Physiologic Consequence of Genetic Variation

遗传变异的生理后果

• 批准号: 8862084
• 负责人: RICHARD M WATANABE
• 金额: $ 82.59万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8862084
• 关键词: Affect; Biochemical; Biochemical Pathway; Biochemical Process; Data; Deposition; Diet; Disease; Effectiveness; Environmental Risk Factor; Enzymes; Equilibrium; Family; Fatty Liver; Fatty acid glycerol esters; Fructose; Functional disorder; Genes; Genetic; Genetic Variation; Genetic screening method; Genetic study; Genotype; Glucokinase; Glucose; Goals; Grant; Hepatic; Human; Human Genetics; Hydrolysis; Individual; Insulin Resistance; Kinetics; Lead; Liver; Liver diseases; Magnetic Resonance Imaging; Measures; Metabolic Diseases; Methods; Mexican Americans; Modeling; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Participant; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Phospholipase; Physiological; Physiological Processes; Physiology; Plasma; Process; Proteins; Recruitment Activity; Regulation; Research; Research Design; Risk; Roentgen Rays; Sampling; Series; Testing; Therapeutic Intervention; Triglycerides; Variant; base; diabetes risk; follow-up; fructose-1-phosphate; gene environment interaction; gene interaction; genetic variant; genome wide association study; glucose uptake; in vivo; insight; intravenous glucose tolerance test; lipid biosynthesis; mathematical model; non-alcoholic fatty liver; novel; programs; public health relevance; risk variant; trait

 DESCRIPTION (provided by applicant): Hundreds of genetic variants underlying risk for type 2 diabetes (T2D) and variation in T2D-related quantitative traits have been identified, but there has been little focus on how these variants alter basic physiology to contribute to the pathophysiology of disease. The over-arching goal of this grant is to establish a research program focused on assessing the physiologic effect of genetic variation in vivo in humans and determining how variation alters physiologic processes to contribute to disease pathogenesis. In this application we specifically focus on how genetic variation in glucokinase (GCK), glucokinase regulator (GCKR), and patatin-like phospholipase domain-containing protein 3 (PNPLA3) might determine the level of liver fat and subsequent hepatic insulin resistance. We propose the hepatic substrate balance hypothesis in which genetic variation contributes to an imbalance in substrate flow into and out of the liver. GCK is responsible for hepatic glucose uptake and GCKR regulates the enzymatic activity of GCK. Thus, one could imagine genetic variation may alter the individual activities of GCK and GCKR, or their interaction, which then alters hepatic glucose uptake, and the conversion of glucose to fat. PNPLA3 hydrolyzes fat to triglyceride and genetic variation could alter the efficiency of PNPLA3 to break down fat in the liver. The amount of fat within the liver is a balance between these two processes and imbalance results in the accumulation of liver fat, which in turn results in hepatic insulin resistance. We also propose the hypothesis that dietary fructose, which itself contributes to liver fat, may also exacerbate the substrate imbalance due to genetic variation through its regulation of GCKR. We propose three aims in this study. In Aim 1 we will recruit 265 new participants and perform detailed phenotyping as previously performed, but include an assessment of liver fat by MRI. These studies will be used to validate preliminary observations of associations between genetic variants and liver enzyme levels. In Aim 2 we proposed to analyze lactate kinetics from the FSIGT to obtain measures of GCK activity and hepatic glycolytic flux. We will test these phenotypes for association with genetic variants to validate our preliminary observation of association between genetic variants and glucose effectiveness and liver enzyme levels. We will also examine the interaction with dietary fructose, since it is known that fructose-1-phosphate regulates GCKR activity. In Aim 3, we propose to test genetic variation from not just these three loci, but also other loci showing evidence for association with hepatic steatosis or liver enzyme levels. In particular, we will focus on gene-gene interaction and gene-dietary fructose interactions to build a comprehensive model of our substrate balance hypothesis.

 描述(申请人提供)：数以百计的遗传变异潜在的2型糖尿病风险(T2D)和与T2D相关的数量性状变异已被确定，但很少有人关注这些变异如何改变基本生理学，以促进疾病的病理生理学。这笔拨款的总体目标是建立一个研究计划，专注于评估人类体内遗传变异的生理效应，并确定变异如何改变生理过程，从而促进疾病的发病。在这一应用中，我们特别关注葡萄糖激酶(GCK)、葡萄糖激酶调节因子(GCKR)和Patatin样磷脂酶结构域包含蛋白3(PNPLA3)的基因变异如何决定肝脏脂肪水平和随后的肝脏胰岛素抵抗。我们提出了肝脏底物平衡假说，在该假说中，遗传变异导致流入和流出肝脏的底物不平衡。GCK负责肝脏葡萄糖摄取，GCKR调节GCK的酶活性。因此，人们可以想象，遗传变异可能会改变GCK和GCKR的个体活性，或者它们的相互作用，从而改变肝脏的葡萄糖摄取，以及葡萄糖到脂肪的转化。PNPLA3将脂肪分解为甘油三酯，基因变异可能会改变PNPLA3分解肝脏脂肪的效率。肝脏中的脂肪量是这两个过程之间的平衡，不平衡会导致肝脏脂肪积累，进而导致肝脏胰岛素抵抗。我们还提出了一种假设，饮食中的果糖本身对肝脏有贡献 脂肪，也可能通过其对GCKR的调节而加剧由于遗传变异而导致的底物失衡。在本研究中，我们提出了三个目标。在目标1中，我们将招募265名新参与者，并像以前一样进行详细的表型鉴定，但包括通过MRI评估肝脏脂肪。这些研究将用于验证对遗传变异和肝酶水平之间关系的初步观察。在目标2中，我们建议从FSIGT中分析乳酸动力学，以获得GCK活性和肝脏糖酵解通量的测量。我们将测试这些表型与遗传变异的关联，以验证我们初步观察到的遗传变异与葡萄糖有效性和肝酶水平之间的关联。我们还将研究与膳食果糖的相互作用，因为已知果糖-1-磷酸调节GCKR活性。在目标3中，我们建议不仅测试这三个基因座的遗传变异，而且测试其他与肝脏脂肪变性或肝酶水平相关的基因座的遗传变异。特别是，我们将重点研究基因-基因相互作用和基因-饮食果糖相互作用，以建立我们的底物平衡假说的全面模型。