Genetics and Pharmacogenetics in FSGS (PPG Project 4)

特发性局灶节段性肾小球硬化症（FSGS）是一种原发性肾小球疾病， 与难治性水肿、严重感染、血栓栓塞并发症和进展相关， 终末期肾病有证据表明，多种致病机制导致FSGS， 最值得注意的是：1）编码podocin（NPHS 2）和WT-1的基因中的单基因突变; 2）a 多因素缺陷，包括但不限于，杂合突变和多态性， 足细胞相关基因;和3）导致循环渗透性因子产生的T细胞病症 从而改变过滤屏障。这种致病异质性具有重要的治疗意义。 例如，在欧洲的研究中，具有两个致病性NPHS 2突变的儿童和成人是类固醇耐药的， 并且对免疫抑制剂如环孢霉素没有反应或至多表现出有限的反应 （CsA）。 NIDDK已经启动了一项前瞻性、对照、随机试验， 用CsA或霉酚酸酯（MMF）治疗的类固醇耐药FSGS儿童和成人。 作为FSGS临床试验（FSGS-CT）的辅助研究，“FSGS综合研究” 开发了五个互动项目，以进一步阐明发病机制，并建立平台 用于开发新的和有针对性的治疗策略。项目4的设计：1）检查FSGSCT 足细胞相关基因突变的队列;确定这些突变在 每个治疗组中的患者;并将突变与对CsA或MMF的应答相关;以及2） 检查CsA或MMF治疗反应与基因中DNA多态性之间的关联 参与免疫抑制作用、足细胞结构生物学和纤维化途径。 中心假设是：1）该FSGS-CT队列将有显著百分比的患者， 单基因缺陷，主要在NPHS 2中。这些患者将不会有，或充其量，有限的反应， 进一步的免疫抑制治疗;和2）参与免疫抑制治疗的主要候选基因的基因型/单倍型。 药物作用/处置（CsA和MMF），足细胞结构生物学和纤维化途径将被 预测治疗结果。项目4是第一个在一个全球性的背景下审查这些问题的研究。 涉及北美FSGS患者的大型治疗试验。在此定义的遗传图谱 种族和人种多样化的队列将指导前瞻性个体化治疗的发展 算法，以便优化治疗反应的可能性，并最小化或避免 主要药物相关不良反应。

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.