Mapping Genes for Atherosclerosis and Insulin Resistance

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最大的原因。新的心血管疾病危险因素包括胰岛素抵抗（IR）和慢性炎症。该建议及其相关进展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，并且这些可以通过家庭研究来确定，利用亚临床病理生理过程的高分辨率表型，例如，在墨西哥裔美国人中，具有这些疾病高风险的IR和颈动脉内膜-内侧厚度（CIMT）超声检测CVD。在我们之前的工作中，我们研究了一个大的墨西哥裔美国人队列，通过冠状动脉疾病（CAD）的索引病例确定。该样本的前半部分（第1组）的基因组扫描发现了CIMT、空腹胰岛素和IR的染色体位点的证据。目标1将通过对样本后半段的全基因组扫描分析来确认这些基因座（集合2）；然后进行精细映射，目标是优先考虑2到3个之间的最佳峰值，以便在Aim 2中使用。Aim 2将测试来自Aim 1的“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试图先验地确定哪些基因是真正的位置候选者的局限性，并且通过关注基因，比染色体标记方法更有效。每个峰下的所有基因将在Set 1中进行测试。阳性结果将在第2组进行确认，只有那些仍然呈阳性的基因将在第4组进一步评估。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Aim 3中，在Set 1中确定与IR、空腹胰岛素或CIMT相关的20个生物候选基因，无论是在项目的第一个周期（n=13）还是由相关进展R01 （n=7）建议（并在Set 1中测试），将在Set 2中进行测试，以确认相关性并优先考虑在Aim 4中研究的基因。这些基因的单倍型将被详细描述，以便在第二组进行测试。在Aim 4中，将在具有不同单倍型和表型的个体中对集1中与CIMT、空腹胰岛素和/或IR相关的基因（来自Aims 2和3）进行测序，并在集2中确认。通过测序发现的新变异将在整个研究人群中进行基因分型，以评估每个基因中可能导致遗传效应的最小变异。基因间的相互作用也将被评估。该建议的一个关键优势在于，样本的大小允许在相同的人群中复制（集1和集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。在这一未充分研究的人群中确定CIMT和IR基因将为风险评估和预防提供新的工具。

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.