SECONDARY ANALYSIS OF A LARGE SCALE GENETIC STUDY IN OBESITY AND RELATED OUTCOMES
大规模肥胖遗传研究及相关结果的二次分析
基本信息
- 批准号:7878272
- 负责人:
- 金额:$ 14.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-08-01 至 2012-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptionAffectAmericanArchitectureArtificial SweetenersBiologicalBiological MarkersBlood PressureBody CompositionBody Weight decreasedBody mass indexBooksCategoriesClinicalCluster AnalysisComplementComplexCoronary ArteriosclerosisDataData SetDatabasesDevelopmentDiastolic blood pressureDietDiseaseDisease OutcomeDyslipidemiasFamily StudyFoodFunding OpportunitiesFutureGene CombinationsGeneral PopulationGenesGeneticGenotypeGoalsHuman GeneticsHypertensionIndividualInheritedLeadLipidsMaintenanceMetabolicMethodsMissionModelingNational Institute of Diabetes and Digestive and Kidney DiseasesNon-Insulin-Dependent Diabetes MellitusObesityOutcomePathway interactionsPatientsPhenotypePhysiciansPlasmaPopulationPreventionPublic HealthRegimenReproducibilityResearchRisk FactorsSamplingSingle Nucleotide PolymorphismSolutionsStagingStatistical ModelsSubgroupSystems BiologyTechniquesTestingTimeTwin Multiple BirthVariantWeightbasecancer typeclinical practicecohortcombinatorialdesigndrinkinggenetic variantgenome wide association studyindexinginnovationinsulin sensitivitynovelobesity riskobesity treatmentpredictive modelingprogramspublic health relevancesuccesstraittreatment durationweight gain preventionweight maintenance
项目摘要
DESCRIPTION (provided by applicant): Obesity is a complex metabolic isorder that affects a significant percentage of the industrialized population and is a significant risk factor for various types of cancer, type 2 diabetes, dyslipidemia, hypertension and coronary artery disease. In the struggle to maintain an optimal body mass index (BMI), Americans also spend approximately $40 billion annually on weight-loss products such as diet foods and drinks, artificial sweeteners, books and weight loss programs. Twin, adoption and family studies indicate that 40-70% of inter-individual variation in body mass index is heritable. Recent genome-wide association studies (GWAS) sampling from the general population have identified multiple genetic variants associated with obesity risk but cumulatively explain only a small fraction of the inherited variability in BMI. A recurring problem in traditional GWAS analysis is the lack of power to detect small effects and lack of reproducibility of variant SNP association in replication studies or in different ethnic populations. The broad, long-term objective and the goal of the specific research proposed here is to address these gaps and establish methods that significantly advance understanding of the complex genetic architecture underlying obesity and weight-loss/weight-maintenance. This will be achieved through a genome-wide association study of carefully phenotyped individuals at the extremes of body mass (instead of sampling from the general population) and by the application of innovative secondary analyses that complement and augment traditional approaches. Specifically, three aims are proposed - (i) to identify variant SNPs associated with obesity, weight-loss and weight-maintenance; (ii) to identify genes and gene-sets (pathways) that associate with obesity and obesity-related outcomes and (iii) to identify predictive markers for sub-categories of weight-loss success and prevention of weight gain. Each specific aim will be achieved through a specific analytic method - (i) traditional, single SNP based association analysis of continuous and discrete traits for specific aim 1; (ii) exploratory, secondary analysis for identifying genes (combination of SNPs) and pathways (combination of genes) associated with disease outcomes using combinatorial, gene-set enrichment techniques for specific aim 2; (iii) predictive modeling for determining trajectories of weight-loss and weight-regain over time and identifying predictive biomarkers of weight-loss outcomes for specific aim 3. The primary analysis (specific aim 1) is required to enable secondary analyses in specific aims 2 and 3. These efforts will lead to a better understanding of specific obesity-related outcomes, inform the design and content of future studies, and identify predictive genetic biomarkers of long term weight-maintenance or prevention of weight gain that can guide future clinical practice in the treatment of weight-related disorders. All of these are directly relevant to the mission of NIDDK.
PUBLIC HEALTH RELEVANCE: The proposed research, 'Secondary nalysis of a Large Scale Genetic Study in Obesity and Related Outcomes' is relevant to public health in two ways. First, the research explores innovative analytic solutions on a genome-wide association study on obesity, weight-loss success and long-term weight maintenance, for the identification of genes and biological pathways that underlie the genetic architecture of obesity and obesity related metabolic traits. These findings could help uncover disease targets for the subsequent development of pharmacologic agents for the treatment of obesity and also help identify genetic biomarkers that have clinical utility in the prediction of long-term weight maintenance or prevention of weight gain. Secondly, the analytic approaches developed and evaluated in this proposal are also applicable to other genome-wide association studies and as such, have far-reaching consequences in enhancing the power of large-scale human genetics to address major public health concerns.
描述(由申请人提供):肥胖是一种复杂的代谢紊乱,影响相当大比例的工业化人口,是各种类型癌症、2型糖尿病、血脂异常、高血压和冠状动脉疾病的重要危险因素。为了保持最佳的身体质量指数(BMI),美国人每年还花费大约400亿美元用于减肥产品,如减肥食品和饮料,人工甜味剂,书籍和减肥计划。双胞胎,收养和家庭研究表明,40-70%的个体间体重指数的变化是遗传的。最近的全基因组关联研究(GWAS)从普通人群中取样,发现了与肥胖风险相关的多种遗传变异,但累积起来只能解释BMI遗传变异的一小部分。传统GWAS分析中反复出现的问题是缺乏检测小效应的能力,并且在复制研究或不同种族人群中缺乏变异SNP关联的再现性。这里提出的广泛的,长期的目标和具体研究的目标是解决这些差距,并建立方法,显着推进对肥胖和减肥/体重维持的复杂遗传结构的理解。这将通过对体重极端的个体进行仔细的表型分析的全基因组关联研究(而不是从一般人群中取样),并通过应用补充和加强传统方法的创新性二次分析来实现。具体而言,提出了三个目标-(i)鉴定与肥胖、体重减轻和体重维持相关的变体SNP;(ii)鉴定与肥胖和肥胖相关结果相关的基因和基因组(途径);以及(iii)鉴定用于体重减轻成功和预防体重增加的亚类的预测标记。每个特定目标将通过特定的分析方法实现-(i)针对特定目标1的连续和离散性状的传统的基于单个SNP的关联分析;(ii)用于识别基因的探索性二次分析。(SNP的组合)和途径(基因的组合)与疾病结果相关,使用组合的基因集富集技术用于特定目的2;(iii)预测建模,用于确定随时间推移的体重减轻和体重恢复的轨迹,并识别用于特定目标的体重减轻结果的预测生物标志物3。需要进行主要分析(具体目标1),以便在具体目标2和3中进行次要分析。这些努力将导致更好地理解特定的肥胖相关结果,为未来研究的设计和内容提供信息,并确定长期体重维持或预防体重增加的预测性遗传生物标志物,以指导未来治疗体重相关疾病的临床实践。所有这些都与NIDDK的使命直接相关。
公共卫生相关性:这项被提议的研究,“肥胖和相关结果的大规模遗传研究的二次分析”,在两个方面与公共卫生有关。首先,该研究探索了关于肥胖,减肥成功和长期体重维持的全基因组关联研究的创新分析解决方案,用于识别肥胖遗传结构和肥胖相关代谢特征的基因和生物学途径。这些发现可以帮助揭示疾病的目标,用于治疗肥胖症的药理学药物的后续开发,也有助于确定在预测长期体重维持或预防体重增加方面具有临床实用性的遗传生物标志物。其次,本提案中开发和评估的分析方法也适用于其他全基因组关联研究,因此,在增强大规模人类遗传学解决重大公共卫生问题的能力方面具有深远的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sujoy Ghosh其他文献
Sujoy Ghosh的其他文献
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{{ truncateString('Sujoy Ghosh', 18)}}的其他基金
Genetic investigations into adiponectin as a biologic mediator and a therapeutic
脂联素作为生物介质和治疗药物的遗传学研究
- 批准号:
8720567 - 财政年份:2014
- 资助金额:
$ 14.95万 - 项目类别:
Genetic investigations into adiponectin as a biologic mediator and a therapeutic
脂联素作为生物介质和治疗药物的遗传学研究
- 批准号:
8353806 - 财政年份:2012
- 资助金额:
$ 14.95万 - 项目类别:
SECONDARY ANALYSIS OF A LARGE SCALE GENETIC STUDY IN OBESITY AND RELATED OUTCOMES
大规模肥胖遗传研究及相关结果的二次分析
- 批准号:
8112752 - 财政年份:2010
- 资助金额:
$ 14.95万 - 项目类别:
Genetic investigations into adiponectin as a biologic mediator and a therapeutic
脂联素作为生物介质和治疗药物的遗传学研究
- 批准号:
8573739 - 财政年份:
- 资助金额:
$ 14.95万 - 项目类别:
Genetic investigations into adiponectin as a biologic mediator and a therapeutic
脂联素作为生物介质和治疗药物的遗传学研究
- 批准号:
8928732 - 财政年份:
- 资助金额:
$ 14.95万 - 项目类别:
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