Association of PPAR-pathway gene polymorphisms with diabetic outcomes in BARI 2D

描述(申请人提供)：在糖尿病(DM)患者中，动脉粥样硬化加速的并发症仍然是主要的死亡原因。糖尿病患者心血管疾病发病率高、预后差的发病机制尚不清楚。BARI 2D是一项多中心随机临床试验，调查不同的冠状动脉疾病治疗方法(血运重建与药物治疗)和糖尿病治疗(胰岛素提供与胰岛素增敏)对糖尿病患者长期结果的影响。到目前为止，很少有研究检验这一假设，即遗传变异可能解释了这些患者对治疗的不同反应和不同的结果。PPAR基因通路由相互关联的基因组成，编码转录因子、酶和下游靶点，并协调作用于调节糖和脂代谢中心的细胞过程。随着越来越多的证据表明PPAR相关基因与胰岛素抵抗、肥胖和糖尿病的发生有关，PPAR基因通路成为进一步研究的关键靶点。利用候选基因方法，PI最近发现了PPARa基因启动子内的SNPs，这些SNPs与糖尿病和急性冠脉综合征(ACS)患者的3年死亡率显著相关。鉴于PPAR途径基因和基因产物之间的复杂相互关系，以及与药物的复杂相互作用，如果利用更全面的基因途径分析，可能会极大地加强遗传和药物遗传学与表型标记和临床结果的相关性的研究。为了实现这一目标，我们建议利用包括来自223个PPAR途径基因的SNPs的靶向基因分型3K芯片：(目的1)确定与BARI 2D患者的临床心血管和糖尿病预后相关的PPAR途径基因SNPs；(目的2)通过检测PPAR途径SNPs与预后动脉粥样硬化和糖尿病表型标志物之间的潜在关联来探讨可能的机制；(目的3)通过随机治疗相互作用检查PPAR途径的基因型，包括血糖控制的药物遗传学和遗传效应对通过早期血运重建与药物治疗降低相对风险的影响；以及(目的4)利用创新的统计模型研究PPAR途径基因的多态之间的“交互效应”。拟议的分析将产生有关糖尿病和心血管疾病患者中PPAR途径基因、表型标记和结果之间的遗传关联的新信息，并允许进行独特的分析，探索这些变异(基因和/或单倍型)与BARI 2D中多个终点之间的显著遗传和药物遗传交互作用。本提案中描述的创新方法具有产生治疗冠心病和糖尿病患者的非常重要的新方法的潜力，特别是在血管重建和药物干预方面。

DESCRIPTION (provided by applicant): Among persons with diabetes mellitus (DM), the complications of accelerated atherosclerosis remain the principal cause of death. The pathogenesis of the high incidence of cardiovascular disease, and worse prognosis, in patients with DM is poorly understood. BARI 2D is a multicenter randomized clinical trial investigating the affect of different approaches to treatment of coronary artery disease (revascularization vs. medical management) and to treatment of DM (insulin-providing vs. insulin-sensitizing) on long term outcomes among patients with DM. To date, few studies have examined the hypothesis that genetic variation may account for different responses to treatment and different outcomes for such patients. The PPAR gene pathway consists of interrelated genes that encode transcription factors, enzymes and downstream targets and coordinately act to regulate cellular processes central to glucose and lipid metabolism. With growing evidence that PPAR-related genes are associated with the development of insulin resistance, obesity, and DM, the PPAR gene pathway represents a key target for further investigation. Using a candidate gene approach, the PI has recently identified polymorphisms (SNPs) within the promoter of the PPARa gene that are significantly associated with 3-year mortality in patients with DM and acute coronary syndromes (ACS). Given the complex interrelationships between PPAR-pathway genes and gene products, as well as complex interactions with medications, investigation into genetic and pharmacogenetic associations with phenotypic markers and clinical outcome may be greatly enhanced if a more comprehensive gene pathway analysis is utilized. To accomplish this goal, we propose to utilize a targeted-genotyping 3K chip including SNPs from 223 PPAR-pathway genes: (Aim 1) To determine PPAR-pathway gene SNPs that show an association with clinical cardiovascular and diabetic outcomes among patients in BARI 2D; (Aim 2) To investigate putative mechanisms by examining potential associations between PPAR-pathway SNPs and prognostic atherosclerotic and diabetic phenotypic markers; (Aim 3) To examine PPAR-pathway genotype by randomized treatment interactions, including the pharmacogenetics of glucose control and genetic effects on the relative risk reduction by an initial strategy of revascularization vs. medical therapy; and (Aim 4) To investigate the "interactive-effect" between polymorphisms of PPAR-pathway genes using innovative statistical models. The proposed analysis should yield novel information about genetic associations between PPAR-pathway genes, phenotypic markers, and outcomes among patients with DM and cardiovascular disease and allow unique analyses probing significant genetic and pharmacogenetic interactions between these variants (genotypes and/or haplotypes) and multiple endpoints in BARI 2D The innovative approach described in this proposal has the potential to yield highly significant, new approaches to the treatment of patients with CAD and DM, specifically with respect to revascularization and pharmaceutical intervention.