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: 8008742
• 负责人: Mark Goodarzi
• 金额: $ 31.85万
• 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/8008742
• 关键词: 5' -AMP-activated protein kinase; AMP Deaminase; AMP-activated protein kinase kinase; ATP Synthesis Pathway; Abbreviations; Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Affect; American; Appetite Regulation; Attention; Binding; Body mass index; Candidate Disease Gene; Cardiovascular Diseases; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Charge; Code; Cohort Studies; Coronary Arteriosclerosis; DNA; Data; Deaminase; Development; Diabetes Mellitus; Disease; Enzymes; Epidemic; Equation; Euglycemic Clamping; Evaluation; Excision; Family; Family Study; Functional disorder; Gene Family; 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; Measures; Metabolic; Metabolic Clearance Rate; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Mexican Americans; Mitochondria; Modality; Names; 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; Risk Factors; Role; STK11 gene; Sagittaria; Sampling; Scanning; Single Nucleotide Polymorphism; Societies; System; Testing; Thick; Tissues; Variant; Work; base; cardiovascular disorder risk; cohort; diabetes risk; diabetic; disorder prevention; fatty acid oxidation; gene discovery; gene interaction; genetic association; genetic risk factor; glucose uptake; improved; indexing; innovation; insight; insulin secretion; insulin sensitivity; insulin sensitivity/resistance; insulin signaling; intima media; lipoprotein lipase; meetings; novel; nucleotide metabolism; prevent; programs; 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（申请人提供）：胰岛素敏感性/抵抗性和胰岛素分泌在易患心血管疾病的代谢性疾病（如糖尿病、肥胖、代谢综合征和多囊卵巢综合征）的研究中受到了广泛关注，而胰岛素清除率也受到了人们的关注。很大程度上被忽视了。胰岛素清除率是一种高度遗传的特征。初步数据显示，单磷酸腺苷脱氨酶（AMPD1 和 AMPD2）和 AMP 激活蛋白激酶 (AMPK) 12 亚基基因的单倍型与胰岛素代谢清除率 (MCRI) 的变化相关。因此，该提议的假设是，参与腺嘌呤核苷酸（AMP、ADP、ATP）相互转化的基因和细胞对这些分子（AMPK 系统）的反应是胰岛素清除的决定因素。本申请提出了进一步的研究，利用生物候选基因方法以及通过全基因组连锁扫描识别的位置候选基因来阐明这些基因和相关基因在胰岛素清除中的作用。在目标 1 中，将在墨西哥-美国冠状动脉的前半部分（第 1 组）中对与腺嘌呤核苷酸代谢和 AMPK 系统相关的约 100 个基因（基于功能的高优先级）中的 1536 个单核苷酸多态性 (SNP) 进行基因分型疾病（MACAD）队列；将分析这些 SNP 和衍生单倍型与 MCRI 的关联。然后将显示与 MCRI 相关性的前 25 个基因进行基因分型（384 个 SNP），并在 MACAD Set 2（该组的后半部分）中测试与 MCRI 的相关性。在目标 3 中，仅评估两组中与 MCRI 相关的基因。在目标 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) 队列）中进行 MCRI 的全基因组连锁扫描。将分析两个队列中发现的峰值 (LOD > 1.4) 下以及任一队列中最显着 (LOD > 2) 峰值下的位置候选基因（预计 50-70 个基因）与 MACAD 中 MCRI 的关联。在目标 3 中，目标 1 和 2 中确定的与 MCRI 相关的基因将在 MA-HTN 队列中进行关联测试，作为最终确认。在目标 4 中，对已确认关联的基因进行测序（在不同基因型和表型的受试者中），以鉴定潜在的功能变异。通过测序鉴定出的变异将在 MACAD 和 MA-HTN 联合队列中评估与 MCRI 的关联。该提案在探索胰岛素清除方面是独一无二的，这是一种尚未得到充分研究的高度遗传性状。同样具有创新性的是对与腺嘌呤核苷酸和细胞能量状态相关的基因的关注。该研究将在多个西班牙裔人群中检查这些基因，从而验证/复制正向遗传关联，并受益于两个队列已经被招募并通过正常血糖-高胰岛素血症对全身胰岛素清除率进行了详细的生理表型分析的事实夹钳。所考虑的新表型和基因可能会给胰岛素代谢带来新的见解。 项目叙述：该提案的目标是发现影响身体消除胰岛素能力的基因。胰岛素水平异常是多种代谢性疾病的特征，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。了解胰岛素去除背后的基因可能会改善这些疾病的预防和治疗。