Genetic Architecture of Obesity and Inflammation in Hispanic Americans

描述（由申请人提供）：肥胖在美国迅速成为一种流行病，在少数民族人群中的患病率和严重程度不断增加。肥胖诱导炎症状态，其涉及不良健康状况，例如胰岛素抵抗、糖尿病和非酒精性脂肪肝疾病。这项提案的首要目标是确定美国最大的少数民族群体西班牙裔人中肥胖和炎症的定量中间表型变异的常见和罕见遗传变异。在胰岛素抵抗性动脉粥样硬化家族研究（IRASFS;由NHLBI资助两个五年周期，现在由NIDDK在GUARDIAN联盟下资助研究葡萄糖稳态遗传学）中，我们招募了一个大型西班牙裔队列，并获得了肥胖，葡萄糖稳态和相关生物标志物的详细和新颖的测量。通过遗传力，连锁，候选基因和试点全基因组关联研究（GWAS），我们已经探索了遗传决定因素，并确定了与这些性状的一个子集的潜在位点。在本申请中，我们建议通过对现有GWAS、外显子组测序和候选基因数据的二次分析来扩展这些发现，以确定与肥胖和炎症相关的常见和罕见遗传变异。拟议研究的优势包括我们西班牙裔队列中的大谱系，以前未通过GWAS检查的高度详细的定量肥胖和炎症表型，测量的生物标志物比聚合性状更接近基因产物，例如糖尿病和心脏病，开发一种新的分析工具，旨在提高检测不常见SNP与定量性状相关性的能力，以及我们长期以来的，高效的协作团队。这项拟议中的研究有可能影响我们对肥胖和炎症遗传结构的理解，这些遗传结构与糖尿病和心脏病交织在一起，在增长最快的美国少数民族人口中。 公共卫生相关性：我们将通过分析定量中间表型和整合现有的连锁、全基因组关联和外显子组测序数据来研究肥胖和炎症的遗传结构。所获得的见解将提供深入了解因果因素和疾病的发病机制，导致先发制人的治疗，新的治疗方法和发病率的总体下降。

DESCRIPTION (provided by applicant): Obesity is rapidly becoming an epidemic in the US with an increasing prevalence and severity of consequence among minority populations. Obesity induces an inflammatory state that is implicated in adverse health conditions, e.g. insulin resistance, diabetes and non-alcoholic fatty liver disease. The over-arching goal of this proposal is to identify common and rare genetic variants underlying variation in quantitative intermediate phenotypes of obesity and inflammation in the largest US minority group, Hispanics. In the Insulin Resistance Atherosclerosis Family Study (IRASFS; funded for two five-year cycles by NHLBI and now funded under the GUARDIAN Consortium by NIDDK to study glucose homeostasis genetics) we have recruited a large Hispanic cohort and obtained detailed and novel measures of obesity, glucose homeostasis and relevant biomarkers. Through heritability, linkage, candidate gene and pilot genome-wide association studies (GWAS), we have explored the genetic determinants and identified potential loci associated with a subset of these traits. In this application, we propose to extend these findings through secondary analysis of existing GWAS, exome sequencing and candidate gene data in an effort to identify common and rare genetic variation associated with obesity and inflammation. The strengths of the proposed study include the large pedigrees in our Hispanic cohort, highly detailed, quantitative obesity and inflammation phenotypes not previously examined via GWAS, measured biomarkers that are more proximal to the gene products than aggregate traits, e.g. diabetes and heart disease, development of a novel analytic tool designed to increase the power to detect uncommon SNP associations with quantitative traits and our long-standing, highly productive collaborative team. The proposed research has the potential to impact our understanding of the genetic architecture of obesity and inflammation, traits intertwined with diabetes and heart disease, in the fastest growing US minority population. PUBLIC HEALTH RELEVANCE: We will investigate the genetic architecture of obesity and inflammation through analysis of quantitative intermediate phenotypes and integration of existing linkage, genome-wide association and exome sequencing data. The insight gained will provide insight into causal factors and disease pathogenesis leading to preemptive treatment, novel therapeutics and an overall decrease in incidence.