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: 9298487
• 负责人: Harald Heinz Herbert Goring
• 金额: $ 60.13万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 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/9298487
• 关键词: Genetic; Study; Blood; Metabolites; Their

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（由申请人提供）：2型糖尿病（T2DM）是一种严重的慢性疾病，严重影响患者的生活质量、发病率和死亡率。它在美国和世界范围内的流行率继续迅速上升，患者和整个社会的成本是天文数字。我们建议通过代谢组学分析来研究这种疾病。代谢物是生物体内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志物。现代技术使在少量样品中同时鉴定和定量许多化合物成为可能。我们建议使用二维气相色谱和飞行时间质谱（GCxGC-TOFMS）来生成血浆的代谢组学谱。这种新颖的、最先进的方法可以检测到~50- 1000u大小范围内的分子（从高度挥发性的小分子到氨基酸、小糖、小脂类和小肽），比传统仪器的灵敏度高得多，可以在万亿分之中高的范围内检测代谢物。具体来说，代谢组学分析将从圣安东尼奥家庭研究（SAFS）的1500名参与者的血浆样本（在两个时间点收集，间隔15-20年）中生成，这是一项长期研究，调查墨西哥裔美国家庭复杂疾病的遗传风险和相关的定量风险因素。然后，我们将利用现有的SNP基因型数据、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定量水平的遗传因素。新的统计方法将用于识别强效应的罕见变异。回顾性和前瞻性分析将用于确定T2DM的生物标志物和相关的数量性状。长期的随访可以在任何疾病迹象（包括任何现有的诊断标记）出现之前检测到非常早期的生物标志物，并开始预防战略或治疗。假定的T2DM生物标志物将在强心脏家族研究的1500名参与者中复制。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。这是一项极具创新性的研究，旨在研究代谢物水平的遗传调控，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SAFS的独特资源。调查小组由代谢组学、分子生物学、统计遗传学和糖尿病方面的专家组成。这项研究有可能在快速增长的墨西哥裔美国少数民族中发现与2型糖尿病风险相关的新发现。