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New scientific finding provides first solid evidence of autoimmune link

Dr. Richard Spritz

A major step has been made on the path to understanding vitiligo. Findings from a study of 1,500 vitiligo patients reported in the April 21, 2010 issue of the New England Journal of Medicine confirm for the first time that generalized vitiligo is an autoimmune disease. So why is this important? We now have a place to begin in our pursuit of the cause, the biology, the treatment, and even the cure of this disease. The greater our understanding of the biology of vitiligo, the more chance we have to design therapies that can maximally control vitiligo. The effectiveness of current vitiligo therapy is variable, as these treatments were not originally developed specifically to treat vitiligo. In autoimmune disease, the patient's immune system is activated against the body's own proteins. Autoimmune diseases, of which there are many such as Crohn's disease, rheumatoid arthritis, type 1 diabetes, and lupus, are generally treated with immunosuppressive medications to decrease the anti-self immune response. Future vitiligo therapies may be among this same class of immunosuppressive medications. Specific vitiligo genes are linked to autoimmunity Richard A. Spritz, M.D., Director of the Human Medical Genetics Program at the University of Colorado School of Medicine, and head of the international team conducting this study told VSI, "Our study provides the first solid proof that vitiligo is an autoimmune disease. Of the 14 genes we discovered linked to vitiligo, at least 13 are directly involved in regulating the immune system or causing autoimmune disease." Therapeutic clues What does this autoimmune connection mean for the patient? According to Dr. Spritz, "The immune system's role in vitiligo should now become the focus of future research to control the specific biochemical pathways that are involved in causing the disease. Knowing which pathways are involved in vitiligo should enable scientists to eventually design specific therapies that target those pathways and thereby provide more effective vitiligo control. In fact, the genetic similarities we found between vitiligo and some other autoimmune diseases suggests some of the current drugs out there being developed to treat other autoimmune disease should also be considered for possible treatment of vitiligo." The largest vitiligo genetics study Dr. Spritz and an international team of researchers compared the genes of 1,500 people with vitiligo to the genes of 2,800 people without, in the largest genome-wide association study (GWAS) done to date in vitiligo, to see what gene differences or variations might be associated with vitiligo (for more information on the NIH and GWAS research, see accompanying article in blue box below). The hoped-for outcome is that these genetic variations are within or near genes that make proteins that play roles in the pathogenesis of vitiligo. Dr. Spritz noted, "Four of the genes we found in our study may well fit together into one biological pathway that is of particular importance for vitiligo." Surprises found A few surprises came out in the research. One was that no genes were found that play roles in any of the non-immune mechanisms that some have suggested might be involved in the pathogenesis of vitiligo. "We had a long list of candidate genes that other scientists had postulated might play a role in vitiligo," Dr. Spritz commented. "None of those genes panned out except those tied to regulating the immune system. That does not mean that those other mechanisms might not play any role in the pathogenesis of generalized vitiligo, but it does make it hard to support roles for supposed mechanisms of disease that don't somehow tie into autoimmunity, at least for typical cases." Another unanticipated discovery was that some of the identified genes that predispose people to vitiligo at the same time protect from melanoma, raising the speculation that people with vitiligo may face less risk of melanoma than the average person. Dr. Spritz went on to explain, "We found a genetic variation that is more common among vitiligo patients, but that is known to protect against melanoma. The human immune system is always surveilling for tumors - killing most of them off as they are discovered. Vitiligo may be an amplification of this immune surveillance process. Our finding suggests that vitiligo patients might have less risk of melanoma, though we don't really know for sure yet." Do these findings help us predict who will get vitiligo? "No," Dr. Spritz responded. "Not yet. Altogether, the genes that we found only account for about 10% of the total risk of developing vitiligo. There's a lot more to the story, and probably there are more genes that we still need to identify. In addition, we still don't know the environmental triggers for vitiligo or, for that matter, any other autoimmune disease. We believe that, for most people, they inherit genes that predispose them to develop vitiligo, but that only happens if they encounter something in the environment that then causes that genetic predisposition to be expressed as vitiligo. We have taken the first big step, identifying some of the most important genes linked to causing vitiligo," but Dr. Spritz cautioned, "There is still a long way to go." Why do only some family members get vitiligo? Dr. Spritz noted that susceptibility results from different combinations of susceptibility genes, even in the same family. "Different family members could easily inherit different genetic combinations, just as for height, intelligence, and many other complex traits." Further, he added, "Even among identical twins, both develop vitiligo only one-fourth of the time. Identical twins share all their genes in common, but they don't share their environmental exposures and other life-events. The more we learn about the genetics of vitiligo, the more chance we have of learning about environmental triggers of vitiligo." What does the future hold? We asked Dr. Spritz where he will go from here in his research. "We are moving in three directions, all at the same time," he said. "This first study was done in Caucasians because they were the only ethnic group from whom we were able to get enough samples to do a study. For genetic studies of this kind, it is essential that we maintain ethnic homogeneity so that we can see the relatively small genetic effects that are due to vitiligo on the much larger background of genetic differences that are due to ethnicity." According to Dr. Spritz, "We are now adding more Caucasian patients and more controls to that first study, to pick up additional genes we missed on the first pass. Second, we are studying those genes that we did find in fine detail, to understand exactly what DNA variants in those genes cause risk of vitiligo, and to understand how they raise disease risk. Third, we are now extending our studies to non-Caucasian populations: southeast Asians, Hispanic, African-American, and persons from the Indian subcontinent." However, Dr. Spritz noted, "We are still very short of minority patients and minority 'controls' with whom the genes of the patients must be compared. That is still a big limitation." (Please see accompanying article "An Appeal to Minority Vitiligo Patients.") Dr. Spritz thanked Vitiligo Support International for being a major contributor of patient volunteers for this international study.