Insulin Clearance: Candidate and Positional Genetic Determinants

胰岛素清除率：候选和位置遗传决定因素

• 批准号: 7547757
• 负责人: Mark Goodarzi
• 金额: $ 32.5万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-10 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547757
• 关键词: 5' -AMP-activated protein kinase; AMP Deaminase; ATP Synthesis Pathway; Abbreviations; Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Affect; American; Appetite Regulation; Atherosclerosis; Attention; Binding; Biology; Body fat; Body mass index; Candidate Disease Gene; Cardiovascular Diseases; Cell Line; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Charge; Chromosome Mapping; Code; Cohort Studies; Coronary Arteriosclerosis; DNA; Data; Deaminase; Development; Diabetes Mellitus; Disease; Enzymes; Epidemic; Equation; Ethnic Origin; Euglycemic Clamping; Evaluation; Excision; Family; Family Study; Functional disorder; Funding; Gene Family; Gene Structure; Genes; Genetic; Genetic Determinism; Genome; Genotype; Glucose; Glucose Clamp; Goals; Grant; Haplotypes; Heritability; Hispanics; Homeostasis; Hyperinsulinism; Hypertension; Individual; Infusion procedures; Inherited; Insulin; Insulin Resistance; Insulinase; Investigation; Knowledge; Lead; Lesion; Light; Link; Linkage Disequilibrium; Lipids; Lod Score; Measures; Metabolic; Metabolic Clearance Rate; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Mexican Americans; Microsatellite Repeats; Mitochondria; Modality; National Heart, Lung, and Blood Institute; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nuclear; Nucleotide Metabolism Pathway; OGTT; Obesity; Oxidative Phosphorylation; Phenotype; Physiological; Play; Polycystic Ovary Syndrome; Positioning Attribute; Prevention; Preventive; Principal Investigator; Process; Production; Quantitative Trait Loci; Recruitment Activity; Regulation; Research; Research Personnel; Resources; Risk; Risk Factors; Role; STK11 gene; Sagittaria; Sampling; Scanning; Signal Transduction; Single Nucleotide Polymorphism; Societies; Structure; System; Testing; Thick; Tissues; Variant; Work; base; cardiovascular disorder risk; cohort; diabetes risk; diabetic; fatty acid oxidation; gene discovery; gene interaction; genetic association; genetic risk factor; genome-wide; glucose uptake; high risk; immortalized cell; improved; indexing; innovation; insight; insulin secretion; insulin sensitivity; insulin sensitivity/resistance; insulin signaling; interest; intima media; lipoprotein lipase; meetings; novel; nucleotide metabolism; prevent; purine metabolism; receptor; response; trait; transmission process

DESCRIPTION (provided by applicant): Insulin sensitivity/resistance and insulin secretion have received much attention in the study of metabolic disorders (such as diabetes, obesity, the metabolic syndrome, and polycystic ovary syndrome) that predispose to cardiovascular disease, while insulin clearance has been largely overlooked. Insulin clearance is a highly heritable trait. Preliminary data show that haplotypes in the genes for adenosine monophosphate deaminase (AMPD1 and AMPD2) and the AMP-activated protein kinase (AMPK) 12 subunit are associated with variation in the metabolic clearance rate of insulin (MCRI). Thus, the hypothesis underlying this proposal is that genes involved in the interconversion of adenine nucleotides (AMP, ADP, ATP) and cellular response to these molecules (AMPK system) are determinants of insulin clearance. This application proposes further research elucidating the role of these and related genes in insulin clearance, using both a biologic candidate gene approach as well as positional candidate genes identified by whole-genome linkage scans. In Aim 1, 1536 single nucleotide polymorphisms (SNPs) in ~100 genes (high-priority based on function) related to adenine nucleotide metabolism and the AMPK system will be genotyped in the first half (Set 1) of the Mexican- American Coronary Artery Disease (MACAD) cohort; these SNPs and derived haplotypes will be analyzed for association with MCRI. The top 25 genes showing association with MCRI will then be genotyped (384 SNPs) and tested for association with MCRI in MACAD Set 2 (second half of that cohort). Only genes associated with MCRI in both Sets will be evaluated in Aim 3. In Aim 2, whole genome linkage scans for MCRI will be carried out in two Hispanic cohorts (MACAD, and the Mexican-American hypertension (MA-HTN) cohort). Positional candidate genes (50-70 genes anticipated) under peaks (LOD >1.4) found in both cohorts and under the most significant (LOD>2) peaks in either cohort will be analyzed for association with MCRI in MACAD. In Aim 3, the genes identified in Aims 1 and 2 as associated with MCRI will be tested for association in the MA-HTN cohort, as a final confirmation. In Aim 4, the genes with confirmed association will then be sequenced (in subjects of divergent genotype and phenotype) to identify potential functional variants. Variants identified by sequencing will be evaluated for association with MCRI in the combined MACAD and MA-HTN cohort. This proposal is unique in its exploration of insulin clearance, an understudied trait that is highly heritable. Also innovative is the focus on genes related to adenine nucleotides and cellular energy state. The study will examine these genes in multiple Hispanic populations, allowing for verification/replication of positive genetic associations, and benefits from the fact that both cohorts have already been recruited and have undergone detailed physiologic phenotyping of whole-body insulin clearance by the euglycemic-hyperinsulinemic clamp. The novel phenotype and genes considered are likely to lead to new insights in insulin metabolism. Project Narrative: The goal of this proposal is to discover genes that influence the body's ability to eliminate insulin. Abnormal levels of insulin are characteristic of several metabolic disorders, such as diabetes, obesity, the metabolic syndrome, and polycystic ovary syndrome, all of which are risk factors for cardiovascular disease. An understanding of the genes underlying insulin removal may lead to improvements in prevention and treatment of these disorders.

描述（由申请人提供）：在研究代谢疾病（例如糖尿病，肥胖，代谢综合征和多囊卵巢综合征）的研究中，胰岛素敏感性/抗药性和胰岛素的分泌引起了很多关注，这些疾病易于心血管疾病，而胰岛素清除率很高。胰岛素清除是一种高度可遗传的特征。初步数据表明，腺苷单磷酸脱氨酶（AMPD1和AMPD2）的基因中的单倍型和AMP激活的蛋白激酶（AMPK）12亚基与胰岛素代谢清除率（MCRI）的代谢清除率的变化有关。因此，该建议的基本假设是与腺嘌呤核苷酸（AMP，ADP，ATP）相互转化的基因和对这些分子（AMPK系统）的细胞反应是胰岛素清除率的决定因素。该应用程序提出了进一步的研究，阐明了这些和相关基因在胰岛素清除率中的作用，同时使用生物学候选基因方法以及通过全基因组链接扫描确定的位置候选基因。在AIM 1中，在〜100个基因（基于功能的高优先级）中，与腺嘌呤核苷酸代谢相关的1536个单核苷酸多态性（SNP）将在上半年（墨西哥 - 美国冠状动脉疾病（MacAD）同胞的上半年进行基因分型；这些SNP和衍生的单倍型将分析与MCRI关联。然后，显示与MCRI关联的前25个基因将进行基因分型（384个SNP），并测试与MACAD Set 2（该队列的后半部分）中的MCRI相关。仅在AIM 3中评估两组中与MCRI相关的基因。在AIM 2中，将在两个西班牙裔队列（MacAD和墨西哥裔美国人高血压（MA-HTN）同伴中进行MCRI的整个基因组链接扫描。在两个队列中发现的峰和最显着（LOD> 2）峰下的峰（LOD> 1.4）下，位置候选基因（预期的50-70个基因）将分析与MacAD中的MCRI相关。在AIM 3中，与MCRI相关的AIM 1和2中鉴定的基因将在MA-HTN队列中进行测试，以作为最终确认。在AIM 4中，将对具有确认关联的基因进行测序（在不同的基因型和表型的受试者中），以鉴定潜在的功能变异。通过测序确定的变体将在联合麦克加和MA-HTN队列中与MCRI缔合。该提议在探索胰岛素清除率的探索方面是独一无二的，这是一种高度遗传的经验研究的特征。创新的重点是与腺嘌呤核苷酸和细胞能状态有关的基因。该研究将在多个西班牙裔人群中检查这些基因，从而验证/复制阳性的遗传关联，并从已经招募了两个同类人群并经历了euglycody胰岛素胰岛素清除率的详细生理表型。新型的表型和基因可能会导致胰岛素代谢的新见解。 项目叙述：该提案的目的是发现影响人体消除胰岛素能力的基因。胰岛素水平异常是几种代谢疾病的特征，例如糖尿病，肥胖，代谢综合征和多囊卵巢综合征，所有这些都是心血管疾病的危险因素。对去除胰岛素去除的基因的理解可能会改善这些疾病的预防和治疗。