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（由申请人提供）：II 型糖尿病 (T2DM) 是一种严重的慢性疾病，极大地影响受影响个体的生活质量、发病率和死亡率。它的患病率在美国和世界范围内持续迅速上升，给患者和整个社会带来的成本是天文数字。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。单个代谢物的存在和数量可以指示健康和疾病，并且特定的化合物被用作各种人类状况的生物标志物。现代技术现在可以在小样本量中同时识别和量化多种化合物。我们在此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特征。这种新颖、最先进的方法可检测尺寸范围约为 50-1000 u 的分子（从高挥发性小分子到氨基酸、小糖、小脂质和小肽），其灵敏度比传统仪器大大提高，可在万亿分之一中到高的范围内进行代谢物检测。 具体来说，将根据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 2 个时间点采集）生成代谢组学谱，该研究是一项长期研究，旨在调查墨西哥裔美国人家庭中复杂疾病的遗传风险和相关定量风险因素。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具有强烈影响的罕见变体。回顾性和前瞻性分析将用于识别 T2DM 和相关数量性状的生物标志物。长时间的随访可以在任何疾病迹象（包括任何现有的诊断标记物）和开始预防策略或治疗之前检测到非常早期的生物标记物。假定的 T2DM 生物标志物将在 Strong Heart Family 研究的 1,500 名参与者中进行复制。将对发现影响代谢水平的最有趣的候选遗传变异进行基于实验室的功能测定。 这是一项高度创新的研究，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。研究小组由代谢组学、分子生物学、统计遗传学和糖尿病领域的专家组成。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获得与 T2DM 风险相关的新发现。