Asprosin, body weight, and risk of type 2 diabetes in U.S. men and women

项目摘要 Asprosin是一种新发现的新生儿早老综合征（Progeroid syndrome，或Marfan）的生糖激素 脂肪营养不良综合征）可能对肥胖症和糖尿病具有治疗和诊断意义。的 编码白色脂肪肽的基因FBN 1具有独特的极端3'突变，导致低血糖症状和低血糖。 血浆胰岛素水平在少数罕见的糖尿病患者。最近有大量证据表明 白色脂肪肽在肝葡萄糖生成调节中的直接作用，以及白色脂肪肽在肝葡萄糖生成调节中的免疫中和作用。 在小鼠模型中治疗肥胖症和糖尿病。白色脂肪肽对2型糖尿病（T2 D）的直接影响 尚未在人群中研究人类发病率。目前的申请旨在调查 在两项大型高质量前瞻性研究中， 一群男人和女人我们计划整合相关遗传变异、生化标记物和 国家妇女健康倡议（WHI）和男性健康倡议中肥胖和T2 D发病率的临床表型 卫生专业人员随访研究（HPFS）。WHI和HPFS均为长期前瞻性队列， 由NIH资助，提供详细和高质量的饮食，生活方式，临床，生化和基因组数据， 以及使用标准化方案的大量充分表征和验证的T2 D事件病例 在20年的随访中，所有具有现有遗传数据和空腹血液的T2 D病例 样本（n1= 2，615）与从相同WHI中随机选择的相同数量的对照（n 0 = 2，615）匹配 将使用相同的嵌套病例纳入女性队列和600对男性病例对照（n '= 1，200）， 控制设计将在另外1，076例T2 D病例对照中进行基因分型和验证分析 对（n”= 2，152）没有现有的遗传数据。采用标准统计方法和最先进的 孟德尔随机化方法进行因果推理，我们将利用这些特殊的资源和 WHI/HPFS研究者在过去二十年中投入了大量时间和精力， 以最具成本效益和及时的方式调查这种新型和有前途的激素-白色脂肪肽的效果 - 肥胖症和T2 D的发展。我们将首先研究1）血浆白色脂肪肽水平的分布 在男性和女性中，2）在不同人群中影响白色脂肪肽功能的遗传变异，以及3） 不同种族人群中白色脂肪肽与肥胖和T2 D之间的潜在因果关系 包括白色或高加索美国人（CA）、非洲裔美国人（AA）和西班牙裔美国人（HA）。

PROJECT SUMMARY Asprosin, a newly identified glucogenic hormone through study of neonatal progeroid syndrome (NPS, or Marfan lipodystrophy syndrome), may have both therapeutic and diagnostic implications for obesity and diabetes. The gene encoding asprosin, FBN1, has unique extreme 3’ mutations resulting in hypoglycemic symptoms and low plasma insulin levels in a few patients with the rare NPS. Considerable evidence has recently demonstrated asprosin’s direct role in hepatic glucose production modulation, and asprosin immunologic neutralization in the treatment of obesity and diabetes in mouse models. The direct effect of asprosin on type 2 diabetes (T2D) incidence in humans has not been investigated in human populations. The current application aims to investigate the potential causal role of asprosin for obesity and T2D development in two large and high-quality prospective cohorts of men and women. We plan to integrate data on relevant genetic variations, biochemical markers, and clinical phenotypes of obesity and T2D incidence in the national Women’s Health Initiative (WHI) and the men’s Health Professionals Follow-Up Study (HPFS). Both WHI and HPFS are long-term prospective cohorts that have been funded by the NIH with detailed and high-quality dietary, lifestyle, clinical, biochemical, and genomic data, and a large number of well-characterized and validated incident T2D cases using standardized protocol consistently over 20 years of follow-up. All incident T2D cases with existing genetic data and fasting blood samples (n1=2,615) matched by an equal number of controls (n0=2,615) randomly selected from the same WHI cohort of women, and 600 case-control pairs of men (n’=1,200) will be included using the identical nested case- control design. Genotyping and validation analyses will be performed in an additional 1,076 T2D case-control pairs (n”=2,152) without existing genetic data. Adopting both standard statistical methods and the cutting-edge Mendelian randomization method for causal inference, we will leverage these exceptional resources and the substantial investment of time and effort by WHI/HPFS study investigators over the past two decades to investigate, in a most cost-efficient and timely manner, the effect of this novel and promising hormone – asprosin – for obesity and T2D development. We will be the first to investigate 1) the distribution of plasma asprosin levels in men and women, 2) the genetic variations affecting asprosin functions in diverse human populations, and 3) the potential causal relation between asprosin and obesity and T2D in human populations of diverse ethnicity including white or Caucasian American (CA), African American (AA), and Hispanic American (HA).