This is a concern which is shared by many parents with an Autoimmune Disorder.
But the hereditary path is not clear cut.
Before we explore the complex genetics of IBD, we'll need to review a few basic principles. Every human being has 46 chromosomes. (We inherit 23 chromosomes from each of our parents.) Each chromosome is made up of hundreds of genes. Both our genes and our chromosomes are composed of deoxyribonucleic acid (DNA). DNA is a long, chainlike molecule that is made up of four chemicals. These chemicals arrange themselves in a multitude of patterns that determine your individual genetic code. The arrangement of a particular set determines how a gene functions--or malfunctions.
Many hereditary traits are passed along in a straightforward manner, known as Mendelianism. Let's look at a fairly simple example. Beverly's parents both have brown eyes. The corresponding genes on each chromosome that Beverly inherited are exactly alike--two genes for brown eyes. Therefore, Beverly has brown eyes. Now Beverly marries a man with blue eyes. Each of their children's gene pair for eye color may well include a gene for brown eyes and an alternate gene, known as an allele, for blue eyes. Their children might have brown eyes or blue eyes--or the genes might combine to produce a new trait, such as hazel eyes. Some diseases are inherited in this straightforward manner. Unfortunately, IBD is not one of them.
IBD researchers are now virtually certain that we are seeking more than one gene--unlike the gene for eye color. They are investigating two theories. The first posits that IBD is caused by a few genes, acting in concert. As Dr. Duerr notes, this could explain why Aunt Susan has Crohn's, but you and your brother have colitis: "One gene may predispose to both [colitis and Crohn's] but be insufficient by itself to result in clinical disease, which would occur only when another [colitis- or Crohn's-specific] gene is present."
The second theory is that there are several different forms of both Crohn's disease and ulcerative colitis. Each of these "subtypes" represents a distinct disease process, with its own set of symptoms and complications. And each subtype might be inherited in a different fashion: one might be caused by a single dominant gene; another might be the product of two genes acting together; and still another might be caused by multiple genes. In other words, IBD might encompass every possible inheritance pattern.
Of course, even if you carry the gene for a particular disease, you may not necessarily become ill. Many people, for instance, carry the gene marker for Type I diabetes. Yet, they never develop the disease. The same may be true for IBD. In fact, most researchers believe that an unidentified environmental factor (possibly an intestinal bacterium) triggers IBD in people who are genetically susceptible. Clearly, we still have much to learn about the relationship between heredity and environment in IBD. Nevertheless, scientists no longer doubt that genetics plays a central role.
Some of the most compelling evidence has come from epidemiological studies. For example, we know that Jews of European descent are at five times greater risk than the general population. "[These rates] are consistent over different times and geographic areas; social and educational factors do not explain this ethnic difference, suggesting that genetic factors are the primary influence," notes Richard H. Duerr, M.D., in "Genetics of Inflammatory Bowel Disease," an article in the spring 1996 issue of CCFA's scientific journal, Inflammatory Bowel Diseases.
A family history of IBD is the greatest risk factor of all. If someone has a relative with the disease, his risk is estimated to be at least 10 times that of the general population. Multiply that number by three if the relative is a sibling. Studies of identical twins have provided especially dramatic data. (Identical twins are produced by one egg, and therefore have the same genetic profiles.) In 68 percent of the twin pairs studied, both developed Crohn's disease; in 20 percent, both members of the pair were affected by colitis. And if a husband and wife both have IBD, the chances that their children also will have the disease are doubled.
Yet, even within families, inheritance patterns can be perplexing. For instance, if your Aunt Susan has Crohn's, why do you and your brother have ulcerative colitis? And why is it that Aunt Susan's kids have not been affected at all? As these questions suggest, these illnesses present a serious challenge to geneticists.
It is likely that there is more than one gene for both Crohn's disease and ulcerative colitis. But even if you carry one or more of these mutant genes, you may not become ill. Interaction with a specific environmental factor (e.g., a bacterium) probably is required to trigger IBD.
In recent years, geneticists have identified many genetic markers (distinctive DNA segments) and learned their locations on various chromosomes. Now, they are screening people from families with multiple cases of IBD to see whether they carry any of these markers. The presence of such a marker may mean that a disease gene lies near it on the same chromosome. Researchers also are studying specific genes, such as those involved in the immune response, which may play a role in IBD.
When researchers find the genes for IBD, they can identify people at greatest risk. They also can begin to develop therapies that replace, alter, or block the activity of defective genes.
Possible Autoimmune Gene
An antibody traditionally associated with rheumatic autoimmune diseases such as lupus, has been identified as a "common thread" in families where at least one member suffers from an autoimmune disorder associated with high levels of the antibody.
The antibody, known as the antiphospholipid antibody (APL), is one of a class of antibodies referred to as auto-antibodies. Common to autoimmune diseases, auto-antibodies are proteins produced by the body to attack itself, rather than invading viruses and bacteria. APL is made to fight certain good body fats called lipids. When the level of APL is high and these proteins float freely throughout the blood, a disease state occurs. The antiphospholipid antibody syndrome (APS) is associated with recurrent clotting events (thrombosis) including premature stroke, repeated miscarriages, phlebitis, venous thrombosis (clot in the vein) and pulmonary thromboembolism (blockage of an artery found in the lung due to a clot that has traveled from a vein). It is also associated with low platelet or blood elements that prevent bleeding. Recently, however, even more disease states have been linked with APL including premature heart attack, migraine headaches, various cardiac valvular abnormalities, skin lesions, diseases that mimic multiple sclerosis, vascular diseases of the eye that can lead to visual loss and blindness, and early peripheral vascular disease that can result in amputations of the extremities and digits.
The St. Mary's/Yale study looked at 23 individual family members with APS, 87 of their blood relatives, 18 spouses and
37 controls. Overwhelmingly, it found clustering of the APL antibody in families. Of the 87 blood relatives, some 50 percent or nearly 60 percent had auto-antibodies, compared with only one spouse. Approximately 33 percent or one-third had antiphospholipid antibodies, while another 37 percent had other auto-antibodies, such as anti-nuclear antibodies. None of the controls tested positive. The study also found that more relatives had suffered from one of the manifestations of APS than did either the spouses or controls. Indeed, several relatives were found to have either lupus (4) or lupus-like syndrome (4), premature stroke (2), recurrent fetal loss (3), recurrent thrombosis (1) or thrombocytopenia (2).
"More important, the APL antibody may be associated with one disease process in one family member and yet another
disease process in another family member,"
Dr. Seldin's team found strong evidence for genetic transmission of APS in analyses of 12 different families. Preliminary
modeling in these studies has suggested the possibility that inheritance of this disease may be due to a single dominant genetic defect with variability in disease penetrance. The workers in collaboration with Dr. Greco and other centers have initiated a study of the gene patterns in families with APL. It is hoped that this "gene hunting study" will ultimately define the genetic defect(s) in this disease.
Recent data presented by French researchers at the October meeting of the American College of Rheumatology also
support the findings of Drs. Greco, Goldberg and Kelly.
In a study on families with antiphospholipid antibodies, many relatives were found to have diseases related to these
proteins as well as many other immunologic diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, crohn's disease, multiple sclerosis, low platelets (ITP), thyroid disease and others. Dr. Greco pointed out that while the prevalence of these proteins among the patients nationwide is relatively low (between 1 and 2 percent), for given families it may be very high, as high as one in every two family members. "If an APL inheritance pattern can be firmly established in future studies, the good news is that we may be able to prevent premature stroke, heart attack, recurrent miscarriage and the other APL-associated diseases by performing simple and inexpensive tests and taking more thorough family histories," explained Dr. Greco. "It may be premature to say, but APL may end up being one of the common threads that ties together all of the seemingly unrelated 80 known autoimmune diseases," said Virginia T. Ladd, president of the American Autoimmune Related Diseases Association (AARDA).
She said large studies of patients with neurologic autoimmune diseases such as multiple sclerosis and myasthenia
gravis, endocrine autoimmune diseases such as thyroid, juvenile and type 1 diabetes, and rheumatic autoimmune diseases including rheumatoid arthritis, lupus, scleroderma and Sjogren's syndrome, need to be conducted to confirm this theory. "If it turns out that APL is a common factor in autoimmune diseases, then the next step for researchers is to begin looking for an autoimmune gene."