Genetics and Pharmacogenetics in FSGS (PPG Project 4)

FSGS 中的遗传学和药物遗传学（PPG 项目 4）

• 批准号: 7289399
• 负责人: Lisa M Guay-Woodford
• 金额: $ 20万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7289399
• 关键词: DNA; artificial immunosuppression; clinical research; clinical trials; drug resistance; fibrogenesis; gene mutation; genetic polymorphism; genotype; glomerulosclerosis; human subject; immunosuppressive; kidney disorder chemotherapy; kidney pharmacology; membrane proteins; mycophenolate mofetil; patient oriented research; pharmacogenetics; podocyte; steroids; structural biology

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.

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，通常 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，多种致病机制可导致 FSGS、 最值得注意的是：1）编码podocin（NPHS2）和WT-1的基因的单基因突变； 2）一个 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； 3) 导致循环渗透因子产生的 T 细胞疾病 这会改变过滤屏障。这种致病异质性具有重要的治疗意义。 例如，在欧洲研究中，具有两种致病性 NPHS2 突变的儿童和成人具有类固醇抗性 对环孢菌素等免疫抑制剂没有反应，或者至多表现出有限的反应 （环孢素A）。 NIDDK 启动了一项前瞻性、对照、随机试验来比较治疗反应 患有类固醇耐药 FSGS 的儿童和成人接受 CsA 或吗替麦考酚 (MMF) 治疗。 作为 FSGS 临床试验 (FSGS-CT) 的辅助研究，“FSGS 综合研究” 开发五个互动项目，进一步阐明发病机制并建立平台 开发新颖且有针对性的治疗策略。项目 4 的设计目的是：1）检查 FSGSCT 足细胞相关基因突变队列；确定这些突变的患病率 每个治疗组的患者；并将突变与 CsA 或 MMF 的反应相关联； 2) 到 检查 CsA 或 MMF 的治疗反应与基因 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形成途径。 中心假设是：1）这个 FSGS-CT 队列中将有很大比例的患者患有以下疾病： 单基因缺陷，主要出现在 NPHS2 中。这些患者对药物没有反应，或者充其量也只有有限的反应。 进一步的免疫抑制治疗； 2) 涉及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形成途径将 预测治疗结果。项目 4 是第一个在以下背景下检验这些问题的研究： 涉及北美 FSGS 患者的大型治疗试验。本文件中定义的遗传图谱 种族和种族多样化的队列将指导前瞻性、个体化治疗的发展 FSGS 患者的算法，以优化治疗反应的可能性并最小化或避免 主要与药物相关的不良反应。