Genetics and Pharmacogenetics in FSGS (PPG Project 4)

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Idiopathic focal segmental glomerulosclerosis (FSGS) is a primary glomerular disorder that is often associated with refractory edema, severe infections, thromboembolic complications, and progression to end-stage renal disease. Evidence indicates that a diverse set of pathogenic mechanisms cause FSGS, most notably: 1) single-gene mutations in the genes encoding podocin (NPHS2) and WT-1; 2) a multifactorial defect that includes, but is not limited to, heterozygous mutations and polymorphisms in podocyte-related genes; and 3) a T-cell disorder that causes production of circulating permeability factor(s) which alters the filtration barrier. This pathogenetic heterogeneity has significant therapeutic implications. For example, in European studies, children and adults with two pathogenic NPHS2 mutations are steroidresistant and exhibit no, or at best, limited response to immunosuppressive agents such as cyclosporine (CsA). The NIDDK has initiated a prospective, controlled, randomized trial to compare the therapeutic response in children and adults with steroid-resistant FSGS treated with either CsA or mycophenolic mofetil (MMF). As an ancillary study to the FSGS Clinical Trial (FSGS-CT), the "Comprehensive Study of FSGS" has developed five interactive projects to further elucidate pathogenetic mechanisms and establish the platform for development of novel and targeted treatment strategies. Project 4 is designed: 1) to examine the FSGSCT cohort for mutations in podocyte-related genes; determine the prevalence of these mutations among patients in each therapeutic arm; and correlate mutations with response to either CsA or MMF; and 2) to examine the association between therapeutic response to CsA or MMF and DNA polymorphisms in genes involved in immunosuppressive action, podocyte structural biology, and fibrogenic pathways. The central hypotheses are: 1) this FSGS-CT cohort will have a significant percentage of patients with ingle-gene defects, predominantly in NPHS2. These patients will have no, or at best, limited response to further immunosuppressive treatment; and 2) genotypes/haplotypes of the major candidate genes involved in drug action/disposition (CsA and MMF), podocyte structural biology, and fibrogenic pathways will be predictive of therapeutic outcomes. Project 4 is the first study to examine these issues in the context of a large therapeutic trial involving North American FSGS patients. The genetic profiles defined in this ethnically and racially diverse cohort will guide the development of prospective, individualized treatment algorithms for FSGS patients, so as to optimize the likelihood of therapeutic response and minimize or avoid major drug-related adverse effects.