TGF-BETA1 AND EXCESS RENAL DISEASE IN AFRICAN AMERICANS

Weill Medical College Of Cornell Univ, New York NY

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Abstract

DESCRIPTION: (Adapted from Applicant's Abstract) The overall objective of this project is to identify mechanisms responsible for end stage renal disease (ESRD), a common disease (73,091 incident cases in 1996) of extraordinary personal suffering and societal costs ($14.55 billion in 1996), and one that is associated with an adjusted death rate of 24% in the first year, despite renal replacement therapy. The specific objective of this application is to test the hypothesis that hyperexpression of transforming growth factor beta (TGF-beta), a multifunctional cytokine clearly shown to induce renal disease in experimental models, is a risk factor for the progression of renal disease to ESRD in humans. That TGF-beta1 over expression is more frequent in African Americans, a population at greater risk for ESRD than Caucasians, and that TGF-beta1 expression is determined, at least in part, by TGF-beta1 DNA polymorphisms will be explored in this study with conceptually interrelated clinical and laboratory studies. The specific aims are as follow. Specific Aim 1 is to identify ESRD-specific differences in TGF-beta1 genotype and phenotype. A discordant sib pair study stratified by race will be performed to determine whether candidate TGF-beta1 DNA polymorphisms are linked to ESRD. African American and Caucasian ESRD patients will be studied to test the hypothesis that TGF-beta1 hyperexpression (increased mRNA and protein levels) is more frequent in 1) ESRD patients compared to a healthy sibling, and 2) African Americans compared to Caucasians. Specific Aim 2 is to test the postulate that TGF-beta1 DNA polymorphisms and TGF-beta1 hyperexpression are more frequent 1) in patients with hypertension compared to age-, gender-, and race-matched normotensive acquaintances, and 2) in African Americans compared to Caucasians. Specific Aim 3 is to test the postulate the TGF-beta1 hyperexpression and TGF-beta1 DNA polymorphisms are correlates of the rate of decline of renal function and the development of adverse renal endpoints in African American and Caucasian children with chronic renal insufficiency. TGF-beta1 phenotype and genotype will be determined at baseline in children followed prospectively by the North American Pediatric Renal Transplantation Cooperative Study (NAPRTCS) Chronic Renal Insufficiency (CRI) Registry. Children (stratified by race) with focal and segmental glomerulosclerosis (FSGS) demonstrated by biopsy will be compared to children with non-immunologic renal disease.