Epidemiology of Precursors to Type 2 Diabetes

描述(申请人提供)：2型糖尿病(T2D)是一个日益严重的健康问题，特别是在少数族裔群体中。遗传背景的祖先变异，加上最近肥胖和不健康的行为和社会因素的迅速增加，导致了T2D的发病率及其在美国的差异。拟议的研究重点放在糖尿病前期，即已知干预可以预防T2D，以及T2D的下游种族-种族差异被怀疑开始的地方。糖尿病前期的表型种族-民族差异已经被表征，但遗传差异还没有。有很强的科学和伦理理由来研究种族-民族在T2D遗传风险上的差异。这是对以患者为中心的研究(K24)职业生涯中期研究员奖的更新。候选人詹姆斯·B·梅格斯医学硕士致力于以患者为导向的研究生涯，研究2型糖尿病的病因和预防。该奖项将支持以下具体目标：1.在多种族人口样本(非裔美国人、西班牙裔、亚洲和欧洲血统)中发现、绘制和表征T2D数量性状相关遗传基因座。这将使用阶段性全基因组关联研究和荟萃分析，以及利用相互作用、结果、生理学、途径和测序研究确定的T2D数量性状基因座的特征来实现。与糖尿病相关的数量性状包括空腹胰岛素、葡萄糖和血红蛋白A1c水平；2.通过纵向和多水平的遗传测量以及社会、行为、环境和生物生理测量空腹血糖升高、糖尿病前期或临床T2D风险的测试，将新的遗传知识转化为临床和人群健康受益的不同种族样本；3.在候选人成功的研究和指导计划的基础上，确保在哈佛大学、马萨诸塞州总医院和广泛的研究合作网络的卓越环境中，为以患者为导向的研究计划发展提供职业中期保护时间，并保持持续的能力，为更多以患者为导向的初级研究人员提供指导。以患者为中心的研究对于将科学知识转化为人群健康利益至关重要。T2是一个迅速增长的临床和公共卫生问题。这项职业生涯中期奖励申请旨在直接满足以患者为中心的研究和指导的需求，重点关注T2D的原因和后果。扩大对T2D前体的了解对于确定预防和控制不断扩大的糖尿病流行的新方法至关重要。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a growing health problem, especially in minority race-ethnic groups. Ancestral variation in genetic background coupled with recent, rapid increases in obesity and unhealthy behavioral and social factors account for rising rates of T2D and its disparities in the U.S. The proposed research focuses on prediabetes, where intervention is known to prevent T2D, and where downstream race-ethnic disparities in T2D are suspected to begin. Phenotypic race-ethnic differences in prediabetes have been characterized, but genetic differences have not. There are strong scientific as well as ethical reasons to study race-ethnic differences in T2D genetic risk. This is a renewal of a mid-career investigator award in patient-oriented research (K24). The candidate, James B. Meigs MD MPH, has devoted his patient-oriented research career to study of the cause and prevention of type 2 diabetes. This award will support the following Specific Aims: 1. Discover, map, and characterize T2D quantitative trait-associated genetic loci in multi-ethnic population samples (African American, Hispanic, Asian and European ancestry). This will be achieved using staged genome-wide association studies with meta-analysis and with characterization of confirmed T2D quantitative trait loci using interaction, outcomes, physiology, pathway, and sequencing studies. Diabetes-related quantitative traits include levels of fasting insulin, glucose, and hemoglobin A1c; 2. Translate new genetic knowledge to diverse race-ethnic samples for clinical and population health benefit using longitudinal and multilevel tests of genetic measures and social, behavioral, environmental and biophysiological measures of risk for elevated fasting glucose, prediabetes, or clinical T2D; 3. Build on the candidate's successful research and mentoring program by ensuring mid-career protected time for patient-oriented research program development within the superb environment of Harvard, Massachusetts General Hospital and an extensive network of research collaborations, and by maintaining the ongoing capacity to provide mentoring to a larger number of junior patient-oriented investigators. Patient-oriented research is critical for the translation of scientific knowledge into population health benefit. T2 is a rapidly growing clinical and public health problem. This mid-career award application seeks to directly address the need for patient-oriented research and mentoring focused on the causes and consequences of T2D. Expanded knowledge of precursors of T2D is critical to identify novel approaches for prevention and control of the widening diabetes epidemic.