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

美国男性和女性的白脂素、体重和 2 型糖尿病风险

基本信息

批准号：
10202592
负责人：
Atul Chopra
金额：
$ 68.25万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202592
关键词：
Adipose tissue Adopted Affect African American Appetite Stimulants Biochemical Biochemical Markers Blood - brain barrier anatomy Blood Circulation Blood specimen Body Weight Body Weight Changes Candidate Disease Gene Clinical Coupled Data Desire for food Development Diabetes Mellitus Diagnostic Epidemic Ethnic Origin FBN1 Fasting Follow-Up Studies Food Funding Genes Genetic Genetic Variation Genome Genotype Glucose Gold HIV-Associated Lipodystrophy Syndrome Health Professional Hepatic Hispanic Americans Hormonal Hormones Human Hypoglycemia Hypothalamic structure Immunologics Incidence Insulin Insulin Resistance Investments Life Style Lipodystrophy Longitudinal prospective study Mediating Mendelian randomization Methodology Methods Molecular Mus Mutation Names Non-Insulin-Dependent Diabetes Mellitus Nutritional Obesity Online Mendelian Inheritance In Man Other Genetics Pathogenesis Pathway interactions Patients Plasma Play Population Population Heterogeneity Prevention strategy Process Prospective cohort Protocols documentation Research Personnel Resources Risk Role Sampling Secondary to Standardization Statistical Methods Symptoms Therapeutic Thinness Time United States National Institutes of Health Validation Variant Wiedemann-Rautenstrauch syndrome Woman Women&apos s Health Work blood glucose regulation case control caucasian American clinical phenotype cohort cost efficient density design diabetes risk dietary epidemiology study ethnic diversity falls feeding follow-up genetic predictors genome wide association study genomic data glucose production high risk loss of function loss of function mutation male health men mouse model novel novel diagnostics novel therapeutic intervention obesity development obesity risk obesity treatment prospective rare genetic disorder sex

项目摘要

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).

项目概要白脂素是一种通过新生儿早衰综合征（NPS 或 Marfan）研究新发现的生糖激素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。编码白脂素的基因 FBN1 具有独特的极端 3' 突变，导致低血糖症状和低血糖最近有大量证据表明，少数患有罕见 NPS 的患者的血浆胰岛素水平。白脂素在肝葡萄糖产生调节中的直接作用，以及白脂素在肝脏中的免疫中和作用治疗小鼠模型中的肥胖和糖尿病白脂素对 2 型糖尿病 (T2D) 的直接影响。尚未在人群中调查人类的发病率。当前的申请旨在调查。两项大型高质量前瞻性研究中白脂素对肥胖和 T2D 发展的潜在因果作用我们计划整合有关遗传变异、生化标记和的数据。国家妇女健康倡议 (WHI) 和男性的肥胖和 T2D 发病率的临床表型健康专业人员随访研究 (HPFS) 是长期前瞻性队列。得到 NIH 的资助，提供详细且高质量的饮食、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充分表征和验证的 T2D 事件病例对所有发生的 T2D 病例进行 20 多年的持续随访，并提供现有的遗传数据和空腹血液。与从同一 WHI 中随机选择的同等数量的对照 (n0=2,615) 相匹配的样本 (n1=2,615) 将使用相同的嵌套病例纳入女性队列和 600 对男性病例对照组 (n’=1,200) 对照设计将在另外 1,076 个 T2D 病例对照中进行。采用标准统计方法和尖端技术的配对（n”=2,152）。用于因果推理的孟德尔随机化方法，我们将利用这些特殊的资源和 WHI/HPFS 研究人员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研究这种新型且有前途的激素——白脂素的效果 – 对于肥胖和 T2D 的发展，我们将首先研究 1) 血浆白脂素水平的分布。在男性和女性中，2) 影响不同人群中白脂素功能的遗传变异，以及 3) 不同种族人群中白脂素与肥胖和 T2D 之间的潜在因果关系包括白人或高加索裔美国人 (CA)、非洲裔美国人 (AA) 和西班牙裔美国人 (HA)。