Strict blood pressure control fails to halt the progression of hypertensive nephrosclerosis (HN) in African Americans, suggesting that factors in addition to high blood pressure are involved in disease causation. This application proposes to determine the natural history of MYH9-associated HN in African Americans, as MYH9 accounts for 70% of all non- diabetic cases of end-stage renal disease (ESRD) in this ethnic group. All individuals who are homozygous for MYH9 risk alleles do not develop kidney disease, demonstrating that MYH9 gene-environment and MYH9 gene-gene interactions contribute to kidney disease risk. This application proposes to recruit and longitudinally evaluate African American individuals who are at high risk for developing HN by virtue of having a first degree relative with hypertension-associated ESRD. The impact of lifestyle and environmental factors causing kidney disease will be evaluated as potential """"""""second hits"""""""" for MYH9-associated nephropathy. A repository of biologic specimens will be collected from participants and we will test for association between development of HN and exposure to latent viral infections potentially predisposing to kidney disease. The rationale for this approach is based on the strong association of MYH9 risk haplotypes with Human Immunodeficiency Virus (HIV)-associated nephropathy (HIVAN) in African Americans. HIVAN and HN may both present as focal segmental glomerulosclerosis. The role of MYH9 gene-gene interaction between MYH9 and other HN susceptibility genes would be explored in concert with our ongoing R01 DK070941. The major components of this project are: (1) recruitment of 1,200 unrelated African American subjects at high risk for HN based upon family history of H-ESRD, with phenotyping for the presence of hypertension, kidney disease and kidney disease-risk factors;(2) longitudinal follow-up to determine the association of MYH9 gene polymorphisms with cross-sectional and longitudinal measures of blood pressure, albuminuria, serum cystatin C and creatinine concentrations, and estimated glomerular filtration rates in members of the cohort;and (3) creation of a repository of biologic specimens to detect environmental factors that may trigger MYH9-associated nephropathy in genetically susceptible individuals. We will test for evidence of latent viral infections associated with HN (MYH9 gene-environment interactions).
From this study we will be able to identify relatives with and without the MYH9 nephropathy genotype and investigate the role of environmental and genetic factors on the development and progression of kidney disease. We expect that this study will aid in predicting risk for progressing to ESRD in families with MYH9-nephropathy. While there may be no immediate benefit to ESRD patients, the study will help anticipate which MYH9 risk homozygotes need to be closely monitored for development of nephropathy. This will benefit individuals at risk who could benefit from therapeutic intervention to alleviate disease at an earlier stage. The anticipated benefits to the population at large outweigh the minimal risk involved in the study.
|Ma, Lijun; Langefeld, Carl D; Comeau, Mary E et al. (2016) APOL1 renal-risk genotypes associate with longer hemodialysis survival in prevalent nondiabetic African American patients with end-stage renal disease. Kidney Int 90:389-95|
|Julian, B A; Gaston, R S; Brown, W M et al. (2016) Effect of Replacing Race with Apolipoprotein L1 Genotype in Calculation of Kidney Donor Risk Index. Am J Transplant :|
|Freedman, Barry I; Cohen, Arthur H (2016) Hypertension-attributed nephropathy: what's in a name? Nat Rev Nephrol 12:27-36|
|Dorr, Casey R; Freedman, Barry I; Hicks, Pamela J et al. (2016) Deceased-Donor Apolipoprotein L1 Renal-Risk Variants Have Minimal Effects on Liver Transplant Outcomes. PLoS One 11:e0152775|
|Guan, Meijian; Ma, Jun; Keaton, Jacob M et al. (2016) Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans. Hum Genet 135:1251-1262|
|Freedman, Barry I; Pastan, Stephen O; Israni, Ajay K et al. (2016) APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors. Transplantation 100:194-202|
|Weckerle, Allison; Snipes, James A; Cheng, Dongmei et al. (2016) Characterization of circulating APOL1 protein complexes in African Americans. J Lipid Res 57:120-30|
|Williams, Robert C; Elston, Robert C; Kumar, Pankaj et al. (2016) Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND). BMC Genomics 17:325|
|Hawkins, Gregory A; Friedman, David J; Lu, Lingyi et al. (2015) Re-Sequencing of the APOL1-APOL4 and MYH9 Gene Regions in African Americans Does Not Identify Additional Risks for CKD Progression. Am J Nephrol 42:99-106|
|Bentley, Amy R; Divers, Jasmin; Shriner, Daniel et al. (2015) APOL1 G1 genotype modifies the association between HDLC and kidney function in African Americans. BMC Genomics 16:421|
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