Genetics and Pharmacogenetics in FSGS (PPG Project 4)

University Of Alabama At Birmingham, Birmingham AL

Investigators

Abstract

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