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. We are engaged in genetic studies to identify FSGS risk genes. We have found four genes to date: WT1 (Wims tumor-1), WIT1 (Wilms tumor interacting gene-1), PDSS2 (enzyme in the ubiquinone synthesis pathway) land NPHS2 (podocin). 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. 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: 1) Working with Martin Pollak at Harvard, we have shown that much of the kidney susceptibility in chromosome 22 is due to variation in ApoL1, with a small amount of residual risk from MYH9. 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 - studies involving MYH9 heterozygous knock-out mice, MYH9 over-expressing mice, and podocyte-specific MYH9 knockout mice and APOL1 transgenic mice 2) tentative identification of cardiotrophin-like cytokine 1 as a component of the FSGS permeability factor, involved in FSGS recurrence following renal transplantation

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2010
Total Cost
$486,955
Indirect Cost
City
State
Country
Zip Code
Lee, Hewang; Roshanravan, Hila; Wang, Ying et al. (2018) ApoL1 renal risk variants induce aberrant THP-1 monocyte differentiation and increase eicosanoid production via enhanced expression of cyclooxygenase-2. Am J Physiol Renal Physiol 315:F140-F150
Hyacinth, Hyacinth I; Carty, Cara L; Seals, Samantha R et al. (2018) Association of Sickle Cell Trait With Ischemic Stroke Among African Americans: A Meta-analysis. JAMA Neurol 75:802-807
Franceschini, Nora; Kopp, Jeffrey B; Barac, Ana et al. (2018) Association of APOL1 With Heart Failure With Preserved Ejection Fraction in Postmenopausal African American Women. JAMA Cardiol 3:712-720
GutiƩrrez, Orlando M; Irvin, Marguerite R; Chaudhary, Ninad S et al. (2018) APOL1 Nephropathy Risk Variants and Incident Cardiovascular Disease Events in Community-Dwelling Black Adults. Circ Genom Precis Med 11:e002098
Hughson, Michael D; Hoy, Wendy E; Mott, Susan A et al. (2018) APOL1 Risk Variants Independently Associated With Early Cardiovascular Disease Death. Kidney Int Rep 3:89-98
GutiƩrrez, Orlando M; Limou, Sophie; Lin, Feng et al. (2018) APOL1 nephropathy risk variants do not associate with subclinical atherosclerosis or left ventricular mass in middle-aged black adults. Kidney Int 93:727-732
Doshi, Mona D; Ortigosa-Goggins, Mariella; Garg, Amit X et al. (2018) APOL1 Genotype and Renal Function of Black Living Donors. J Am Soc Nephrol 29:1309-1316
Beckerman, Pazit; Bi-Karchin, Jing; Park, Ae Seo Deok et al. (2017) Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat Med 23:429-438
Ng, Derek K; Robertson, Catherine C; Woroniecki, Robert P et al. (2017) 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 32:983-990
Kopp, Jeffrey B (2017) Chronic Kidney Disease in the Aging Human Immunodeficiency Virus-Infected Population. J Infect Dis :

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