Genetic and physiological causes of inherited Vascular and Metabolic Diseases

遗传性血管和代谢疾病的遗传和生理原因

• 批准号: 8298186
• 负责人: Arya Mani
• 金额: $ 40.96万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298186
• 关键词: Abdomen; Adipose tissue; Affect; Age; Arginine; Beta Cell; Biological Assay; Biological Markers; Biopsy; Body Composition; Cause of Death; Cell physiology; Cells; Cholesterol; Clinical Research; Code; Complex; Computers; Control Groups; Coronary Arteriosclerosis; Coronary artery; Cysteine; Defect; Deposition; Development; Diabetes Mellitus; Disease; Electron Microscopy; Enzymes; Epidermal Growth Factor; Etiology; Euglycemic Clamping; Family; Family member; Fatty acid glycerol esters; Functional disorder; GYS1 gene; Gender; Gene Mutation; General Population; Genes; Genetic; Genetic Transcription; Genotype; Glucose; Glucose Clamp; Glucose-6-Phosphate; Glycogen; Glycogen (Starch) Synthase; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Goals; Health; Hepatic; Human; Hyperglycemia; Hyperlipidemia; Hypertension; Impairment; In Vitro; Individual; Infusion procedures; Inherited; Insulin; Insulin Resistance; Intra-abdominal; Intramuscular; Investigation; Isotopes; Lead; Link; Liver; Liver Glycogen; Low Density Lipoprotein Receptor; Measurement; Measures; Metabolic; Metabolic Diseases; Metabolic syndrome; Mitochondria; Molecular; Morbidity - disease rate; Mus; Muscle; Mutation; Nonesterified Fatty Acids; OGTT; Pathway interactions; Patients; Peptides; Phenotype; Phosphorylation; Physiological; Prevalence; Protein Tyrosine Kinase; Proteins; Protons; Risk Factors; Serine; Serum; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Spectrum Analysis; TCF7L2 gene; Testing; Threonine; Triglycerides; United States; Variant; Vascular Diseases; Weight; basal insulin; base; cohort; density; disease phenotype; disorder risk; early onset; epidermal growth factor precursor; glucose disposal; glucose metabolism; glucose output; glucose transport; impaired glucose tolerance; insight; insulin secretion; insulin signaling; intrahepatic; kindred; mortality; mutation carrier; non-diabetic; novel; receptor; research study; sex; subcutaneous; therapeutic target; tomography

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is the most common cause of morbidity and mortality worldwide. A cluster of metabolic phenotypes known as metabolic syndrome has been established as a major risk factor for CAD. The mechanisms that link these phenotypes to one another and to CAD are not well understood. We have identified the disease causing gene in a large family with autosomal dominant early onset coronary artery disease (CAD), diabetes, hyperlipidemia, and hypertension. The mutation, substitutes cysteine for arginine (R611C) at a highly conserved residue of the second epidermal growth factor precursor domain in the LDL receptor like protein (LRP6), which encodes a co-receptor in the Wnt signaling pathway. A second mutation (R473Q) was identified in a large kindred with early onset CAD and phenotypes that are consistent with the overall picture of the metabolic syndrome. In vitro studies have indicated that these mutations impair Wnt signaling. Genotype phenotype correlation showed that the mutations impact number of the metabolic phenotypes that are present in these kindreds. These findings have established a causal link between Wnt signaling impairment caused by LRP6 mutation and coronary artery/metabolic syndrome and raise the possibility of complex downstream effects of the mutation which warrants further investigation. Oral glucose tolerance tests in nondiabetic R611C mutation carriers have shown that they are hyperinsulinemic, indicating that insulin resistance is likely the major cause of impaired glucose tolerance in the mutation carriers. The mechanisms of insulin resistance caused by LRP6 mutation are not known. Defect in glycogen synthesis of the skeletal muscle is thought to be one of the major causes of insulin resistance. The rate limiting enzyme for glycogen synthesis, glycogen synthase (GS), is phosphorylated and inactivated by glycogen synthase kinase 3ss (GSK3ss). GSK3ss is negatively regulated by Wnt signaling activation. The expression and activity of GSK3ss is increased in lymphoblastoid cells of the mutation carriers. We hypothesize that LRP6 mutation directly affect glycogen synthesis by impairment of glycogen synthase activity. To examine this hypothesis and to identify the major site of insulin resistance, insulin-stimulatedglucose disposal rate and sensitivity to insulin suppression of hepatic glucose output will be measured with infusion of [6, 6- 2H]-glucose isotope in both nondiabetic mutation carriers and non-carrier family members in the two kindreds. Glycogen synthesis in liver and muscle wil be assessed using 13C MRS and insulin stimulated changes in intramuscular glucose-6-phosphate concentration will be measured using 31P MRS. Glycogen synthesis and GS activity in the skeletal muscle biopsies of the mutation carriers and healthy controls will be compared. In addition, to explore the prevalence and spectrum of LRP6 mutations in patients with metabolic syndrome and CAD, a cohort of 200 cases with early onset CAD, diabetes and metabolic syndrome will be screened for non conservative mutation(s) in the coding region of LRP6. These studies hold great promise in providing important insight into the pathophysiology of metabolic syndrome and CAD and identifying novel biomarkers and therapeutic targets for these disorders. PUBLIC HEALTH RELEVANCE: Coronary artery disease (CAD) and its consequences are the single largest cause of death in the United States. CAD risk factors include high blood pressure, high cholesterol and diabetes. These risk factors are often associated with one another and referred to as metabolic syndrome. The causes of metabolic syndrome remain vastly unknown. We have identified a novel gene mutation in families with early coronary artery disease and metabolic syndrome. The identified gene (LRP6) is a receptor that in normal condition activates a certain pathway known as Wnt signaling pathway, which is impaired in the affected family members due to the gene mutation. Our finding is the first evidence for relationship between impairment of this pathway and development of CAD and metabolic syndrome in humans. The current study goals are investigating the effect of the mutation on metabolism of glucose and insulin secretion and function in patients with this mutation.

描述（由申请人提供）：冠状动脉疾病（CAD）是全球发病率和死亡率的最常见原因。一组称为代谢综合征的代谢表型已被确定为CAD的主要危险因素。将这些表型与彼此联系在一起的机制和CAD尚不清楚。我们已经确定了引起常染色体显性冠状动脉疾病（CAD），糖尿病，高脂血症和高血压的大家族中引起基因的疾病。突变，在LDL受体（如蛋白质（LRP6））中，在第二表皮生长因子前体域的高度保守的残基上取代半胱氨酸（R611c），该残基编码了Wnt信号通路中的共受体。在与代谢综合征的整体情况一致的大型幼虫中鉴定出第二个突变（R473Q）。体外研究表明这些突变会损害Wnt信号传导。基因型表型相关性表明，突变会影响这些亲属中存在的代谢表型的数量。这些发现建立了由LRP6突变引起的Wnt信号传导障碍与冠状动脉/代谢综合征之间的因果关系，并提高了突变的复杂下游效应的可能性，这需要进一步研究。非糖尿病R611c突变载体中的口服葡萄糖耐量测试表明它们是高胰岛素的，表明胰岛素抵抗可能是突变载体中葡萄糖耐受性受损的主要原因。 LRP6突变引起的胰岛素抵抗的机制尚不清楚。骨骼肌糖原合成缺陷被认为是胰岛素抵抗的主要原因之一。糖原合成酶（GS）的速率限制酶被磷酸化并被糖原合酶激酶3SS（GSK3SS）灭活。 GSK3SS受Wnt信号激活负面调节。突变载体的淋巴母细胞细胞中GSK3SS的表达和活性增加。我们假设LRP6突变直接通过糖原合酶活性损害影响糖原合成。为了检验这一假设并确定胰岛素抵抗的主要部位，将通过在两种非糖类突变携带者和两种种类的非carrier家族成员的[6，6-2H] - 葡萄糖同位素输注[6，6-2H] - 葡萄糖同位素。将使用13C MRS评估肝和肌肉中的糖原合成，并使用31p MRS测量肌肉内葡萄糖-6-磷酸浓度的胰岛素变化。将比较突变载体的骨骼肌活检中的糖原合成和GS活性。此外，为了探索代谢综合征和CAD患者的LRP6突变的患病率和频谱，将筛选200例早期发作CAD，糖尿病和代谢综合征的病例，以筛选LRP6编码区域的非保守性突变。这些研究在提供代谢综合征和CAD的病理生理学的重要见解方面具有巨大的希望，并确定了这些疾病的新型生物标志物和治疗靶标。公共卫生相关性：冠状动脉疾病（CAD）及其后果是美国最大的死亡原因。 CAD危险因素包括高血压，高胆固醇和糖尿病。这些危险因素通常相互关联，称为代谢综合征。代谢综合征的原因仍然鲜为人知。我们已经确定了早期冠状动脉疾病和代谢综合征家族的一种新型基因突变。已鉴定的基因（LRP6）是一种受体，在正常状态下激活某种称为Wnt信号通路的途径，由于基因突变，该途径在受影响的家庭成员中受损。我们的发现是这种途径损害与人类中CAD的发展与代谢综合症之间关系的第一个证据。当前的研究目标是研究突变对这种突变患者的葡萄糖和胰岛素分泌代谢以及功能的影响。