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

描述（由申请人提供）：在糖尿病（DM）患者中，加速动脉粥样硬化的并发症仍然是死亡的主要原因。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，旨在调查不同冠状动脉疾病治疗方法（血运重建vs药物管理）和糖尿病治疗方法（胰岛素提供vs胰岛素敏感化）对糖尿病患者长期预后的影响。迄今为止，很少有研究检验遗传变异可能解释这类患者对治疗的不同反应和不同结果的假设。PPAR基因通路由相互关联的基因组成，这些基因编码转录因子、酶和下游靶点，并协调调节葡萄糖和脂质代谢的细胞过程。随着越来越多的证据表明PPAR相关基因与胰岛素抵抗、肥胖和糖尿病的发展有关，PPAR基因通路是进一步研究的关键目标。利用候选基因方法，PI最近发现了PPARa基因启动子内的多态性（snp），该多态性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通路基因和基因产物之间复杂的相互关系，以及与药物的复杂相互作用，如果采用更全面的基因通路分析，可能会大大加强对表型标记物和临床结果的遗传和药物遗传学关联的研究。为了实现这一目标，我们建议利用含有223个ppar通路基因snp的靶向基因分型3K芯片：（目的1）确定与BARI 2D患者临床心血管和糖尿病结局相关的ppar通路基因snp；（目的2）通过检测ppar通路snp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研究可能的机制；（目的3）通过随机治疗相互作用检查ppar通路基因型，包括葡萄糖控制的药物遗传学和血管重建与药物治疗的初始策略对相对风险降低的遗传效应；（目的4）利用创新的统计模型研究ppar通路基因多态性之间的“相互作用”。提议的分析将产生关于ppar通路基因、表型标记和糖尿病和心血管疾病患者预后之间的遗传关联的新信息，并允许进行独特的分析，探测这些变体（基因型和/或单倍型）与BARI 2D中多个终点之间的重要遗传和药理学相互作用。冠心病和糖尿病患者治疗的新方法，特别是关于血运重建和药物干预。

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.