The molecular genetics of vitiligo and associated autoimmune diseases and the forensic genetics of DNA database relatedness searches

Vitiligo is a common autoimmune related disease that results in depigmentation of the skin due to the loss of melanocytes from the involved areas. It is often related to other autoimmune disorders such as: autoimmune thyroid disease, pernicious anemia, Addison's disease, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, and latent autoimmune diabetes in adults. This work was done to identify genes involved in the pathogenesis of vitiligo and possibly the other autoimmune disorders related to vitiligo. We focused on determining the genetic association of the CTLA4 and PTPN22 genes and related these results to existing data from our laboratory with NLRP1 in gene-gene interaction studies.;The PTPN22 gene encodes a protein tyrosine phosphatase, Lyp which is a 110kDa protein expressed in hematopoietic cells, including T-cells, which is directly involved in setting thresholds for T-cell receptor signaling by binding to intracellular kinases such as Csk. A functional polymorphism in PTPN22 (the risk allele R620W; SNP rs2476601) leading to an arginine to tryptophan substitution has been found to be associated with many autoimmune diseases including vitiligo. Similarly, the CTLA4 gene encodes a cell surface molecule on activated T-cells which functions as a negative regulatory molecule in the immune system. Specific CTLA4 polymorphisms have been studied and also found to be associated with different autoimmune diseases.;Work is also presented on the genetics of forensic DNA database familial searches. The work presented here is the first known in the United States based on forensic short tandem repeat-STR DNA databases, extended with simulation studies to evaluate and validate the performance of the searching system so as to establish interpretation guidelines and determine performance characteristics. Data presented that forms the basis for interpretation and for the development of a national criminal database searching system.;This work is grounded in both the rigorous evaluation of genes and how they contribute to autoimmune disease, and of how knowledge of human genetics can be used to establish creative methods for determining investigative leads in the field of forensic science.