Generalized vitiligo is a common, non-contagious disorder, characterized by progressive patchy loss of pigmentation of the skin, overlying hair, oral mucosa, and occasionally eyes, due to progressive loss of pigment forming melanocytes in the affected areas Vitiligo is thought to be autoimmune in origin, and frequently is associated with other autoimmune disorders. The prevalence of vitiligo is approximately 0.1 to 0.3 percent in different ethnic or racial groups. Vitiligo is most significant in dark-skinned populations, for its pigmentary disfigurement produces social stigmatization and is often confused with leprosy or other socially terrifying infectious diseases. But it can be a devastating disorder to those affected in any population. In preparation for this study, we conducted a survey of vitiligo patients in the United Kingdom, the largest ever done, thereby ascertaining a large cohort of families with vitiligo. These data were consistent with other studies in suggesting a total risk to first-degree relative of probands of about 7%. Further, one or more susceptibility loci appears to account for an apparent autosomal dominant inheritance of vitiligo. Further, one or more susceptibility loci appears to account for an apparent autosomal dominant inheritance of vitiligo in a fraction (approximately 8%) of families. However, the major gene(s) in these families does not account for the total increased risk for vitiligo in relatives, suggesting that susceptibility alleles with lower penetrance at the same or different loci are important in other families. These results suggest a mixed model for the inheritance of vitiligo, which has also been reported for many other complex disorders. The proposed studies will combine the UK vitiligo family cohort with a similarly sized vitiligo family cohort in the USA. Utilizing these resources, and 400 polymorphic markers spaced at approximately 10 cM intervals throughout the genome, we proposed a two-phased approach to mapping vitiligo susceptibility loci.
The specific aims are: 1) Map autosomal dominant vitiligo susceptibility loci by parametric linkage analysis in families with 4 or more affected relatives; and (2) map other vitiligo susceptibility loci by parametric linkage analysis in families with 4 or more affected relatives; and (2) map other susceptibility genes using non-parametric linkage analysis in affected sib pairs. This rational and comprehensive approach will provide the greatest likelihood of mapping vitiligo susceptibility loci, thereby accelerating the identification, and the molecular, cellular, clinical, and epidemiological characterization, of the disease genes.
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