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

项目总结 通过对新生儿孕激素综合征(NPS或Marfan)的研究发现的一种新的促糖激素--Asprosin 脂肪营养不良综合征)，可能对肥胖和糖尿病具有治疗和诊断意义。这个 编码天冬氨酸的基因FBN1具有独特的极端3‘突变，导致低血糖症状和低血糖 少数少见NPS患者的血浆胰岛素水平。最近有大量证据表明 天冬氨酸在肝脏葡萄糖生成调节中的直接作用及天冬氨酸免疫中和作用 治疗肥胖和糖尿病的小鼠模型。天冬氨酸对2型糖尿病的直接作用(T2D) 人类的发病率还没有在人群中进行调查。目前的应用程序旨在调查 在两个大而高质量的前瞻性研究中，阿司匹林对肥胖和T2D发展的潜在因果作用 一群男人和女人。我们计划整合有关遗传变异、生化标记和 国家妇女健康倡议(WHI)和男性肥胖的临床表型和T2D发病率 卫生专业人员随访研究(HPFS)。WHI和HPFS都是长期预期队列， 由美国国立卫生研究院资助，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， 以及使用标准化协议的大量经过良好表征和验证的事件T2D案例 始终如一地进行了20多年的随访。所有有遗传资料和空腹血液的T2D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(N0=2,615)匹配 女性队列和600对男性病例对照(n‘=1,200)将使用相同的嵌套病例纳入- 控制设计。将在另外1,076例T2D病例对照中进行基因分型和验证分析 配对(n“=2,152)，没有现有的遗传数据。采用标准的统计方法和尖端的 孟德尔随机化方法用于因果推断，我们将利用这些特殊的资源和 在过去20年里，WHI/HPFS研究调查人员投入了大量时间和精力来 以最具成本效益和最及时的方式研究这种新的和有希望的激素-天冬氨酸的效果 -用于肥胖和T2D发育。我们将第一个调查1)血浆中天冬氨酸水平的分布 在男性和女性中，2)影响不同人群中天冬氨酸功能的遗传变异，以及3) 不同种族人群中天冬氨酸氨基转移酶与肥胖和T2D的潜在因果关系 包括白人或高加索美国人(CA)、非裔美国人(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).