Epigenetic modifications to DNA, such as methylation, are an important mechanism for regulating the expression of genes that do not affect the underlying genetic sequence. Recent research has implicated DNA methylation in the development of chronic conditions such as cancer and inflammation. DNA methylation has also been recently implicated as a risk factor for autoimmune disease, including lupus. Epigenetic factors also provide a crucial link between an individual’s genetic risk of disease and the environment. Further, recent work in cancer indicates that the methylation status of specific gene regions may influence the response to treatment, and this is a virtually unexplored area in lupus research. We have performed preliminary work demonstrating that the DNA methylation status of genes, including some genes that influence the production of interferon, differs significantly between lupus patients according to the severity of their disease, as measured by the production of certain autoantibodies. Our overall goal for this project is to define the mechanisms by which differences in DNA methylation status influence the severity and outcome of lupus. More specifically, in Aim 1 we will apply a new method for targeted sequence-based DNA methylation profiling within specific cell subtypes in order to identify the specific cell subpopulation(s) most strongly predictive of disease severity and outcome. We will utilize the unique population-based California Lupus Epidemiology Study (CLUES) longitudinal cohort and all individuals will be carefully characterized for autoantibody status, kidney involvement and cumulative damage. Longitudinal data methods will increase the power of our analyses and will allow us to assess change in methylation profiles over time and in relation to lupus activity and treatment status. The availability of comprehensive genetic data for study participants will allow us to determine whether DNA methylation differences mediate genetic associations with lupus severity and outcome. Through access to “geocodes”, we will also be able to assess the impact of community characteristics and other exposures on epigenetic variation in lupus. In Aim 2, we will further characterize DNA methylation changes associated with lupus severity and outcome by investigating their correlation with levels of gene expression. To accomplish this aim we will study levels of gene expression for the most compelling results obtained in Aim 1 using a targeted sequence-based method of gene expression profiling. Once completed, this study will be the most comprehensive examination of DNA methylation patterns in lupus to date and serve as a model for similar research in other autoimmune diseases. Further, the existence of a number of drugs that work by targeting DNA methylation or other epigenetic mechanisms would allow rapid translation of epigenetic findings in lupus to epigenetic therapies.