Gastroesophageal reflux disease (GERD) is a common. Gastroesophageal Reflux Disease in Monozygotic and Dizygotic Twins

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1 GASTROENTEROLOGY 2002;122:55 59 Gastroesophageal Reflux Disease in Monozygotic and Dizygotic Twins ALAN J. CAMERON,* JESPER LAGERGREN,, CHRISTER HENRIKSSON, OLOF NYREN, G. RICHARD LOCKE III,*, and NANCY L. PEDERSEN *Division of Gastroenterology and Hepatology, and Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota; Department of Medical Epidemiology, Karolinska Institute; and Department of Surgery, Karolinska Hospital, Stockholm, Sweden Background & Aims: Gastroesophageal reflux disease (GERD) interferes with the quality of life and carries an increased risk for esophageal adenocarcinoma. We investigated genetic influence in the development of reflux. Methods: We compared concordance for reflux in monozygotic (MZ) and dizygotic (DZ) twins. All twins age 55 and older in the nationwide Swedish Twin Registry were invited to participate. Data were collected by computer-assisted telephone interviews. Reflux disease was defined by symptomatic heartburn or acid regurgitation occurring at least weekly. Results: A total of 2178 monozygotic, 3219 same-sex dizygotic, and 3014 unlike-sex dizygotic twin provided information. Overall, 15.3% of the twins had reflux. In men, the intraclass correlation for reflux was 0.29 (95% confidence interval [CI], ) for monozygotic and 0.13 (95% CI, ) for dizygotic. In women, the correlation was 0.33 (95% CI, ) for monozygotic and 0.14 (95% CI, ) for dizygotic. For unlike-sex dizygotic, the correlation was 0.06 (95% CI, 0.01 to 0.14). Concordance for reflux was not caused by inherited obesity or alcohol use; inherited smoking may be a minor factor. Conclusions: The increased concordance for reflux in monozygotic, compared with dizygotic, indicates genetic rather than shared environmental effects. Heritability accounted for 31% (23% 39%) of the liability to reflux disease in this population. Gastroesophageal reflux disease (GERD) is a common disorder. Some 14% 24% of adults in Western populations experience heartburn and acid regurgitation, the principal symptoms of GERD, at least once per week; 4% 9% have daily symptoms. 1 3 Some patients with GERD develop Barrett s esophagus, 4 a metaplasia of the esophageal mucosa that predisposes to adenocarcinoma of the esophagus. 5 The incidence of this cancer has increased greatly in recent decades. 6 Case-control studies show that individuals with GERD have an increased risk for esophageal adenocarcinoma. 7,8 In a recent report, the relative risk for adenocarcinoma of the esophagus was 7.7 for those with reflux symptoms occurring at least weekly, and 43.5 for those with long-standing severe reflux symptoms. 8 In addition to the cancer risk, GERD has an adverse impact on quality of life, 9 and the cost of longterm medical therapy is substantial. 10 The pathophysiology of GERD has been extensively studied. Factors including lower esophageal sphincter weakness, inappropriate sphincter relaxations, and hiatal hernia 11 lead to gastroesophageal reflux, which may cause reflux esophagitis and sometimes Barrett s esophagus. It is less clear why some individuals have GERD and others do not. Obesity was associated with GERD in 2 recent studies, 10,12 but not in another study. 13 Smoking may predispose to GERD, 14 but the evidence is conflicting. 10 The role of genetic factors in the etiology of GERD is uncertain. Individuals with GERD were more likely to report relatives with reflux symptoms than controls. 10 Familial Barrett s esophagus with other relatives having GERD has been described. 15,16 In 2 studies, first-degree relatives of patients with reflux diseases were questioned directly about reflux symptoms. 14,17 In both studies, more relatives of patients with Barrett s esophagus had reflux symptoms than unrelated persons. Relatives of patients with uncomplicated GERD had reflux more often than controls in 1 study, 17 whereas the other study showed a nonsignificant trend to increased reflux in the relatives. 14 Familial aggregation of GERD could be caused by genetic factors or by shared environmental risk factors. Our aim was to estimate the contribution of genetic factors to the development of GERD. We compared the concordance of GERD in monozygotic (MZ; all genes shared) and dizygotic (DZ; average 50% of genes shared) twin. We postulated that, if concordance was Abbreviations used in this paper: DZ, dizygotic; GERD, gastroesophageal reflux disease; MZ, monozygotic by the American Gastroenterological Association /02/$35.00 doi: /gast

2 56 CAMERON ET AL. GASTROENTEROLOGY Vol. 122, No. 1 greater in MZ, genetic factors in the etiology of GERD were probable. Materials and Methods Screening Across the Lifespan Twin Study Data were collected between March 1998 and November 2000 as part of the Screening Across the Lifespan Twin Study. All twins age 55 or older in the nationwide Swedish Twin Registry 18,19 were invited to participate. The most recent information on last name and address was linked to the telephone company s files to obtain telephone numbers. Computer-assisted telephone interviews were conducted by trained professional interviewers. Items were presented in a branching format such that individuals were asked follow-up items if they responded positively to key introductory items. The Screening Across the Lifespan Twin Study included a large number of questions about multiple disorders, the questions on reflux being a fraction of the telephone interview. A number of introductory items were asked of all twins. Among these were validated questions to determine zygosity, and questions about height, weight, medication use, and consumption of alcohol and tobacco. Obesity was defined as a body mass index of 30 or greater. Alcohol use was defined as taking 300 grams of ethanol per month or more. Smoking status was defined as current smoker or current nonsmoker. Reflux data. The 10 reflux questions used (in Swedish) were based on previous work from our 2 institutions. 3,8 An English translation of the reflux questions is given in the Appendix. Such structured questionnaires to define reflux symptoms are considered quite specific for GERD. 10,20 All individual twins were asked if they had heartburn, pain behind the breastbone, or regurgitation of bitter or sour fluid into the mouth. If a positive response was given to any of these 3 questions, 7 more questions were asked. These asked about the frequency and duration of symptoms, radiation of discomfort toward the neck, night waking, antacid relief, and use of histamine-receptor antagonist or proton pump inhibitor medications. After the start of the study, the question about retrosternal pain was modified with the intent to clarify the distinction between cardiac and reflux symptoms; the modification had little effect on the overall results, and data from the earlier and modified versions were therefore pooled. A positive history for GERD was defined a priori as the occurrence, at least once a week, of either retrosternal pain with antacid relief, or retrosternal burning with antacid relief or radiation toward the neck; or regurgitation of bitter fluid. Individuals reporting these symptoms before current treatment with acid-suppressant medications were also considered to have GERD. Twins with no reflux symptoms, or symptoms less than once a week, were defined as not having GERD. Zygosity Determination Each twin, independently, was asked, During childhood, were you and your twin partner as alike as two peas in a pod or not more alike than siblings in general? If both individuals of a pair responded, Alike as two peas in a pod, they were classified as MZ, if both responded, not alike, they were classified as DZ. If the twins did not agree, the zygosity was considered, not determined, and these were excluded. This method of zygosity determination was shown to be 98% accurate compared with analysis of 13 DNA polymorphisms. 19,21 Statistical Analysis rates were compared for MZ and DZ twins. is the number of affected twins in concordant divided by the total number of affected twins. Intraclass (tetrachoric) correlations were calculated by the MX program. 22 Tetrachoric correlations are more statistically efficient than direct comparisons of concordance rates because use is made of the data in in which neither twin has the disease. To estimate the relative importance of genetic effects (heritability) and to test whether the genetic component of variance differed between men and women, models based on 2 by 2 contingency tables (Twin A s status by Twin B s status) for 5 zygosity groups (MZ men, MZ women, DZ men, DZ women, unlike-sex ) were constructed. The study was approved by the Ethics Committee of the Karolinska Institute, and by the Mayo Institutional Review Board. Results The telephone interview was completed by 25,958 individual twins. The response rate was 75.5%. Table 1. Concordance Rates for GERD in Monozygotic and Dizygotic Twins (Men) rate n/n (%) a Intraclass correlation b MZ /139 (23.0) 0.27 ( ) DZ /250 (20.8) 0.13 ( 0.03 to 0.28) 65 MZ /110 (29.1) 0.34 ( ) DZ /171 (19.9) 0.14 ( 0.05 to 0.32) Total MZ /249 (25.7) 0.29 ( ) DZ /421 (20.4) 0.13 ( ) a rate (number of affected twins in concordant )/(total number of affected twins). b 95% confidence intervals in parentheses.

3 January 2002 GASTROESOPHAGEAL REFLUX IN TWINS 57 Table 2. Concordance Rates for GERD in Monozygotic and Dizygotic Twins (Women) rate n/n (%) Intraclass correlation MZ /235 (31.5) 0.34 ( ) DZ /297 (20.9) 0.15 ( ) 65 MZ /175 (29.7) 0.33 ( ) DZ /272 (20.7) 0.15 ( ) Total MZ /410 (30.7) 0.33 ( ) DZ /569 (21.1) 0.14 ( ) GERD symptoms were reported by 15.7% of twins ages and 15.0% aged 65 and older, and by 14.8% of men and 15.8% of women. There were 8401 (16,802 individuals) in which both twins completed the interview, and question-based zygosity was established. There were 2178 MZ, 3219 same-sex DZ, and 3004 unlike-sex DZ. A randomly selected sample of 105 twins were asked to participate in a repeat interview, 2 weeks ( 1 day) later, and 102 twins participated. The agreement between 2 occasions for GERD was 84.3%, and the value was Concordance rates for like-sex twin are shown in Tables 1 and 2. MZ twin concordance for GERD was greater than DZ concordance in each of 4 independent subgroups; men or women, and aged 55 64, or 65 and over. The intraclass correlations for MZ twin were 0.29 (95% CI, ) for men and 0.33 ( ) for women. For both men and women, the correlation was greater for MZ than for DZ twin. The correlations for DZ twin were 0.13 ( ) for men, and 0.14 ( ) for women. Concordance rates for unlike-sex twin (Table 3) were somewhat lower than for like-sex DZ. The unlike-sex DZ intraclass correlation was 0.06 ( 0.01 to 0.14) and was not statistically significant. Models were constructed to estimate the relative importance of different genetic effects in men and women. The best-fit model (Table 4) showed that the relative importance of genetic effects was of equal magnitude in each sex, but there may be some difference in the genes or genetic effects involved for men compared with women. Heritability for GERD in both sexes combined was 31% (95% CI, ). Obesity, smoking, and alcohol intake had no major influence on the genetic impact for GERD. Table 5 summarizes the cross-twin cross-trait tetrachoric correlations for GERD and smoking, obesity, and alcohol in all twin groups. The lack of MZ-DZ differential in these correlations suggests that genetic effects for obesity and alcohol are not shared for GERD. A small effect of smoking in the heritability for GERD is possible. Discussion This population-based study included a majority of all twin living in Sweden in the age groups investigated. The reflux questions were part of a larger inquiry involving multiple disorders. The interviewers were trained to ask the questions in a standard manner, and were blind to the zygosity and responses of the twin partner. These factors should minimize selection or observer bias in respect to GERD. The large study size added strength to the conclusions and permitted evaluation of subgroups. Previous twin studies have shown the importance of genetic effects in obesity, 23 smoking, 24,25 and alcoholism. 26 However, we found that concordance for GERD was similar whether or not 1 or both members of the pair was obese or used alcohol regularly. Multivariate models are necessary to test whether some of the genetic liability to GERD reflects genetic liability to the covariates, but even with these large sample sizes, our power was limited for evaluating such effects. The cross-twin cross-trait correlations suggest that some of the genetic liability for GERD may be shared with smoking. The finding of increased concordance for GERD in MZ twin is consistent with genetic influence, but Table 3. Probandwise Concordance Rates for GERD in Unlike-Sex (US) Pairs rate n/n (%) Intraclass correlation US /558 (17.2) 0.02 ( 0.08 to 0.13) 65 US /386 (19.2) 0.12 ( ) Total US /944 (18.2) 0.06 ( 0.01 to 0.14)

4 58 CAMERON ET AL. GASTROENTEROLOGY Vol. 122, No. 1 Table 4. Best Fitting Model to Assess Variation of Genetic and Environmental Components for GERD in Men and Women Parameter estimates Fit of model Model Sex A C E Rg 2 df Prob AIC AE model Rg free Men 0.31 ( ) 0.69 ( ) Women 0.31 ( ) 0.69 ( ) ( ) NOTE. Genetic effects are equally important in men and women, but the genetic component is freely estimated. Some difference in gene effects for men and women. A, genetic effects; C, shared environmental effects; E, environmental effects (nonshared); Rg, genetic correlation; df, degrees of freedom; AIC, Akaike Information Criterion ( 2 2 df). comparison with DZ is also important. MZ twin share 100% of their genes, whereas DZ twin share on average 50% of their genes. If familial aggregation of GERD was caused entirely by shared environment, rather than shared genes, the concordance for GERD should be similar in MZ and DZ. Instead, we found that concordance for GERD was greater in MZ than DZ, indicating principally genetic rather than shared environmental effects. The model-fitting analyses confirmed the absence of shared environmental variance, and showed that genetic influences explained about 30% of the total variation. This study was part of an investigation of multiple disorders in twins age 55 and older. Although we did not study younger twins, we note that the prevalence of GERD is similar between ages years, 3 and that reflux symptoms may persist for many years. 3,27 In a recent abstract report of 1015 with a mean age of 46 years, 28 pair-wise concordance for GERD was 19% in MZ and 4.3% in DZ twins (P 0.001). Thus, genetic influences are likely important in younger individuals, though this needs further evaluation. The mechanism of the genetic contribution to GERD is unknown. In extended pedigrees with familial Barrett s esophagus, 15,16 GERD was present in consecutive generations and an autosomal-dominant reflux trait was suggested. A family with hiatal hernia in 4 generations and onset of GERD in childhood, sometimes persisting beyond age 60, has been reported, 29 and an autosomaldominant inheritance for hiatal hernia was proposed. Hu Table 5. Cross-Twin, Cross-Trait, Intraclass Correlations for Smoking, Obesity, and Alcohol MZ DZ Unlike-sex smoking twin (0.03) 0.02 (0.02) 0.06 (0.03) obesity twin (0.04) 0.10 (0.03) 0.07 (0.03) alcohol twin (0.03) 0.00 (0.03) 0.06 (0.03) NOTE. Standard errors in parentheses. et al. 30 reported 5 families with severe pediatric GERD, showing an autosomal-dominant pattern, with a gene of undetermined function mapped to chromosome 13q14. In some of these family members, GERD persisted into adult life, and further studies of this gene in adults with GERD are awaited. 30 Our data indicate there may be some differences in the functioning genes in the 2 sexes. Possibly, several genes of small and additive effect contribute to the liability to the common form of GERD. In adults, GERD shows a spectrum of severity, and there is no well-defined phenotype to identify affected individuals. At this time, genomic screening for genes related to the common form of GERD in adults may be premature. In brief, we showed an increased concordance for GERD in MZ compared with DZ twins. We conclude that about 31% of the liability to GERD is caused by genetic influences. References 1. Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Dig Dis Sci 1976; 21: Thompson WG, Heaton KW. Heartburn and globus in apparently healthy people. Can Med Ass J 1982;126: Locke GR III, Talley NJ, Fett SR, Zinsmeister AR, Melton LJ III. Prevalence and clinical spectrum of gastroesophageal reflux: a population based study in Olmsted County, Minnesota. Gastroenterology 1997;112: Winters C, Spurling TJ, Chobanian SJ, Curtis DJ, Esposito RL, Hacker JF, Johnson DA, Cruess DF, Cotelingam JD, Gurney MS, Cattau EL. Barrett s esophagus. A prevalent, occult complication of gastroesophageal reflux disease. Gastroenterology 1987;92: Tytgat GNJ. Does endoscopic surveillance in esophageal columnar metaplasia have any real value? Endoscopy 1995;27: Devesa SS, Blot WJ, Fraumeni JF. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83: Chow WC, Finkle WD, McLaughlin JK, Frankl H, Ziel HK, Fraumeni JF. The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia. JAMA 1995;274: Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340: Eloubeidi MA, Provenzale D. Health-related quality of life and severity of symptoms in patients with Barrett s esophagus and

5 January 2002 GASTROESOPHAGEAL REFLUX IN TWINS 59 gastroesophageal reflux disease without Barrett s esophagus. Am J Gastroenterol 2000;95: Locke GR III, Talley NJ, Fett SR, Zinsmeister AR, Melton LJ III. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106: Van Herwaarden MA, Samsom A, Smout AJPM. Excess gastroesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology 2000;119: Wilson LJ, Ma Wenzou M, Hirschowitz BI. Association of obesity with hiatal hernia and esophagitis. Am J Gastroenterol 1999;94: Lagergren J, Bergstrom R, Nyren O. No relation between body mass and gastrooesophageal reflux symptoms in a Swedish population-based study. Gut 2000;47: Romero Y, Cameron AJ, Locke III GR, Schaid DJ, Slezak JM, Branch CD, Melton III LJ. Familial aggregation of gastroesophageal reflux in patients with Barrett s esophagus and esophageal adenocarcinoma. Gastroenterology 1997;113: Crabb DW, Berk MA, Hall TR, Conneally PM, Biegel AA, Lehman GA. Familial gastroesophageal reflux and development of Barrett s esophagus. Ann Intern Med 1985;103: Jochem VJ, Fuerst PA, Fromkes JJ. Familial Barrett s esophagus associated with adenocarcinoma. Gastroenterology 1992;102: Trudgill NJ, Kapur KC, Riley AS. Familial clustering of reflux symptoms. Am J Gastroenterol 1999;94: Lichtenstein P, Holm NV, Verkasolo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skyrrhe A, Hemminki K. Environmental and heritable factors in the causation of cancer. Analyses of cohorts of twins from Sweden, Denmark and Finland. N Engl J Med 2000;343: Pedersen NL, Lichtenstein P. The Swedish Twin Registry: a presentation. In: Smedby B, Lundberg I, Sörensen TIA, eds. Scientific evaluation of the Swedish Twin Registry. Stockholm: Swedish Council for Planning and Coordination of Research, 2000: Dent J, Jones R, Kahrilas P, Talley NJ. Management of gastrooesophageal reflux disease in general practice. BMJ 2001;322: Svedberg P, Lichtenstein P, Pedersen NL. Age and sex differences in genetic and environmental factors for self-rated health: a twin study. J Gerontol B Psychol Soc Sci 2001;56:S Neale MC, Boker SM, Xie G, Maes HH. MX: Statistical Modeling (ed 5). VCU Box , Richmond, VA: Department of Psychiatry, Maes HHM, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997;27: Carmelli D, Swan GE, Robinette D, Fabsitz R. Genetic influence on smoking a study of male twins. N Engl J Med 1992;327: Kendler KS, Karkowski LM, Pedersen NL. Tobacco consumption in Swedish twins reared apart and reared together. Arch Gen Psychiatry 2000;57: Prescott CA, Kendler KS. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry 1999;156: Isolauri J, Luostarinen M, Isolauri E, Reinikainen P, Viljakka M, Keyrilainen O. Natural course of gastroesophageal reflux disease: year follow-up of 60 patients. Am J Gastroenterol 1997;92: Zaman MS, Hur C, Jones MP, Krueger RF, Chavez NF, Talley NJ, Lembo T. Concordance of reflux among monozygotic and dizygotic twins (abstr). Gastroenterology 2001(suppl);120:A Carre IJ, Johnston BT, Thomas BS, Morrison PJ. Familial hiatal hernia in a large five generation family confirming true autosomal dominant inheritance. Gut 1999;45: Hu FZ, Preston RA, Post JC, White GJ, Kikuchi LW, Wang X, Leal SM, Levenstien MA, Ott J, Self TW, Allen G, Stiffler RS, McGraw C, Pulsifer-Anderson EA, Ehrlich GD. Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14. JAMA 2000;284: Received July 1, Accepted September 6, Address requests for reprints to: Alan J. Cameron, M.D., Division of Gastroenterology and Hepatology, Mayo Clinic W19, 200 First Street SW, Rochester, Minnesota cameron.alan@mayo.edu; fax: (507) Supported by grants from AstraZeneca, NIA grant AG 08724, and the Swedish Council for the Planning and Coordination of Research. Appendix Reflux questions (English translation) used in the telephone inquiry. 1. Do you often have heartburn, often meaning more than 50 times per year? 2. Did you ever have a burning pain or discomfort behind the breastbone? 3. How old were you when you were first bothered by breastbone pain or burning? 4. How often do or did you have breastbone pain or burning? a) less than once a month b) probably less than once a week c) one or more times a week but not every day d) probably every day 5. Did you ever wake up at night due to breastbone pain or burning? 6. Does or did your breastbone pain often go up towards the neck? 7. Does or did your breastbone pain or burning improve when you took antacids? 8. Do or did you take any of the following medicines to prevent breastbone pain or burning? (A list of all histamine H-2 receptor antagonists and proton pump inhibitors available in Sweden was then read.) 9. Do or did you ever have regurgitation of bitter or sour fluid coming up into the mouth or throat from the esophagus? 10. How often do or did you have regurgitation of bitter fluid? a) less than once a month b) probably less than once a week c) one or more times a week but not every day d) probably every day