680442 hasConceptScore W2087680442C43270747 @default.
• W2087680442 hasConceptScore W2087680442C71924100 @default.
• W2087680442 hasConceptScore W2087680442C90924648 @default.
• W2087680442 hasIssue "5" @default.
• W2087680442 hasLocation W20876804421 @default.
• W2087680442 hasLocation W20876804422 @default.
• W2087680442 hasOpenAccess W2087680442 @default.
• W2087680442 hasPrimaryLocation W20876804421 @default.
• W2087680442 hasRelatedWork W1972259282 @default.
• W2087680442 hasRelatedWork W1990872639 @default.
• W2087680442 hasRelatedWork W2042374557 @default.
• W2087680442 hasRelatedWork W2044197209 @default.
• W2087680442 hasRelatedWork W2050449592 @default.
• W2087680442 hasRelatedWork W2076239091 @default.
• W2087680442 hasRelatedWork W2076707606 @default.
• W2087680442 hasRelatedWork W2140237808 @default.
• W2087680442 hasRelatedWork W2899792496 @default.
• W2087680442 hasRelatedWork W3141404013 @default.
• W2087680442 hasVolume "34" @default.
• W2087680442 isParatext "false" @default.
• W2087680442 isRetracted "false" @default.
• W2087680442 magId "2087680442" @default.
• W2087680442 workType "article" @default.