Association of PPAR-pathway gene polymorphisms with diabetic outcomes in BARI 2D
BARI 2D 中 PPAR 通路基因多态性与糖尿病结局的关联
基本信息
- 批准号:7481145
- 负责人:
- 金额:$ 11.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-09 至 2010-06-30
- 项目状态:已结题
- 来源:
- 关键词:2,4-thiazolidinedioneAccountingAcuteAffectAlbuminuriaAngioplastyAtherosclerosisBindingBlood specimenBypassCandidate Disease GeneCardiovascular DiseasesCardiovascular systemCause of DeathCell physiologyCessation of lifeClassClinicalClinical MarkersComplexComplications of Diabetes MellitusConsensusCoronaryCoronary ArteriosclerosisCustomDataDeath RateDevelopmentDiabetes MellitusDiseaseEnd PointEnzymesEvaluationEventFamilyFibratesFrequenciesGene TargetingGenesGeneticGenetic PolymorphismGenetic VariationGenotypeGlucoseGlycosylated hemoglobin AGoalsGovernmentHaplotypesHemoglobinHospitalizationHypoglycemiaHypoglycemic AgentsIn VitroIncidenceIndividualInsulinInsulin ResistanceInterventionInvestigationIschemiaLeft Ventricular FunctionLinkage DisequilibriumLipidsMeasuresMedicalMetabolicMolecular TargetMonitorMorbidity - disease rateMyocardialMyocardial InfarctionNon-Insulin-Dependent Diabetes MellitusNuclear Hormone ReceptorsNuclear ReceptorsObesityOutcomePathogenesisPathway AnalysisPathway interactionsPatientsPeroxisome Proliferator-Activated ReceptorsPersonsPharmaceutical PreparationsPharmacogeneticsPharmacologic SubstancePhenotypePopulationPrevalencePromoter RegionsProteinsPurposeRandomizedRandomized Clinical TrialsRateReceptor GeneRecurrenceRelative (related person)RiskRisk ReductionRoleSNP genotypingSamplingSiteSourceStatistical ModelsStrokeTechniquesThiazolidinedionesTreatment outcomeUnited StatesVariantacute coronary syndromebaseblood glucose regulationcohortdesigndiabeticfollow-upgenetic analysisgenetic associationglycemic controlinnovationlipid metabolismmortalitynovelnovel strategiesoutcome forecastprognosticprogramspromoterresponsetranscription factor
项目摘要
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.
描述(由申请人提供):在糖尿病(DM)患者中,加速动脉粥样硬化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,其发病机制尚不清楚。巴里2 D是一项多中心随机临床试验,旨在研究不同的冠状动脉疾病治疗方法(血运重建与药物管理)和糖尿病治疗方法(胰岛素提供与胰岛素增敏)对糖尿病患者长期结局的影响。到目前为止,很少有研究已经检查了遗传变异可能导致对治疗的不同反应和这些患者的不同结果的假设。PPAR基因通路由编码转录因子、酶和下游靶标的相关基因组成,并协调作用以调节对葡萄糖和脂质代谢至关重要的细胞过程。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DM的发生相关,PPAR基因通路成为进一步研究的关键靶点。利用候选基因的方法,PI最近鉴定了PPARa基因启动子内的多态性(SNP),这些多态性与DM和急性冠状动脉综合征(ACS)患者的3年死亡率显著相关。考虑到PPAR-pathway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,如果利用更全面的基因途径分析,可能会大大增强对遗传和药物遗传学与表型标志物和临床结果的相关性的研究。为了实现这一目标,我们提出利用靶向基因分型3 K芯片,包括来自223个PPAR-pathway基因的SNPs:(目的1)在巴里2D中确定PPAR-pathway基因的SNPs,其显示与患者的临床心血管和糖尿病预后相关;(目的2)通过检查PPAR-pathway SNPs与动脉粥样硬化预后和糖尿病表型标记物之间的潜在关联来研究推定的机制;(目的3)通过随机治疗相互作用检查PPAR-pathway基因型,包括血糖控制的药物遗传学和通过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)使用创新的统计模型研究PPAR-pathway基因多态性之间的“相互作用”。拟议的分析应产生新的信息之间的遗传关联的PPAR途径基因,表型标记物,并与糖尿病和心血管疾病患者的结果,并允许独特的分析探测这些变异之间的显着遗传和药物遗传学的相互作用(基因型和/或单倍型)和多个终点在巴里2D中本提案中描述的创新方法具有产生高度显著,治疗CAD和DM患者的新方法,特别是血运重建和药物干预。
项目成果
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SHARON CRESCI其他文献
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