| There is strong clinical and epidemiological evidence supporting a genetic link between type 2 diabetes associated end-stage kidney disease (T2D-ESKD) and African ancestry. Incidence and prevalence of T2D-ESKD, in addition to non-diabetic forms of ESKD, are markedly higher in African Americans compared to all other ethnicities even after adjustment for socioeconomic factors. Familial aggregation studies also support a strong genetic component to T2D-ESKD in African Americans. In this series of studies we examined this health care disparity from a genetics perspective by leveraging state-of-the-art genetic methodologies, including whole exome sequencing and bioinformatic tools, in an effort to further elucidate the genetic architecture of T2D-ESKD and non-T2D ESKD in several samples of African Americans, and to a lesser extent, in European Americans.;Data from these investigations provided wide-ranging genetic insights into T2D-ESKD, non-T2D ESKD, and also T2D in the absence of kidney disease. We have implicated rare- and low-frequency missense variants in the gene NPHS1 (which codes for the protein nephrin) that contribute to ESKD in the general African American population. Previously, NPHS1 variants were believed to contribute to monogenic diseases and uncommon forms of nephropathy. Moreover, we identified novel roles for the gene RREB1, coding for the ras responsive element binding protein 1, with implications for T2D, T2D-ESKD, and non-T2D ESKD in populations of both African and European ancestry. Data from an additional study demonstrate that genetic variations in the complement factor H gene (CFH) influence susceptibility to common, non-diabetic forms of ESKD in African Americans. Previously, CFH had been linked primarily to IgA nephropathy and dense deposit disease (DDD) in Asian and European populations.;Data from the aforementioned studies, in addition to those in the Appendix, provide new insights into T2D, T2D-ESKD, and non-T2D ESKD in both African and European Americans. The ultimate goals of any genetic study are to aid in prognostication of disease risk, provide biologic insights into disease pathogenesis, and to identify tractable drug targets. The investigations presented here expand our knowledge of the genetic underpinnings of T2D, T2D-ESKD, and non-T2D ESKD, laying the foundational framework for future studies aiming to construct a comprehensive genetic prognostication panel for T2D-ESKD and non-T2D ESKD, in addition to identifying a novel drug target (RREB1 ) which may have implications for T2D, T2D-ESKD, and non-T2D ESKD. |
