Systemic lupus erythematosus (SLE) affects a significant number of young African American women. The prevalence and severity of SLE in African American women is increasing despite recent advances in diagnosis and treatment. The etiology of the aggressive disease phenotype in African Americans is unknown. Development of SLE is believed to be due to a genetically susceptible individual being exposed to a triggering environmental factor(s). To what degree and how genetic/environmental interactions contribute to development and severity of SLE in African Americans is unclear. The prevalence of SLE in African Americans is in contradiction to the reported SLE prevalence in West Africa, where it is a rare disease. This prevalence difference led to the "gradient hypothesis" that environmental and genetic differences between West Africans and African Americans resulted in the increased prevalence of SLE in the United States. The prevalence gradient suggests that comparative studies of genetically related cohorts from the two continents may provide insight into the gene-environment interactions that result in the development of SLE and SLEr elated autoimmunity. The Sea Island Gullah population of South Carolina is unique in their genetic homogeneity and low levels of genetic admixture. They offer a unique opportunity to study genetic, environmental and epigenetic differences between themselves and individuals living in their ancestral home of Sierra Leone. Environmental exposures are clearly different in Sierra Leone and coastal South Carolina while genetics are similar. Based on prior studies by others and our collaborative group, we hypothesize that there are gene-environment interactions leading to the development SLE and that comparing the Gullah versus Sierra Leoneans will allow identification of key pathogenic factors in SLE. To test this hypothesis, we will pursue the following Specific Aims: Aim 1. Test the hypothesis that differences in certain environmental exposures between Sierra Leone and coastal South Carolina are associated with the presence of SLE and SLE-related autoimmunity. Aim 2. Test the hypothesis that certain environmental exposures induce epigenetic changes that differ between the Gullah patients and controls and Sierra Leone Africans, and that these differences correlate with the presence of SLE and SLE-related autoimmunity. Aim 3. Test the hypothesis that genetic factors influencing expression of nitric oxide and other reactive intermediate genes are involved in the development of SLE. Using two unique cohorts genetically and culturally linked in novel genetic/environmental studies will likely identify key factors associated with development of SLE in African Americans.

RELEVANCE (See instructions): Systemic lupus erythematosus (SLE) is a devastating disease primarily affecting young African American women. The cause of SLE is felt to be a combination of genetics and environmental exposures. Determining these genetic and environmental factors will provide new understanding of SLE and perhaps lead to identification of preventative strategies and/or new therapies. This project uses two unique cohorts, one from Africa and one from South Carolina, that are genetically and culturally linked yet differ significantly in environmental exposures. Studies of these cohorts will lead to new understanding of the causes of SLE.