Grant Title : “The Role of Genetics in Vitiligo Susceptibility”

Period being reported: June 1, 2006 – May 31, 2007

Principal Investigator : Margaret R. Wallace, Ph.D.

Professor, Dept. of Molecular Genetics and Microbiology

Box 100266 , University of Florida College of Medicine

1600 S.W. Archer Road

Gainesville , FL 32610-0266

(352) 392-3055 (phone)

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Co-Principal Investigator : Wayne T. McCormack, Ph.D.

Associate Professor,

Dept. of Pathology, Immunology, & Laboratory Medicine

Box 100275 Health Science Center

University of Florida College of Medicine

Gainesville , FL 32610-0275

(352) 392-7413 (phone)

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Summary of Progress :

Vitiligo is a skin disorder that results in areas of depigmentation that may gradually enlarge. Vitiligo is common, and the average age of onset is about 20 years old, so half of all vitiligo patients develop the condition during childhood or adolescence. Vitiligo may predispose affected persons to sunburn, and an increased risk for some other autoimmune diseases, such as thyroid conditions. Most current treatments for vitiligo are difficult, expensive, and often disappointing.

The cause of vitiligo is unknown, but it is thought to involve both genetic and environmental factors. Vitiligo sometimes runs in families, and one study found that 20% of the relatives of vitiligo patients also have the disease, with the highest risks for children and siblings of patients. This suggests that some people are born with genes that make them more susceptible to developing vitiligo. However, environmental factors such as traumatic skin injury, sunburn, or stress, appear to influence whether or not an individual with those “susceptibility genes” will develop vitiligo during their lifetime. In some patients, progression of the vitiligo appears to involve an immune response against the patient's own melanocytes (pigment-producing cells); therefore, vitiligo is considered an autoimmune disease.

By identifying vitiligo susceptibility genes, we can learn more about the cause of this disorder. Depending on the genes involved, their normal functions, and the genetic changes that we, it might be possible to design new treatments based on understanding those genes. This knowledge may also lead to genetic testing to identify people predisposed to developing vitiligo. For these individuals, environmental risk factors can be more carefully avoided. Theoretically, future advances in gene therapy might also be developed to treat vitiligo, based on our discoveries.

In our 2006 AVRF grant project, we outlined our experimental design for genetic studies to test the hypothesis that susceptibility to vitiligo is a complex genetic trait involving a number of genes. With the help of hundreds of vitiligo patients and family members, our research at the University of Florida College of Medicine has been examining the genetic basis for predisposition to vitiligo. Several years ago, we collected DNA samples from vitiligo patients and their family members, and from healthy individuals with no vitiligo or autoimmune diseases, in order to perform “genetic association” studies of candidate genes. Candidate genes are genes that might be involved in causing vitiligo based on their functions in the melanocyte cells, in DNA repair, in oxidative stress, or in the immune system. In these genes, we have looked at variations in the DNA to see how common these variants are in vitiligo patients compared to people without vitiligo or other autoimmune disorders. The theory is that if a particular genetic marker is more common in vitiligo patients, then that marker may be “linked” to another nearby genetic change that alters the gene's function or regulation, and therefore contributes to the disease process. The long-term goals of this research include determining whether “at risk” individuals can be identified in families with a history of vitiligo (which might influence the choice of strategies for treatment or prevention of vitiligo), and contributing to the development of new therapies to prevent or treat vitiligo based on better understanding of the genetics of vitiligo. In addition, these studies may contribute to understanding other autoimmune diseases.

To date, we have characterized several genetic variants (called genotyping) in eight candidate genes in over 800 vitiligo patients and their family members. The results from these experiments allow us to do family-based association tests to determine if a candidate gene is associated with vitiligo. In a family-based association test, families with one or more affected members can be analyzed using statistical tests to determine whether a particular genetic change is seen more frequently in vitiligo patients than in family members. Another advantage of family-based association studies is that information from multiple ethnic and/or geographical populations can be combined. This statistical analysis is underway, now that the genotyping has just been completed.

An additional analysis we are doing with this data involves looking for differences in the frequency of genetic markers in vitiligo patients with different clinical characteristics. For example, we can examine if particular markers are associated with segmental vitiligo versus non-segmental. Also, information like the age of vitiligo onset, or the presence or absence of other autoimmune diseases can be analyzed. Because vitiligo is a complex disorder, this type of statistical analysis allows us to determine if certain genetic markers are associated with particular clinical features of vitiligo.

We are currently genotyping the same genetic markers examined in vitiligo patients in DNA from a group of healthy volunteers with no vitiligo or known autoimmune diseases. The genetic findings from this group will allow us to do a different type of statistical analysis, called a case-control study. Case-control studies compare the frequencies of a genetic marker in a patient group and a control group. The two groups are matched for ethnic and geographic origins, due to variations in gene frequencies among different populations. A marker is considered to be positively associated (or predisposing) when its frequency is significantly higher in patients than in controls. It is considered to be negatively associated (or protective) when it occurs at a significantly lower frequency in patients than in controls. Once we have all the DNA results from this control group, we can do the statistical analysis. If we find any positive (or negative) associations, we will look harder at those genes and variants to find out why they appear to contribute to (or protect from) vitiligo. If we do not find any significant associations, we have plans to study the next set of logical candidate genes with the same methods.

In summary, our AVRF-funded research seeks to identify gene markers linked to vitiligo susceptibility. Genetic markers are being compared for vitiligo patients, their family members, and control subjects. The ultimate goal of our research is to increase our understanding of what causes vitiligo in terms of susceptibility, disease onset, and progression. These studies aid in understanding the genetic factors involved in vitiligo. This genetic information may lead to clinical tests to determine if individuals are predisposed to having vitiligo, and may be the basis for developing treatments or preventions.