Searching for Scleroderma GenesBy Maureen Mayes, M.D., M.P.H., Professor of Medicine, University of Texas Health Science Center at Houston (originally published in "Scleroderma Voice," 2002 #1) Five years ago, most doctors thought genes did not play a significant role in scleroderma. However, in the last few years several things have happened to challenge that assumption. Dr. Frank Arnett, along with several other researchers in Houston, and my colleagues and I in Detroit, took a closer look at our patients in Texas and Michigan, focusing on family history. The results were surprising. The Growing Evidence for Genetic InvolvementA little over 1% of scleroderma patients had a close relative (mother/father/brother/sister) who also had scleroderma. In addition, another 1 % had a family member with lupus or another autoimmune disease. Although 1 % may not sound like much, it is far more than what would be expected in the general population, where scleroderma occurs in about 1 in 4,000 individuals. At the same time, several groups of researchers identified "gene regions" (not specific genes) clearly associated with lupus. They have not yet identified the precise genes that exist in these gene regions but they are well on their way to doing so. What has also become clearer in the past few years is that there are many genes involved, perhaps as many as 20 or more, and that not all patients will have all genes. In addition, just having the right combination of genes will not guarantee that someone will get the disease, only that he or she is more likely to get it. In addition, some genes may determine which internal organs will become involved or which will be protected. It seems quite probable, although not yet proven, that some of the "lupus genes" will also turn out to be "scleroderma genes," whereas other genes will be specific for the particular disease. The obvious next question is, "What are these genes?" There are several good candidates to be investigated, including genes that are key to inflammation and immune function. Some of these genes have already been studied and have not turned out to be associated. As usual in research, we have far more questions than answers. The information derived from the Human Genome Project, as well as some recent advances in genetic technology that allows us to search for thousands of genes at a time (high throughput DNA analysis) presents us with a terrific opportunity and a daunting challenge. Where Do We Go From Here?Considering all of the above, how do we move from where we are now, with "hunches" about the role of genes in scleroderma, to where we want to be: having solid data about specific genes? The answer to this question is straightforward but not easy. To pursue these issues, we need health histories and blood samples (to get DNA information) from:
The Scleroderma Family Registry and DNA RepositoryFortunately, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), which is a branch of the National Institutes of Health (NIH), agreed to fund this study and established the "Scleroderma Family Registry and DNA Repository" in September 2000.1 am leading this effort with Drs. Frank Arnett and John Reveille at the University of Texas/Houston, and Dr. Li Jin at the University of Cincinnati. The purpose of the Registry is to study possible genetic links with scleroderma. As noted above, the key questions are the following:
To begin to answer these questions, we need to determine which genes are more commonly found in scleroderma patients than in people without scleroderma. The Scleroderma Family Registry is designed to address these questions. The Repository part of it involves "banking" DNA samples (as well as serum samples) so that many other investigators can study sclero derma genetics and accelerate this research effort. The approach that the Registry will use to do the genetic analysis involves getting blood samples from three types of families: "singleton" families, "multiplex" families, and "childhood-onset" families. Singleton FamiliesThe first type of family that the Registry is interested in recruiting is one in which there is only one case of scleroderma (99% of cases). A very powerful genetic-analysis technique involves studying the DNA from "trios"—that is, a scleroderma patient and both parents. When one parent is unavailable, we can analyze DNA from sisters or brothers. In this type of analysis, we identify the genes that are selectively passed on to the scleroderma patient. We plan to include about 500 scleroderma patients and 1,000-1,500 family members in this part of the study. It is essential for the analysis to include unaffected family members. They are as important as the cases. In addition to family members, we need "control" samples from people who are not blood relatives of cases and who have no autoimmune diseases. The perfect group for control samples is spouses of patients or spouses of their relatives. One reason they are "perfect" is that they tend to be available and willing to become involved in the study. (So this is one situation in which your spouse gets to give a blood sample when you go to the doctor.) Multiplex FamiliesSometimes a family will have several cases of scleroderma, plus lupus, plus other autoim mune diseases. Although rare, these situations are very important in helping us track down the responsible genes. Because this is so uncommon, we will need to do a nationwide search to identify our target sample of 100 families. In this situation, we would like to draw blood from all available family members. Healthy family members are just as important to our study as those with scleroderma, because we need to know which genes are not associated with this disease. That is, we need to "subtract out" unimportant genes found in the healthy relatives. Other FamiliesFor some purposes, it may be helpful to have samples from three generations (both the parents and the grown children of the scleroderma case). This will depend on the individual situation. Childhood-Onset FamiliesThe systemic form of scleroderma rarely occurs in childhood (younger than age 16). However, these childhood-onset cases may be telling us something very important about the disease. These children (some of whom are now adults) may have a "stronger" genetic component than the adult cases, so they represent an important part of our study. We plan to collect blood samples from 50 childhood-onset cases and their families. Since this is a rare event, our nationwide search for multiplex families will include a call for childhood-onset families. To Learn More About the RegistryThe way to participate in the Registry and become a "registrant" is to call Marilyn Perry, the Registry Coordinator, at 800-736-6864. Her complete contact information is: Marilyn Perry She will explain the study further and send a consent form for you to sign and return. Once we receive the signed consent form, we will send you a kit that includes blood-drawing tubes, instructions, and a return prepaid FedEx envelope for you to take to your local doctor's office or lab. Part of the consent form is a release of medical information that permits registry personnel to review your medical records to verify the diagnosis, and to determine some features of your particular type of scleroderma. All information is kept strictly confidential. It is not considered part of your medical record, and will not be available to your insurance company. This is true for all participants in the Registry: patients, family members, and controls such as spouses or friends. |