Mapping Genes for Atherosclerosis and Insulin Resistance

绘制动脉粥样硬化和胰岛素抵抗基因图谱

• 批准号: 7434575
• 负责人: Jerome I Rotter
• 金额: $ 76.41万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434575
• 关键词: 5' -AMP-activated protein kinase; ADRB2 gene; Abbreviations; Accounting; Adenosine Monophosphate; Adipose tissue; Angiotensinogen; Animals; Atherosclerosis; Blood Pressure; Body mass index; C-reactive protein; Candidate Disease Gene; Cardiovascular Diseases; Cell Line; Chromosome Mapping; Chronic; Companions; Complement component C5; Coronary Arteriosclerosis; Data; Databases; Deaminase; Diabetes Mellitus; Epidemic; Equation; Ethnic Origin; Euglycemic Clamping; Family; Family Study; Family history of; Fasting; Frequencies; Functional disorder; G-substrate; GNB3 gene; GTP-Binding Proteins; Gene Frequency; Gene Structure; Genes; Genetic; Genetic Models; Genetic Programming; Genetic Variation; Genome Scan; Genomics; Genotype; Glucose; Glucose Clamp; Glucose Intolerance; Goals; Grant; Haplotypes; High Prevalence; Hispanics; Human; Hypertension; IL4R gene; IL6 gene; Impaired fasting glycaemia; Individual; Inflammation; Inflammatory; Infusion procedures; Insulin; Insulin Resistance; Interleukin 4 Receptor; Interleukin-4; Interleukin-6; International; Intervention; Knowledge; Lead; Link; Linkage Disequilibrium; Lipids; Lod Score; Maps; Measures; Medial; Metabolic syndrome; Mexican Americans; Minor; Morbidity - disease rate; Mus; Myocardial Infarction; N-propionylprocainamide; NOS3 gene; Natriuretic Peptides; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Peptidyl-Dipeptidase A; Phenotype; Physiological; Plasminogen Activator Inhibitor 1; Population; Population Study; Prevention; Principal Investigator; Process; Program Research Project Grants; Protein C; Quantitative Trait Loci; Rate; Receptor, Angiotensin, Type 1; Research Personnel; Resistance; Resources; Risk; Risk Assessment; Risk Factors; Role; SNP genotyping; Sample Size; Sampling; Single Nucleotide Polymorphism; Smoking; Sodium Channel; Staging; Structure; TNF gene; Testing; Thick; Ultrasonography; Underserved Population; Variant; Western World; Width; Work; adducin; base; beta-2 Adrenergic Receptors; calpain 10; cardiovascular risk factor; cohort; computer program; design; disorder risk; gene interaction; genetic epidemiology; genetic linkage analysis; genome wide association study; genotyping technology; glucose tolerance; guanine nucleotide binding protein; human NOS3 protein; immortalized cell; impaired glucose tolerance; indexing; insulin secretion; insulin sensitivity; insulin sensitivity/resistance; intima media; lipoprotein lipase; man; mortality; polypeptide; programs; receptor; response; sortilin; tool; trait; transmission process; tumor; voltage

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the largest cause of morbidity and mortality in the Western world. New risk factors for CVD include insulin resistance (IR) and chronic inflammation. The hypothesis of this proposal and its linked Progression R01 is that genetic factors are in significant measure responsible for the interrelationship between CVD, IR and inflammation, and that these can be identified by family studies utilizing high definition phenotyping of subclinical pathophysiologic processes, such as euglycemic clamp for IR and carotid intima-medial thickness (CIMT) by ultrasound for CVD, in a Mexican-American population at high risk for these disorders. In our prior work, we studied a large Mexican-American cohort, ascertained through an index case with coronary artery disease (CAD). Genome scans in the first half of this sample (Set 1) identified evidence for chromosomal loci for CIMT, for fasting insulin, and for IR. Aim 1 will confirm these loci by analysis of a genome wide scan in the second half of the sample (Set 2); followed by fine mapping with the goal of prioritizing the best peaks, between two and three, for use in Aim 2. Aim 2 will test all the genes under the "best" linkage peaks from Aim 1, taking advantage of growing resources that allow identification of tagged SNPs. This approach simultaneously avoids the limitation of trying to a priori decide what genes are true positional candidates, and yet by focusing on genes, is more efficient than a chromosomal marker approach. All genes under each peak will be tested in Set 1. Positive results will be confirmed using Set 2 and only those genes still positive will be evaluated further in Aim 4. This two-stage design provides the power to identify the relevant genes while minimizing false positives. In Aim 3, 20 biologic candidate genes identified as associated with IR, fasting insulin, or CIMT in Set 1, either during the first cycle of the Program (n=13) or suggested by the linked Progression R01 (n=7) (and tested in Set 1), will be tested in Set 2 to confirm the associations and prioritize the genes for study in Aim 4. These genes will have their haplotypes characterized in detail for testing in Set 2. In Aim 4, genes (from Aims 2 and 3) associated with CIMT, fasting insulin, and/or IR in Set 1 and confirmed in Set 2, will be sequenced in individuals with divergent haplotypes and phenotypes. New variants discovered by sequencing will be genotyped in the entire study population to assess the minimum variant(s) within each gene that appear responsible for the genetic effect. Gene-gene interactions will also be evaluated. A key strength of this proposal is that the size of the sample allows replication (Set 1 and Set 2) of both linkage and association results in the same population, with the same ethnicity, same ascertainment, and the same phenotyping. Identifying the genes for CIMT and IR in this understudied population will provide new tools for risk assessment and prevention.

描述（由申请人提供）：心血管疾病（CVD）是西方世界发病率和死亡率的最大原因。 CVD的新风险因素包括胰岛素抵抗（IR）和慢性炎症。 The hypothesis of this proposal and its linked Progression R01 is that genetic factors are in significant measure responsible for the interrelationship between CVD, IR and inflammation, and that these can be identified by family studies utilizing high definition phenotyping of subclinical pathophysiologic processes, such as euglycemic clamp for IR and carotid intima-medial thickness (CIMT) by ultrasound for CVD, in a墨西哥裔美国人对这些疾病的高风险。在先前的工作中，我们研究了一个大型墨西哥裔美国人队列，并通过冠状动脉疾病（CAD）的索引病例确定。基因组在该样品的上半年（集1）在CIMT，禁食胰岛素和IR的染色体基因座的证据中进行了扫描。 AIM 1将通过分析样品后半段的基因组宽扫描来确认这些基因座（集2）；然后进行精细映射，其目标是优先考虑两到三个之间的最佳峰值，以在AIM 2中使用。AIM2将利用允许识别标签SNP的越来越多的资源来测试AIM 1中“最佳”链接峰下的所有基因。这种方法同时避免了试图先验决定哪些基因是真正的位置候选者的局限性，但是通过关注基因，比染色体标记方法更有效。每个峰下方的所有基因将在第1次测试中进行测试。将使用集合2确认阳性结果，并且只有这些基因仍将在AIM 4中进一步评估阳性。这种两阶段的设计提供了识别相关基因的能力，同时最小化假阳性。在AIM 3中，在计划的第一个周期（n = 13）中，或由链接的进展R01（n = 7）提出的20个生物学候选基因在第1集（n = 13）中所建议的（n = 7）（并在集合1中进行了测试），将在第2集中进行测试，以确认与这些基因的基因相关，以确认这些基因4。 2。在AIM 4中，与CIMT，禁食胰岛素和/或IR相关的基因（来自AIM 2和3）将在第1集中确认，将在具有不同的单倍型和表型的个体中进行测序。通过测序发现的新变体将在整个研究人群中进行基因分型，以评估每个基因中似乎负责遗传效应的最小变异。基因 - 基因相互作用也将进行评估。该提议的一个关键优势在于，样本的大小允许连锁和关联的复制（集合1和集合2）导致相同的人群，具有相同的种族，相同的确定性和相同的表型。在此研究的人群中识别CIMT和IR的基因将为风险评估和预防提供新的工具。