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: 7624596
• 负责人: Jerome I Rotter
• 金额: $ 75.41万
• 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/7624596
• 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; Disease; 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; NOS3 gene; Natriuretic Peptides; Non-Insulin-Dependent Diabetes Mellitus; 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; 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; fasting glucose; gene interaction; genetic epidemiology; genetic linkage analysis; genome wide association study; genotyping technology; glucose tolerance; guanine nucleotide binding protein; high risk; 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）是西方世界发病和死亡的最大原因。 CVD 的新危险因素包括胰岛素抵抗 (IR) 和慢性炎症。该提案及其相关进展 R01 的假设是，遗传因素在很大程度上负责 CVD、IR 和炎症之间的相互关系，并且可以通过利用亚临床病理生理过程的高清表型的家庭研究来识别这些因素，例如 IR 的正常血糖钳夹和 CVD 的超声颈动脉内膜中层厚度 (CIMT)。 墨西哥裔美国人患这些疾病的风险很高。在我们之前的工作中，我们研究了一个大型墨西哥裔美国人队列，通过冠状动脉疾病 (CAD) 指标病例进行确定。该样本前半部分（第 1 组）的基因组扫描确定了 CIMT、空腹胰岛素和 IR 染色体位点的证据。目标 1 将通过分析样本后半部分（第 2 组）的全基因组扫描来确认这些位点；然后进行精细作图，目标是优先考虑两个到三个之间的最佳峰，用于目标 2。目标 2 将测试目标 1 中“最佳”连锁峰下的所有基因，利用不断增长的资源来识别标记的 SNP。这种方法同时避免了尝试先验决定哪些基因是真正的候选基因的限制，而且通过关注基因，比染色体标记方法更有效。每个峰下的所有基因都将在第 1 组中进行测试。阳性结果将使用第 2 组进行确认，只有那些仍然呈阳性的基因才会在目标 4 中进行进一步评估。这种两阶段设计提供了识别相关基因的能力，同时最大限度地减少假阳性。在目标 3 中，在第 1 组中确定与 IR、空腹胰岛素或 CIMT 相关的 20 个生物候选基因，无论是在计划的第一个周期 (n=13) 中，还是由关联的进展 R01 (n=7) 建议（并在第 1 组中进行测试），都将在第 2 组中进行测试，以确认关联性并优先考虑目标 4 中研究的基因。这些基因将对其单倍型进行详细表征，以便在组中进行测试。 2. 在目标 4 中，与第 1 组中的 CIMT、空腹胰岛素和/或 IR 相关并在第 2 组中得到确认的基因（来自目标 2 和 3）将在具有不同单倍型和表型的个体中进行测序。通过测序发现的新变异将在整个研究群体中进行基因分型，以评估每个基因内似乎与遗传效应有关的最小变异。基因与基因之间的相互作用也将被评估。该提案的一个关键优势是样本的大小允许在相同人群中复制（组 1 和组 2）连锁和关联结果，具有相同的种族、相同的确定和相同的表型。在这一待研究人群中鉴定 CIMT 和 IR 基因将为风险评估和预防提供新工具。