African Americans suffer from kidney disease at dramatically higher rates than Caucasian Americans. While socioeconomic factors explain some part of this disparity, genetic factors appear to account for much of the increased disease burden. Work by our team has shown that the major genetic risk is conferred by variants in the APOL1 gene. These variants are coding changes that, in the heterozygous state, provided protection against the trypanosomes that cause African Sleeping Sickness, explaining their high frequency in populations with recent African ancestry. However, two copies of the variants promote kidney disease. We are aware of few if any disease-causing variants of similarly high frequency (the combined allele frequency of the two risk alleles is greater than 30% in African Americans) that carry such high risk of severe disease. Little is known about the precise clinical phenotype conferred by AP0L1 variants. Now that we are able to classify patients by AP0L1 genotype, we can perform clinical studies aimed at understanding how AP0L1- associated kidney disease differs from non-APOLI associated disease. We can begin to determine if the large fraction of African Americans with the high risk genotype differ in the rate of kidney disease progression, response to medication, rate of extra-renal complications, and transplant outcomes. Defining this phenotype in detail will have implications both for understanding the mechanism of this form of disease and for developing better methods of kidney disease prevention and treatment. We have assembled a team of five investigators from four Boston institutions with differing areas of expertise in order to develop a new research aimed at defining the detailed AP0L1-associated phenotype. RELEVANCE: This work is aimed at precisely defining the clinical phenotype of kidney disease in African-Americans recently shown to be highly associated with variants in the AP0L1 gene. This appears to be the most important genetic factor contributing to the high rate of kidney disease in African Americans. We anticipate that this work will lead us to a much better understanding of how to care for and prevent kidney disease in this population.