A Genetic Study of Blood Metabolites and Their Relationship To Diabetes Risk.

血液代谢物及其与糖尿病风险关系的遗传学研究。

• 批准号: 8599297
• 负责人: Harald Heinz Herbert Goring
• 金额: $ 64.98万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8599297
• 关键词: Affect; Age; Amino Acids; Biological Assay; Biological Markers; Blinded; Blood; Body mass index; Chemicals; Chronic Disease; Complex; Data; Detection; Development; Diabetes Mellitus; Diagnostic; Disease; Early identification; Ensure; Family; Family Sizes; Family Study; Fasting; Gas Chromatography; Gene Expression; Genes; Genetic; Genetic Risk; Genomics; Glucose; Glycosylated hemoglobin A; Goals; Health; Heart; Heritability; Hour; Human; Individual; Insulin; Investigation; Laboratories; Lead; Libraries; Life; Lipids; Lymphocyte; Mass Spectrum Analysis; Metabolic; Metabolism; Mexican Americans; Mind; Minority; Molecular Biology; Molecular Profiling; Morbidity - disease rate; Noise; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Participant; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Plasma; Population; Prevalence; Prevention; Prevention strategy; Procedures; Process; Quality Control; Quality of life; Regulation; Resources; Risk; Risk Factors; Running; SNP genotyping; Sampling; Signal Transduction; Societies; Staging; Techniques; Time; Variant; base; clinical phenotype; conventional therapy; cost; density; diabetes mellitus genetics; diabetes risk; follow-up; genetic analysis; genetic risk factor; genetic variant; genome sequencing; genome-wide linkage; improved; innovation; instrumentation; interest; metabolomics; mortality; novel; outcome forecast; prospective; public health relevance; sex; small molecule; sugar; trait; two-dimensional

DESCRIPTION (provided by applicant): Type II diabetes mellitus (T2DM) is a serious chronic disease that greatly impacts quality-of-life, morbidity and mortality of affected individuals. Its prevalence continues to rise rapidly in the US and worldwide, and the costs to patients and society as a whole are astronomic. We propose to study the disorder via metabolomic profiling. Metabolites occur as part of the many metabolic processes in a living being. The existence and quantity of individual metabolites can be indicative of health and disease, and specific chemical compounds are used as biomarkers for a variety of human conditions. Modern techniques make it now possible to identify and quantify many chemical compounds simultaneous in a small sample volume. We propose here to use two-dimensional gas chromatography and time-of-flight mass spectrometry (GCxGC-TOFMS) to generate metabolomic profiles of blood plasma. This novel, state-of-the-art approach detects molecules in the size range of ~50-1000 u (from highly volatile small molecules to amino acids, small sugars, small lipids, and small peptides), with much increased sensitivity over traditional instrumentation, allowing metabolite detection in the mid to high part-per- trillion range. Specifically, metabolomic profiles will be generated on blood plasma samples (collected at 2 time points 15-20 years apart) from 1,500 participants in the San Antonio Family Study (SAFS), a long-running study investigating genetic risk for complex diseases and associated quantitative risk factors in Mexican Americans families. We will then identify genetic factors influencing the quantitative levels of individual metabolites, taking advantage of the existing SNP genotype data, whole-genome sequence (WGS) data, and lymphocyte gene expression profiles. Novel statistical approaches will be used to identify rare variants of strong effect. Retrospective and prospective analyses will be used to identify biomarkers for T2DM and related quantitative traits. The long follow-up period allows for detection of very early biomarkers, before any sign of disease (including by any existing diagnostic markers) and commencement of prevention strategies or treatment. Putative T2DM biomarkers will be replicated in 1,500 participants in the Strong Heart Family Study. Laboratory-based assays of functionality will be conducted on the most interesting candidate genetic variants found to influence metabolite levels. This is a highly innovative study to investigate th genetic regulation of metabolite levels, and to identify metabolomic signatures of diabetes. The study is feasible because it leverages the unique resources of the SAFS. The investigative team comprises experts in metabolomics, molecular biology, statistical genetics, and diabetes. The proposed study has the potential for novel discoveries related to T2DM risk in the fast growing Mexican American minority population.

描述(申请人提供)：II型糖尿病(T2 DM)是一种严重的慢性疾病，极大地影响受影响个人的生活质量、发病率和死亡率。它的流行率在美国和世界范围内继续迅速上升，患者和整个社会的成本是天文数字。我们建议通过代谢组图谱来研究这种疾病。代谢物是生物体许多代谢过程的一部分。个体代谢物的存在和数量可以指示健康和疾病，特定的化合物被用作各种人类状况的生物标记物。现代技术使得现在可以在小样本体积内同时识别和定量许多化合物。我们建议使用二维气相色谱和飞行时间质谱仪(GCxGC-TOFMS)来生成血浆的代谢图谱。这种新颖的、最先进的方法检测大小为~50-1000u的分子(从高挥发性小分子到氨基酸、小糖、小脂类和小肽)，与传统仪器相比灵敏度大大提高，使代谢物检测能够在中到高万亿分之一的范围内进行。具体地说，将在圣安东尼奥家庭研究(SAFS)的1,500名参与者的血浆样本(在相隔15-20年的两个时间点收集)上生成代谢组谱，SAFS是一项长期研究，调查墨西哥裔美国人家庭中复杂疾病的遗传风险和相关的量化风险因素。然后，我们将利用现有的SNP基因数据、全基因组序列(WGS)数据和淋巴细胞基因表达谱，确定影响个体代谢物数量水平的遗传因素。新的统计方法将被用来识别罕见的强效应变异。将使用回顾和前瞻性分析来确定T2 DM和相关数量性状的生物标记物。漫长的随访期允许在疾病的任何迹象(包括任何现有的诊断标记)和开始预防战略或治疗之前检测非常早期的生物标记。在强心脏家族研究中，假定的T2 DM生物标记物将在1500名参与者中重复。基于实验室的功能分析将对发现的影响代谢物水平的最有趣的候选遗传变异进行。这是一项高度创新的研究，旨在研究代谢物水平的遗传调节，并确定糖尿病的代谢组学特征。这项研究是可行的，因为它利用了南部非洲金融服务的独特资源。研究团队由代谢组学、分子生物学、统计遗传学和糖尿病方面的专家组成。这项拟议的研究有可能在快速增长的墨西哥裔美国少数民族人口中发现与T2 DM风险相关的新发现。