Genetic Architecture of Obesity and Inflammation in Hispanic Americans

描述(申请人提供)：肥胖症正在美国迅速成为一种流行病，在少数族裔人群中的流行率和后果日益严重。肥胖导致炎症状态，这与不良健康状况有关，例如胰岛素抵抗、糖尿病和非酒精性脂肪性肝病。这项建议的总体目标是确定美国最大的少数群体拉美裔肥胖和炎症的数量中间表型变异背后的常见和罕见的遗传变异。在胰岛素抵抗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资助，研究葡萄糖稳态遗传学)中，我们招募了大量西班牙裔队列，并获得了肥胖、血糖稳态和相关生物标记物的详细和新的测量方法。通过遗传力、连锁、候选基因和试点全基因组关联研究，我们探索了遗传决定因素，并确定了与这些性状的子集相关的潜在基因座。在这一应用中，我们建议通过对现有GWA的二次分析、外显子组测序和候选基因数据来扩展这些发现，以努力识别与肥胖和炎症相关的常见和罕见的基因变异。这项拟议的研究的优势包括：我们拉美裔队列中的大型家系；非常详细的量化肥胖和炎症表型以前没有通过GWAS进行检查；测量到的生物标记物更接近基因产品，而不是聚合性状，如糖尿病和心脏病；开发一种新的分析工具旨在提高检测罕见SNP与数量性状关联的能力；以及我们长期高效合作的团队。这项拟议的研究有可能影响我们对肥胖和炎症的遗传结构的理解，这些特征与糖尿病和心脏病交织在一起，在美国增长最快的少数民族人口中。 公共卫生相关性：我们将通过定量中间表型分析以及整合现有的连锁、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。所获得的洞察力将提供对病因和疾病发病机制的洞察，从而导致先发制人的治疗、新的疗法和总体发病率的降低。

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.