Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndromes characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. FSGS can be classified as follows: idiopathic FSGS, genetic FSGS and post-adaptive FSGS (associated with glomerular hypertrophy and hyperfiltration, and due to reduced renal mass, renal toxins, obesity, and sickle cell disease). A related syndrome is collapsing glomerulopathy, associated with podocyte hyperplasia whereas FSGS is associated with podocyte depletion. Collapsing glomerulopathy can be classified as HIV-associated or idiopathic. The incidence of idiopathic FSGS is increased by a factor of 4 in African Americans, and the incidence of HIV-associated collapsing glomerulpathy is increased by a factor of 18 in African Americans. In prior years, we have shown that most of this effect is due to genetic variation in MYH9 and APOL1, adjacent genes on chromosome 22. A related project pursues that hypothesis that other scarring disorders which are more common in individuals of African descent are associated with genetic mutations. We have identified a number of families of diverse geographical ancestry with familial keloids, and will use genome scans to identify the responsible locus. An exome scan has identified several promising candidate loci which we are further characterizing. In order to identify causes of idiopathic collapsing glomerulopathy, we have initiated studies to identify possible viral causes, using blood and urine derived DNA and RNA applied to a viral gene chip. Our progress during the past year included the following: - Description of the phenotype of FSGS in those with and without APOL1 risk alleles (JASN, Nov 2011 - Showing in CARDIA that APOL1 risk alleles are associated with albuminuria and reduced eGFR (ASN oral presentation, Dec 2011) - Showing that in the AASK study, renal progression is associated with APOL1 risk alleles (Kidney Int, 2012) - Analysis of a Mississippi autopsy cohort to show that African Americans with two APOL1 risk alleles have, with larger body mass index, for larger glomeruli, larger kidneys and larger hearts (suggesting that left ventricular hypertrophy might be an APOL1 risk allele phenotype) Current projects - extension to other kidney diseases, including sickle cell nephropathy, pre-eclampsia, and renal transplantation - characterization of the phenotpye of hypertensive patients with kidney disease and APOL1 risk variants, - have generated Alb/APOL1 mice that express circulating ApoL1 and are characterizing the mice - have generated Alb/CLC mice that express circulating CLC and are characterizing the mice - have shown that indoxyl sulfate, a uremic toxin and a ligand for the dioxin receptor (Ahr), injures podocytes in vivo and in vitro

Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2012
Total Cost
$527,667
Indirect Cost
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State
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Hughson, Michael D; Hoy, Wendy E; Mott, Susan A et al. (2016) APOL1 Risk Alleles are Associated with More Severe Arteriosclerosis in Renal Resistance Vessels with Aging and Hypertension. KI Rep 1:10-23
Sampson, Matthew G; Robertson, Catherine C; Martini, Sebastian et al. (2016) Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects. J Am Soc Nephrol 27:814-23
Bodonyi-Kovacs, Gabor; Ma, Jennie Z; Chang, Jamison et al. (2016) Combined Effects of GSTM1 Null Allele and APOL1 Renal Risk Alleles in CKD Progression in the African American Study of Kidney Disease and Hypertension Trial. J Am Soc Nephrol 27:3140-3152
Peralta, Carmen A; Bibbins-Domingo, Kirsten; Vittinghoff, Eric et al. (2016) APOL1 Genotype and Race Differences in Incident Albuminuria and Renal Function Decline. J Am Soc Nephrol 27:887-93
Ng, Derek K; Robertson, Catherine C; Woroniecki, Robert P et al. (2016) APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts. Nephrol Dial Transplant :
Limou, Sophie; Nelson, George W; Lecordier, Laurence et al. (2015) Sequencing rare and common APOL1 coding variants to determine kidney disease risk. Kidney Int 88:754-63
Nichols, Brendan; Jog, Prachi; Lee, Jessica H et al. (2015) Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int 87:332-42
Hoy, Wendy E; Hughson, Michael D; Kopp, Jeffrey B et al. (2015) APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults: An Autopsy Study. J Am Soc Nephrol 26:3179-89
Kasembeli, Alex N; Duarte, Raquel; Ramsay, Michèle et al. (2015) APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans. J Am Soc Nephrol 26:2882-90
Dummer, Patrick D; Limou, Sophie; Rosenberg, Avi Z et al. (2015) APOL1 Kidney Disease Risk Variants: An Evolving Landscape. Semin Nephrol 35:222-36

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