DOCTOR'S VIEW ARCHIVE
Medical Author: Jay W. Marks, M.D.
Medical Editor: Leslie J. Schoenfield, M.D., Ph.D.
Patients occasionally ask me if their heartburn (the main symptom of gastro-esophageal reflux disease, or GERD) is inherited. They usually mention that one or more of their parents, brothers, or sisters suffer from heartburn. Until now, there's not been a lot to tell them. Yes, some studies have shown an increase in heartburn among parents, brothers, sisters, and children of people who have heartburn. However, the association of heartburn within families could be due to inherited genes or it could be due to their shared environment that contains GERD-promoting factors. An important study was published in January, 2002 in the journal Gastroenterology that addressed the issue of the genetics (inheritance) of GERD. It attempted to determine how important inherited genes are as a cause of GERD.
The genetics of heartburn was studied as part of a larger study of twins that were members of the nationwide Swedish Twin Registry. Sets of twins older than 55 years of age were contacted by telephone and asked about symptoms of GERD. The symptoms were defined as heartburn, pain behind the breastbone, and regurgitation of bitter or sour fluid into the mouth. Additional questions were asked to differentiate heart pain from heartburn. They also asked about other factors that are known to influence the development and/or severity of GERD, including weight, tobacco use, alcohol intake, and medications.
The study was able to contact both members of 8,401 pairs of twins, which amounted to 75% of the twins in the registry. The investigators then determined how frequently both members of a pair of twins suffered from heartburn. The twin pairs were divided into those that were identical, in which the two members shared all of their genes, and those that were fraternal, in which the two members shared only half of their genes. The fraternal twins were divided further into like-sex pairs in which both members of a twin pair were either male or female, and unlike-sex pairs in which one member was female and the other member was male. (It was not necessary to divide the identical twins similarly by their sex since by sharing 100% of their genes, all identical twins are of like-sex.) The frequency with which both members of a twin pair suffered from symptoms of GERD was compared between like-sex identical twins and like-sex fraternal twins.
Among like-sex fraternal twins (who share 50% of their genes), both members of the twin pairs suffered from GERD in 14% of the female pairs and 13 % of the male pairs. Among like-sex identical twins (who share 100% of their genes), both members of the twin pairs suffered from GERD in 33% of the female pairs and 29% of the male pairs. Thus, the more genetically alike identical twins were approximately twice as likely to share symptoms of GERD as the less genetically alike fraternal twins. This strongly supports the hypothesis that inherited genes are important in explaining the development of GERD. The factors of weight, tobacco use, alcohol intake, and medications had little effect on the results, suggesting that these environmental factors were not confusing the results.
The investigators then did another interesting calculation to estimate the relative importance of genetic factors in explaining GERD. That is, they estimated how important inherited genes were as compared to all other factors. They found that inherited genes were responsible for 31% of GERD. In other words, inherited genes were likely to be an important cause of GERD, but non-genetic factors were responsible for most cases of GERD. Unfortunately, it is not clear what these factors are. (Additional analyses in this study of twins found that tobacco use, weight, and alcohol intake did not explain most of the non-genetic factors.)
One criticism of this study of Swedish twins is that it used symptoms to classify patients, which are subjective and can be unreliable. It would have been better to have used an objective sign of GERD, for example, either esophageal damage determined endoscopically or the amount of acid that refluxes into the esophagus as determined by 24-hour esophageal acid studies. These determinations, however, would be very difficult, and probably impossible, to make in such a large-scale study.
Of course the next important question to ask is, what specific gene(s) are responsible for GERD and how do they cause GERD. Do they promote acid reflux? Do they reduce the ability of the esophagus to withstand the damage caused by acid reflux? These will be difficult questions to answer, and they will not be answered soon.
How can I now answer my patients who ask me if their GERD is genetic? I can tell them that the genes that they inherited from their parents are important in the development of GERD, but they are only part of the story.